WO2015034054A1

WO2015034054A1 - Bisoprolol-containing patch preparation

Info

Publication number: WO2015034054A1
Application number: PCT/JP2014/073509
Authority: WO
Inventors: 祥孝井上; 準石倉; 和宏青柳; 智雨山; 智也田中; 悠立川; 中村　哲也; 邦弘南; 修一朗湯浅
Original assignee: 日東電工株式会社; トーアエイヨー株式会社
Priority date: 2013-09-06
Filing date: 2014-09-05
Publication date: 2015-03-12
Also published as: KR20160049535A; CN105530925A; JP6528154B2; JP2015071591A; TW201542249A

Abstract

The present invention pertains to a bisoprolol-containing patch preparation containing a support body and an adhesive layer laminated to one surface of the support body and containing an adhesive agent and free bisoprolol, the stress relaxation percentage of the adhesive layer being 20-90%, and the shear stress of the adhesive layer being 1.0-6.5 N/30 mm width. The bisoprolol-containing patch preparation has suppressed peeling during use, has superior skin adhesiveness, and suppresses skin irritation during delamination. As the adhesive agent, a rubber-based adhesive is preferable, and a polyisobutylene and/or styrene-isoprene-styrene block copolymer is more preferable.

Description

Patch preparation containing bisoprolol

The present invention relates to a bisoprolol-containing patch preparation for continuously absorbing bisoprolol into a living body through the skin surface.

Bisoprolol, which is a highly selective antagonist of β1 receptor of sympathetic nerve, is used to improve essential hypertension, angina pectoris, arrhythmia, etc., and its fumarate is orally administered as a tablet. On the other hand, in the case of oral administration, there are drawbacks such as lack of persistence of pharmacological effects and rapid changes in blood concentration after administration, and side effects are likely to occur. In recent years, preparations have attracted attention.

Such a preparation for transdermal administration can avoid, for example, drug metabolism and various side effects due to the first passage of the liver, and can continuously administer the drug over a long period of time. Among these, since the administration work is easy and the dosage can be strictly controlled, the development of a patch preparation containing a drug in an adhesive has been actively conducted. Under such circumstances, various bisoprolol percutaneous absorption preparations have been developed in recent years.

A transdermal administration preparation generally has a support composed of a woven fabric, a non-woven fabric, a plastic film, and the like, and a pressure-sensitive adhesive layer containing a drug laminated on the support, and usually on the pressure-sensitive adhesive layer. It is provided in a form with a laminated release liner.

As a feature of recent transdermal preparations, a large amount of liquid component is contained in the adhesive layer for the purpose of improving the soft feeling when applied to the skin or reducing the skin irritation caused by exfoliation of the stratum corneum during peeling. There has been proposed a pressure-sensitive adhesive layer that contains a gel and is subjected to a crosslinking treatment to form a gel (Patent Document 1). Such a gel-like pressure-sensitive adhesive layer can relax and disperse the stress applied to the skin surface at the time of peeling, while maintaining high adhesiveness to the skin surface to be applied. Accordingly, these pressure-sensitive adhesive layers are suitably employed for transdermally absorbable preparations because they have little physical irritation to the skin and very little peeling of the stratum corneum.

However, the percutaneously absorbable preparation obtained by laminating the gel-like pressure-sensitive adhesive layer on the support may have reduced adhesion and fixation on the skin surface (sweat resistance) in summer when sweating is intense. In particular, the skin adhesive strength at the peripheral edge of the transdermally absorbable preparation was lowered, and the peripheral edge was likely to be turned over.

Japanese Unexamined Patent Publication No. 6-23029

The present invention has been found in view of the above circumstances, and the problem to be solved is bisoprolol which suppresses turning-up during use, has excellent skin adhesiveness, and suppresses skin irritation during peeling. It is to provide a containing patch preparation.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that when the adhesive layer containing bisoprolol satisfies a specific stress relaxation rate and a specific displacement stress, it is applied to and peeled from the skin surface. The present inventors have found that the stress can be relaxed and dispersed, exhibit excellent skin adhesiveness, and can reduce irritation at the time of peeling, thereby completing the present invention.

That is, the present invention is as follows.
[1] A support and a pressure-sensitive adhesive layer containing free bisoprolol and a pressure-sensitive adhesive laminated on one side of the support, the pressure-sensitive adhesive layer having a stress relaxation rate of 20 to 90%, and A bisoprolol-containing patch preparation in which the deviation stress of the adhesive layer is 1.0 to 6.5 N / 30 mm width.
[2] The bisoprolol-containing patch according to [1], wherein the stress relaxation rate of the pressure-sensitive adhesive layer is 40 to 90%, and the displacement stress of the pressure-sensitive adhesive layer is 1.0 to 4.0 N / 30 mm width. Formulation.
[3] The bisoprolol-containing patch preparation according to the above [1] or [2], wherein the adhesive comprises a rubber-based adhesive.
[4] The bisoprolol-containing patch preparation according to the above [3], wherein the rubber-based adhesive is a polyisobutylene and / or a styrene-isoprene-styrene block copolymer.
[5] The bisoprolol-containing patch preparation according to the above [4], wherein the polyisobutylene is a polyisobutylene having a viscosity average molecular weight of 40,000 to 5,500,000.
[6] The polyisobutylene includes a first polyisobutylene (a) having a viscosity average molecular weight of 1,800,000 to 5,500,000 and a second polyisobutylene having a viscosity average molecular weight of 40,000 to 85,000 (b And the blending ratio (a: b) of the first polyisobutylene (a) and the second polyisobutylene (b) is from 1: 0.1 to 1: 3 by weight [4] ] The patch preparation containing bisoprolol according to any one of the above.
[7] The bisoprolol-containing patch preparation according to the above [4], wherein the styrene-isoprene-styrene block copolymer has a styrene ratio of less than 30% by weight.
[8] The bisoprolol-containing patch preparation according to [4] or [7] above, wherein the content of the styrene-isoprene-styrene block copolymer in the pressure-sensitive adhesive layer is 5 to 50% by weight.

The bisoprolol-containing patch preparation of the present invention exhibits excellent skin adhesiveness with little curling at the peripheral edge of the preparation during application, and reduces skin irritation caused by exfoliation of the stratum corneum during peeling Has the effect of

It is a typical sectional view showing one embodiment of a patch preparation of the present invention. It is a typical top view which shows the state which installed the patch preparation which peeled the release liner 3 from the patch preparation of FIG. 1 in the tension test machine. FIG. 3 is a cross-sectional view taken along the line III-III in FIG. FIG. 3 is a schematic plan view when the patch preparation installed in the tensile tester of FIG. 2 is deformed in the shear direction.

FIG. 1 is a schematic cross-sectional view showing one embodiment of a bisoprolol-containing patch preparation of the present invention (hereinafter sometimes abbreviated as “patch preparation”). A patch preparation 10 shown in FIG. 1 includes a support 1, a pressure-sensitive adhesive layer 2 laminated on one side of the support 1, and a release liner 3 laminated on the pressure-sensitive adhesive layer 2. The release liner 3 may be omitted. The pressure-sensitive adhesive layer 2 contains free bisoprolol and a pressure-sensitive adhesive.

“Free bisoprolol” means the free base of bisoprolol. In order to contain free bisoprolol in the pressure-sensitive adhesive layer, free bisoprolol may be blended as it is, or the pharmaceutically acceptable salt of bisoprolol is desalted at the time of blending or after preparation of a patch preparation. Bisoprolol may also be used. That is, it suffices if the adhesive layer contains free bisoprolol at the time of using the patch preparation. Examples of the pharmaceutically acceptable salt of bisoprolol include fumarate and hydrochloride. In addition, since free bisoprolol used in the present invention is a liquid drug at room temperature (for example, 25 ° C.), by including it in the adhesive layer, not only the pharmacological action as bisoprolol but also the plasticizing action peculiar to bisoprolol. The pressure-sensitive adhesive layer tends to be soft and has an effect of improving the soft feeling when applied to the skin and reducing skin irritation caused by exfoliation of the stratum corneum.

The content of free bisoprolol can be appropriately set as necessary, but is usually 0.5 to 40% by weight, preferably 0.5 to 30% by weight in the pressure-sensitive adhesive layer. When the content is 0.5% by weight or more, a therapeutically effective amount of drug release can be expected. When the amount is 40% by weight or less, a sufficient therapeutic effect can be exhibited and economically advantageous. When the amount is 30% by weight or less, it is economically more advantageous.

The pressure-sensitive adhesive is not particularly limited. For example, acrylic pressure-sensitive adhesive such as acrylic polymer; styrene-diene-styrene block copolymer (for example, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer) Polymer), rubber-based adhesives such as polyisoprene, polyisobutylene and polybutadiene; silicone-based adhesives such as silicone rubber, dimethylsiloxane base and diphenylsiloxane base; vinyl ethers such as polyvinyl methyl ether, polyvinyl ethyl ether and polyvinyl isobutyl ether Adhesive; Vinyl ester adhesive such as vinyl acetate-ethylene copolymer; Carboxylic acid component such as dimethyl terephthalate, dimethyl isophthalate, dimethyl phthalate and polyhydric alcohol such as ethylene glycol Minutes was a polyester-based pressure-sensitive adhesive such as polyester and the like. Among these, a rubber-based adhesive is preferable.

Preferred rubber-based pressure-sensitive adhesives include rubber-based pressure-sensitive adhesives mainly composed of at least one selected from polyisobutylene, polyisoprene, butyl rubber, styrene-isoprene-styrene block copolymer, and styrene-butadiene-styrene block copolymer. Agents. Among these, polyisobutylene and / or styrene-isoprene-styrene block copolymers are preferably used from the viewpoint of high drug stability and compatibility of necessary adhesive force and cohesive force. In the present invention, “styrene-isoprene-styrene block copolymer” means a block copolymer of a triblock (polymer chain having polystyrene blocks bonded to both ends of a polyisoprene block) alone, or a triblock It is a concept including a block copolymer comprising a mixture of diblocks (polymer chains in which one end of a polyisoprene block is bonded to one end of a polystyrene block), preferably a block copolymer comprising a mixture of triblock and diblock It is.

When polyisobutylene is used as the rubber-based pressure-sensitive adhesive, the polyisobutylene may be contained alone, or two or more polyisobutylenes having different molecular weights may be contained.
When polyisobutylene is contained alone, the content of polyisobutylene in the pressure-sensitive adhesive layer is preferably 15 to 60% by weight, more preferably 15 to 55% by weight. If the polyisobutylene content is less than 15% by weight, it may be difficult to impart the necessary internal cohesive force to the pressure-sensitive adhesive layer. On the other hand, if it exceeds 60% by weight, the adhesiveness and tackiness of the pressure-sensitive adhesive layer may be reduced. May decrease.
When polyisobutylene is contained alone, the molecular weight of polyisobutylene is not particularly limited, and the viscosity average molecular weight is preferably 40,000 to 5,500,000, more preferably 45,000 to 5,000. , 000. If the viscosity average molecular weight is less than 40,000, it may be difficult to impart the necessary internal cohesive force to the pressure-sensitive adhesive layer. On the other hand, if it exceeds 5,500,000, the adhesiveness and tackiness of the pressure-sensitive adhesive layer may be reduced. May decrease.

In order to easily achieve both an appropriate cohesive force of the pressure-sensitive adhesive layer and an appropriate flexibility and skin adhesiveness, it is preferable to contain two or more types of polyisobutylene having different molecular weights. As used herein, “two or more polyisobutylenes having different molecular weights” refers to polyisobutylene having molecular weight distribution peaks measured by gel permeation chromatography (GPC) in two or more independent regions. Each polyisobutylene generally has one molecular weight distribution peak. Examples of “two or more polyisobutylenes having different molecular weights” include two or more polyisobutylenes having different viscosity average molecular weights.

As the two or more types of polyisobutylene having different molecular weights, for example, a mixture of the first polyisobutylene and the second polyisobutylene having a relatively smaller molecular weight than the first polyisobutylene is preferable. The first polyisobutylene can impart an appropriate cohesive force to the pressure-sensitive adhesive layer, and the second polyisobutylene can impart an appropriate softness and skin adhesiveness to the pressure-sensitive adhesive layer. The molecular weights of the first polyisobutylene and the second polyisobutylene are not particularly limited, but in order to obtain good adhesion and sufficient release of bisoprolol, the viscosity average of the first polyisobutylene The molecular weight is preferably 1,800,000 to 5,500,000, more preferably 2,000,000 to 5,000,000, and the viscosity average molecular weight of the second polyisobutylene is preferably 40,000, 000 to 85,000, more preferably 45,000 to 65,000. If the viscosity average molecular weight of the first polyisobutylene is less than 1,800,000, it may be difficult to impart the necessary internal cohesive force to the pressure-sensitive adhesive layer, and if it exceeds 5,500,000, There is a possibility that the adhesiveness and tackiness of the agent layer may be reduced. Further, when the viscosity average molecular weight of the second polyisobutylene is less than 40,000, the pressure-sensitive adhesive layer may have a sticky feeling and may contaminate the skin surface. There is a risk that the skin adhesion and tackiness of the layer may be reduced. In addition, 1st and 2nd polyisobutylene can be used in combination of 2 or more type within the range of each molecular weight distribution.

In this specification, the viscosity average molecular weight is calculated from the Staudinger index (J) at 20 ° C. from the flow time of the capillary of the Ubbelohde viscometer by the following formula (1) (Schulz-Blaschke formula) The value calculated | required by following formula (2) using J value is said.

J ₀ = η _SP /c(1+0.31 _ηSP ) (cm ³ / g) (Schulz-Blaschke equation) (1)
η _SP = t / t _o −1
t: Flow time of solution (according to Hagenbach-Couette correction formula)
t ₀ : Flow time of solvent (according to Hagenbach-Couette correction formula)
c: Solution concentration (g / cm ³ )
J ₀ = 3.06 × 10 ⁻² Mv ^0.65 (2)
M _v : viscosity average molecular weight

When two or more types of polyisobutylene having different molecular weights are used as the rubber-based pressure-sensitive adhesive, the total content of polyisobutylene in the pressure-sensitive adhesive layer is preferably 15 to 70% by weight, more preferably 30 to 65% by weight, most preferably Preferably, it is 50 to 65% by weight. If the total content of polyisobutylene is less than 15% by weight, it may be difficult to impart the necessary internal cohesive force to the pressure-sensitive adhesive layer. On the other hand, if the total content exceeds 70% by weight, There is a risk that tack will be lowered.
When two types of polyisobutylene having different molecular weights are used as the rubber-based pressure-sensitive adhesive, in the embodiment using the first polyisobutylene (a) and the second polyisobutylene (b), the first polyisobutylene (a) and The blending ratio (a: b) of the second polyisobutylene (b) is preferably 1: 0.1 to 1: 3, more preferably 1: 0.5 to 1: 2, and still more preferably by weight ratio. 1: 0.65 to 1: 0.97, most preferably 1: 0.77 to 1: 0.97. Of these two types of polyisobutylene, if the blending ratio of the second polyisobutylene (b) exceeds the above upper limit, the internal cohesive force of the pressure-sensitive adhesive layer may be greatly decreased, and on the other hand, if it is less than the lower limit. There is a possibility that the skin adhesive force of the pressure-sensitive adhesive layer is greatly reduced.

When a styrene-isoprene-styrene block copolymer is used as the rubber adhesive, the styrene-isoprene-styrene block copolymer preferably has a styrene ratio of less than 30% by weight. A diblock ratio of 0 to 80% by weight is preferable, and a diblock ratio of 10 to 50% by weight is more preferable. The content of the styrene-isoprene-styrene block copolymer in the pressure-sensitive adhesive layer is preferably 5 to 50% by weight, more preferably 10 to 30% by weight. If the content of the styrene-isoprene-styrene block copolymer is less than 5% by weight, it may be difficult to impart the necessary internal cohesive force to the pressure-sensitive adhesive layer. On the other hand, if the content exceeds 50% by weight, the pressure-sensitive adhesive There is a risk that the skin adhesion and tackiness of the layer may be reduced.

Furthermore, by changing the styrene ratio of the styrene-isoprene-styrene block copolymer and the content of the styrene-isoprene-styrene block copolymer in the adhesive layer, the desired stress relaxation rate and shear stress can be obtained. It becomes easy to be done.
For example, when a styrene-isoprene-styrene block copolymer is used alone as a rubber-based adhesive, a styrene ratio of 10 to 24% by weight is preferable, and a styrene ratio of 15 to 24% by weight is more preferable. . When the styrene ratio of the styrene-isoprene-styrene block copolymer is 10% by weight or more and less than 15% by weight, the content of the styrene-isoprene-styrene block copolymer in the pressure-sensitive adhesive layer is 10 to 30% by weight. When the styrene ratio of the styrene-isoprene-styrene block copolymer is 15 to 24% by weight, the content of the styrene-isoprene-styrene block copolymer in the pressure-sensitive adhesive layer is 17.5 to 22.5% by weight. % Is preferred.

When a styrene-isoprene-styrene block copolymer and polyisobutylene are used as the rubber-based adhesive, the styrene ratio of the styrene-isoprene-styrene block copolymer is preferably greater than 24% by weight and less than 30% by weight. The total content of styrene-isoprene-styrene block copolymer and polyisobutylene in the pressure-sensitive adhesive layer is preferably 5 to 50% by weight. The blending weight ratio (l / m) of the polyisobutylene (l) and the styrene-isoprene-styrene block copolymer (m) is preferably 0.20 to 0.80, more preferably 0.30 to 0.70. Preferably, 0.40 to 0.60 is most preferable.

When an acrylic pressure-sensitive adhesive is used as the pressure-sensitive adhesive, a preferred acrylic pressure-sensitive adhesive is a polymer (hereinafter abbreviated as “acrylic polymer”) having (meth) acrylic acid alkyl ester as an essential monomer. An acrylic ester-based pressure-sensitive adhesive contained as a main component can be mentioned. Examples of the acrylic polymer include a homopolymer or a copolymer having a (meth) acrylic acid alkyl ester as a monomer. Here, the carbon number of the alkyl group in the (meth) acrylic acid alkyl ester is preferably 4 to 12. The alkyl group may be linear or branched. Examples of the alkyl group include butyl, t-butyl, pentyl, hexyl, heptyl, octyl, isooctyl, 2-ethylhexyl, nonyl, isononyl, decyl, undecyl, dodecyl and the like. -Ethylhexyl is preferred. The (meth) acrylic acid alkyl ester is used alone or in combination of two or more. The content of the acrylic polymer in the acrylic ester adhesive is preferably 50% by weight or more, more preferably 60% by weight or more.

Further, the acrylic polymer may contain a copolymer of the (meth) acrylic acid alkyl ester and another monomer copolymerizable therewith. Examples of such other monomers include monomers having a carboxy group such as (meth) acrylic acid, itaconic acid, maleic acid, maleic anhydride; styrene sulfonic acid, allyl sulfonic acid, sulfopropyl (meth) Monomers having a sulfo group such as acrylate, (meth) acryloyloxynaphthalene sulfonic acid, and acrylamide methyl sulfonic acid; Monomers having a hydroxy group such as hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate; (Meth) acrylic acid derivatives having an amide group such as (meth) acrylamide, dimethyl (meth) acrylamide, N-butyl (meth) acrylamide, N-methylol (meth) acrylamide, hydroxyethyl (meth) acrylamide; (meth) acrylic Aminoethyl acid, (meth) acetate (Meth) acrylic acid aminoalkyl esters such as dimethylaminoethyl oxalate, t-butylaminoethyl (meth) acrylate; methoxyethyl (meth) acrylate, ethoxyethyl (meth) acrylate, tetrahydrofluro (meth) acrylate (Meth) acrylic acid alkoxy esters such as furyl; (meth) acrylic acid methoxyethylene glycol, (meth) acrylic acid methoxydiethylene glycol, (meth) acrylic acid methoxypolyethylene glycol, (meth) acrylic acid methoxypolypropylene glycol, etc. Alkoxyalkylene glycol acrylate; (meth) acrylonitrile; vinyl acetate, vinyl propionate, vinyl pyrrolidone, methyl vinyl pyrrolidone, vinyl pyridine, vinyl piperidone, vinyl pyrimi Emissions, vinylpiperazine, vinyl pyrrole, vinyl imidazole, vinyl caprolactam, vinyl oxazole, vinyl compounds such as vinyl morpholine. As for the (meth) acrylic acid alkyl ester and other monomers which are monomer units of the copolymer, only one type may be used, or two or more types may be used in combination.

When an acrylic pressure-sensitive adhesive is used, the content of the acrylic pressure-sensitive adhesive in the pressure-sensitive adhesive layer is preferably 30 to 75% by weight, more preferably 35, in order to impart sufficient adhesiveness to the pressure-sensitive adhesive layer. It is ˜70% by weight, more preferably 40 to 65% by weight.

In the case where the pressure-sensitive adhesive layer contains a rubber-based pressure-sensitive adhesive, in order to impart appropriate pressure-sensitive adhesiveness to the pressure-sensitive adhesive layer, for example, rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin, terpene-phenol resin, It is preferable to use a tackifier such as a xylene resin. Only 1 type may be used for a tackifier and it may use 2 or more types together. The tackifier is preferably a petroleum resin. Petroleum resins include aliphatic (C5) petroleum resins, aromatic (C9) petroleum resins, copolymer (C5-C9) petroleum resins, and aromatic (C9) petroleum resins. Examples thereof include alicyclic saturated hydrocarbon resins obtained by hydrogenation or complete hydrogenation.

The softening point of the tackifier is preferably 90 to 150 ° C, more preferably 95 to 145 ° C. When the softening point is 90 ° C. to 150 ° C., it tends to be compatible with each component of the pressure-sensitive adhesive layer and tends to be uniformly mixed. The softening point in the present invention is a value measured by the ring and ball method.

The content of the tackifier in the pressure-sensitive adhesive layer is preferably 10 to 55% by weight, more preferably 10 to 50% by weight, and particularly preferably 10 to 45% by weight. When the content of the tackifier is less than 10% by weight, tack and cohesive force may be poor. On the other hand, when the content exceeds 55% by weight, the pressure-sensitive adhesive layer becomes hard and the skin adhesiveness tends to decrease.

In addition, various liquid or paste-like organic components may be added to these pressure-sensitive adhesive layers from the viewpoint of imparting a soft feeling during skin application. Here, the “liquid or paste-like organic component” means one having a viscosity of 0.01 mPa · s to 10,000 Pa · s at 25 ° C. The viscosity can be measured 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, but preferably has a transdermal absorption promoting effect. Examples of liquid or pasty organic components include glycols such as ethylene glycol, diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, and polypropylene glycol; glycerin; oils and fats such as olive oil, castor oil, squalane, and lanolin; Hydrocarbons such as paraffin; surfactants such as polyoxyethylene hydrogenated castor oil; ethoxylated stearyl alcohol; glycerin monoesters such as oleic acid monoglyceride, caprylic acid monoglyceride, lauric acid monoglyceride, glycerin diesters, caprylic acid triglyceride, etc. Glycerin triesters or mixtures thereof; ethyl laurate, isopropyl myristate, isotridecyl myristate, maleic acid palmitate Fatty acid alkyl esters such as chill, isopropyl palmitate, ethyl oleate, diisopropyl adipate, diethyl sebacate; fatty acids such as oleic acid, caprylic acid; 1-dodecanol, 1-tetradecanol, 1-hexadecanol, Long chain alcohols such as 2-hexyl-1-decanol, 2-octyl-1-dodecanol and 2-hexyl-1-tetradecanol; N-methylpyrrolidone; 1,3-butanediol and the like. As the liquid or paste-like organic component, fatty acid alkyl esters and long-chain alcohols are preferably used because they greatly contribute to promoting absorption of bisoprolol and improving the solubility of bisoprolol in the pressure-sensitive adhesive layer. The liquid or paste-like organic component may be used alone or in combination of two or more.

When a fatty acid alkyl ester and a long-chain alcohol are used in combination as a liquid or paste-like organic component, it is preferable from the viewpoint of further improving the permeability and solubility of bisoprolol and the skin adhesiveness of the pressure-sensitive adhesive layer. The blending weight ratio (c: d) of the fatty acid alkyl ester (c) and the long chain alcohol (d) is preferably 1: 0.01 to 1: 2, more preferably 1: 0.01 to 1: 1.5. is there. Among these two kinds of organic components, when the blending weight ratio (d / c) of the long-chain alcohol (d) to the fatty acid alkyl ester (c) is 0.01 to 2, the solubility of bisoprolol and the pressure-sensitive adhesive layer A sufficient improvement in skin adhesion is observed.

When the pressure-sensitive adhesive layer contains a liquid or pasty organic component, the content of the organic component in the pressure-sensitive adhesive layer is 5 to 70% by weight in order to prevent the organic component from protruding from the pressure-sensitive adhesive layer. It is preferably 10 to 65% by weight, more preferably 20 to 50% by weight.

In addition, in the patch preparation of the present invention, an appropriate filler can be contained in the pressure-sensitive adhesive layer as necessary in order to improve the cohesive force of the pressure-sensitive adhesive layer. Such fillers are not particularly limited, but include silica, titanium oxide, zinc oxide, magnesium oxide, iron oxide, aluminum hydroxide, talc, kaolin, bentonite, barium sulfate, calcium carbonate and other inorganic fine particles, lactose, carbon black And organic fine particles such as polyvinylpyrrolidone, polyester, polyolefin, polyurethane, polyamide, cellulose, and acrylic resin, and fibers such as polyester, polyolefin, polyurethane, polyamide, cellulose, acrylic resin, and glass.

Further, if desired, a cover tape or the like may be applied so as to cover a part or the entire surface of the patch preparation of the present invention to reinforce the skin adhesiveness and supplement the adhesion to the skin.

In addition, these pressure-sensitive adhesives can be used for physical crosslinking by radiation irradiation such as ultraviolet irradiation and electron beam irradiation, isocyanate compounds such as trifunctional isocyanate, organic peroxides, organic metal salts, metal alcoholates, metal chelate compounds, You may perform the chemical crosslinking process using various crosslinking agents, such as a functional compound (Polyfunctional external crosslinking agent and monomers for multifunctional internal crosslinking, such as diacrylate and dimethacrylate).

The thickness of the pressure-sensitive adhesive layer is preferably 10 to 300 μm, more preferably 10 to 250 μm, and most preferably 15 to 250 μm. When the pressure-sensitive adhesive layer contains a liquid or paste-like organic component, the organic component or the like may protrude from the peripheral edge of the patch before use or the cut formed in the release liner. However, by making the content of the liquid or paste-like organic component in the pressure-sensitive adhesive layer and the thickness of the pressure-sensitive adhesive layer within the above range, from the peripheral edge of the patch before use or the cut formed in the release liner The organic component and the like can be prevented from protruding.

The support is not particularly limited, and a plastic film, non-woven fabric, paper, woven fabric, knitted fabric, metal foil, or a laminate thereof can be used. Furthermore, you may use what gave metal vapor deposition to the said support body.

The material of the plastic film is not particularly limited. For example, polyvinyl chloride; monomers such as ethylene, propylene, vinyl acetate, acrylic acid, acrylic ester, methacrylic acid, methacrylic ester, acrylonitrile, styrene, and vinylidene chloride Copolymer with other monomers; olefin polymers such as polyethylene, polypropylene and ethylene-vinyl acetate copolymer; polyester polymers such as polyethylene terephthalate (PET) and polyether polyester; polyether polyamide block copolymer Examples thereof include polyamide polymers such as polymers.

The thickness of the support is, for example, 5 to 500 μm, preferably 10 to 200 μm.

The adhesive preparation of the present invention may further have a release liner on the surface opposite to the support side of the adhesive layer (the adhesive surface on the skin). The release liner covers the pressure-sensitive adhesive layer and protects the patch preparation until it is used.

The release liner is not particularly limited. 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.); a metal-deposited plastic film obtained by depositing a metal on the plastic film Papers such as Japanese paper, Western paper, kraft paper, glassine paper, and high-quality paper; fibrous materials such as non-woven fabrics and fabrics; and metal foils. In addition, a laminate sheet of a plastic film and paper, a laminate sheet of a plastic film and a metal foil, and the like can be used as a release liner.
There are many types of industrial products, many of which are suitable for use in patch preparations are commercially available, and it is easy to select the desired quality. Therefore, a plastic film is preferred as the release liner, and a polyester film is more preferred. Preferably, PET film is more preferable. The thickness of the release liner is not particularly limited and is, for example, 10 to 200 μm, preferably 25 to 150 μm.

The release liner may be formed with a cut in order to be easily peeled off from the pressure-sensitive adhesive layer, or may be formed with a light release layer subjected to a release treatment on the side in contact with the pressure-sensitive adhesive layer.

The stress relaxation rate and deviation stress in the present invention are calculated by the following measuring method. As shown in FIG. 2, two separate bakelite plates 21 (width 100 mm × length 30 mm) are fixed to the upper and lower chuck portions 31 of a tensile tester (EZ-S manufactured by SHIMADZU). The distance between the plates 21 is 0. Adjust parallel to 1 mm. A patch preparation (test piece) cut to a width of 30 mm and a length of 12 mm was pasted in parallel with a 2 kg roller so as to pass two pieces of bakelite, and then in an environment of 23 ° C. and 65% relative humidity. Left for 2 minutes. Thereafter, the stress when the adhesive layer was deformed from the starting point to a length of 0.5 mm (0.1 mm + 0.5 mm) at a speed of 1 mm / min in the shear direction of the adhesive layer was measured, and the stress was measured as the deviation stress of the present invention. (F1). Next, the stress (F2) after holding the state at the time of deformation of 0.5 mm (0.1 mm + 0.5 mm) from the starting point for 120 seconds was measured. The stress relaxation rate was calculated according to the following formula.

Stress relaxation rate (%) = [1− (stress after holding for 120 seconds after deformation of 0.5 mm (F2)) / (stress during deformation of 0.5 mm (F1))] × 100

The preferred deviation stress in the present invention is 1.0 to 6.5 N / 30 mm width, more preferably 1.0 to 4.0 N / 30 mm width, and particularly preferably 1.5 to 3.0 N / 30 mm width. is there. By setting the deviation stress to 1.0 to 6.5 N / 30 mm width, the pressure-sensitive adhesive layer is easily deformed, contributing to the soft feeling of the pressure-sensitive adhesive layer, suppressing the feeling of tension during application, and skin irritation There is an effect of reducing the above. In addition, when a shift stress exceeds 6.5 N / 30 mm width, since an adhesive layer becomes difficult to deform | transform, favorable followable | trackability cannot be obtained with respect to a skin surface.

In the present invention, a preferable stress relaxation rate is 20 to 90%, preferably 40 to 90%, and particularly preferably 50 to 80%. By setting the stress relaxation rate to 20 to 90%, even when the pressure-sensitive adhesive layer is deformed, the stress is quickly relaxed, and the stress tends to be quickly reduced. For this reason, even if it is applied to the skin surface, it works to reduce the stress applied to the adhesive preparation with respect to the movement of the skin surface. Exhibits adhesiveness. In addition, when the stress relaxation rate exceeds 90%, the pressure-sensitive adhesive layer becomes excessively soft, and therefore, adhesive residue tends to occur during peeling.

Stress relaxation rate and shear stress are the content of each component depending on the type of adhesive included as an essential component in the adhesive layer, tackifier included as necessary, liquid or pasty organic component, etc. It can be set within the above range by increasing / decreasing or increasing / decreasing the thickness of the pressure-sensitive adhesive layer as required. For example, when the first polyisobutylene (a) and the second polyisobutylene (b) having different viscosity average molecular weights are used as the rubber-based pressure-sensitive adhesive, the first polyisobutylene (a) in the pressure-sensitive adhesive layer is used. And the total content of the second polyisobutylene (b) is preferably 15 to 70% by weight, more preferably 30 to 65% by weight, and most preferably 50 to 65% by weight. The blending weight ratio (a: b) of the first polyisobutylene (a) and the second polyisobutylene (b) is preferably 1: 0.1 to 1: 3, more preferably 1: 0.5 to 1. : 2, more preferably 1: 0.65 to 1: 0.97, most preferably 1: 0.77 to 1: 0.97. The thickness of the pressure-sensitive adhesive layer is preferably 10 to 300 μm, more preferably 10 to 250 μm, and most preferably 15 to 250 μm. As described above, when the first polyisobutylene (a) and the second polyisobutylene (b) are used as the rubber-based pressure-sensitive adhesive, the component (a) and (b) in the pressure-sensitive adhesive layer are mainly used. By setting the total content of the components and the blending weight ratio of the component (a) and the component (b) so as to fall within the preferred range, the stress relaxation rate and the deviation stress can be set within the preferred range, Those numbers can be increased or decreased.

Next, the present invention will be specifically described by way of examples, but these examples do not limit the present invention. Abbreviations used in Examples and the like are as follows.

BSP: Free Bisoprolol PIB1: Polyisobutylene Viscosity average molecular weight 4,000,000
PIB2: polyisobutylene viscosity average molecular weight 400,000
PIB3: Polyisobutylene Viscosity average molecular weight 55,000
SIS1: Styrene-isoprene-styrene block copolymer (styrene ratio 25% by weight, diblock ratio 17% by weight)
SIS2: Styrene-isoprene-styrene block copolymer (styrene ratio 25% by weight, diblock ratio 42% by weight)
SIS3: Styrene-isoprene-styrene block copolymer (styrene ratio 22% by weight, diblock ratio 15% by weight)
SIS4: Styrene-isoprene-styrene block copolymer (styrene ratio 14% by weight, diblock ratio 26% by weight)
TF1: tackifier alicyclic saturated hydrocarbon resin softening point 100 ° C
TF2: tackifier alicyclic saturated hydrocarbon resin softening point 140 ° C
Flow para: liquid paraffin IPM: isopropyl myristate ODO: 2-octyl-1-dodecanol

(Examples 1 to 8, Comparative Examples 1 to 8)
A viscous toluene solution of the pressure-sensitive adhesive composition was prepared according to the blending ratio shown in Table 1, and the resulting solution was dried on a polyethylene terephthalate (PET) liner (thickness 75 μm) subjected to silicone release treatment. The coating was applied so that the thickness was as shown in Table 2, and this was dried in a hot air circulating dryer at 100 ° C. for 5 minutes to form an adhesive layer. This pressure-sensitive adhesive layer was bonded to the nonwoven fabric side of a laminated film of a PET film having a thickness of 2 μm and a PET nonwoven fabric having a thickness of 12 g / m ² to obtain a sheet-like patch preparation. Table 2 shows the results of measuring the stress relaxation rate and deviation stress of the obtained patch preparation by the above methods. In addition, the mixture ratio of each component of Table 1 is a ratio (weight%) with respect to the whole adhesive composition.

(1) Adhesive strength The adhesive strength of the patch preparations obtained in Examples 1 to 8 and Comparative Examples 1 to 8 was measured by the following method. The surface of a stainless steel plate (SUS304 steel plate defined in JIS G4305) was first uniformly polished with a # 360 water-resistant abrasive paper, and then washed with a cloth soaked with ethyl acetate. The bisoprolol-containing patch preparation was cut to prepare a test piece having a width of 24 mm and a length of 50 mm. The adhesive surface of the test piece from which the liner was peeled was bonded to the polished and cleaned surface of a stainless steel plate using a rubber roller having a mass of 2 kg (rubber roller passing speed 300 mm / min, number of passes twice). The stainless steel plate on which the test piece was bonded was 23 ± 2 ° C., 65 ± 10% R.D. H. For 30 minutes. About 5 mm of one end of the test piece was peeled off from the stainless steel plate, turned back to a 180 ° angle, and an auxiliary paper (width 30 mm) was attached. Using a tensile tester, one end of the auxiliary paper was sandwiched between the upper clasp and a stainless steel plate was sandwiched between the lower clasp, 23 ± 2 ° C., 65 ± 10% R.S. H. The test piece was continuously peeled off in the 180 ° direction at a speed of 300 mm / min in the atmosphere, and the adhesive strength was measured. The results are shown in Table 3.

(2) Stickability From the above adhesive strength, stickability was determined according to the following criteria.
When the adhesive strength was 0.1 N / 24 mm width or less, the adhesive strength was weak and there was a risk of peeling at the time of application.
If the adhesive strength is more than 0.1 N / 24 mm width and less than 2.0 N / 24 mm width, it has an appropriate adhesive strength and there is no possibility of causing skin irritation at the time of peeling. did.
If the adhesive strength is 2.0N / 24mm width or more and less than 3.0N / 24mm width, it has excellent skin adhesion and there is no risk of skin irritation at the time of peeling, so the sticking property is excellent (◎) It was determined.
If the adhesive strength is 3.0 N / 24 mm width or more and less than 3.9 N / 24 mm width, skin irritation at the time of peeling may occur, and thus it was determined that the adhesive property was acceptable (Δ).
When the adhesive strength was 3.9 N / 24 mm width or more, the adhesive strength was strong, and skin irritation occurred at the time of peeling.
The results are shown in Table 3.

(3) Stretchability of pressure-sensitive adhesive layer From the stress relaxation rate, the stretchability of the pressure-sensitive adhesive layer was determined according to the following criteria.
When the stress relaxation rate is less than 20%, the followability to the skin surface is not sufficient, and there is a possibility that the skin may feel awkward or peel off at the time of application.
When the stress relaxation rate was 20% or more and 90% or less, it had moderate followability, and did not cause a sense of incongruity at the time of sticking or turning of the peripheral edge, so the stretchability was judged as good (◯).
When the stress relaxation rate is more than 90%, the pressure-sensitive adhesive layer becomes too soft, and adhesive residue may be generated at the time of peeling.
The results are shown in Table 3.

(4) Presence / absence of transferred material In (1) Adhesive strength, the surface of the stainless steel plate after the adhesive strength was measured was visually observed, and the presence or absence of the transferred material on the surface of the stainless steel plate was determined according to the following criteria. evaluated. The results are shown in Table 3.
○: No transcript was present.
Δ: Partial transcript was present.
X: The transferred material was present on the entire surface of the pasted portion.

As is apparent from Table 3, Examples 1 to 8 in which the deviation stress and the stress relaxation rate are shown in the preferred ranges in Table 2 exhibit good sticking properties and stretchability, and are covered after peeling. There was no transfer to the adherend, and good peelability was exhibited. In addition, Examples 1 to 4 and 7 exhibit a sufficiently high stress relaxation rate, so that they are excellent in reducing the stress applied to the patch preparation against the movement of the skin surface when applied to the skin surface, and the peripheral edge of the preparation is turned upside down. It was inferred that this can be prevented more effectively.
On the other hand, Comparative Examples 1 to 3 in which the deviation stress was shown to be less than the lower limit of the preferred range in Table 2 had remarkably low adhesive strength and inferior adhesive properties. Moreover, since the adhesive layer component could not be retained in the adhesive layer and oozing was observed on the surface, the transferred product was present on the adherend after peeling.
In Comparative Examples 4 to 8, in which the preparation was peeled off from the adherend during the stress relaxation test, the stress relaxation rate was assumed to be 10% or less, and the skin surface where the adherend surface was stretched or shrunk, It was inferred that it did not show sufficient followability and would peel off during application.
Based on the above, by setting the stress relaxation rate to 20 to 90% and the deviation stress to 1.0 to 6.5 N / 30 mm width, the stress can be relaxed and dispersed when applied to and peeled from the skin surface. In addition to exhibiting excellent skin adhesiveness, it was possible to reduce irritation during peeling.

Although the invention has been described in detail with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.
This application is based on a Japanese patent application filed on September 6, 2013 (Japanese Patent Application No. 2013-185601) and a Japanese patent application filed on September 2, 2014 (Japanese Patent Application No. 2014-177675). Which is incorporated by reference in its entirety.

DESCRIPTION OF SYMBOLS 1 Support body 2 Adhesive layer 3 Release liner 10 Patch preparation (test piece)
21 Bakelite plate 31 Chuck part

Claims

A support, and a pressure-sensitive adhesive layer containing free bisoprolol and a pressure-sensitive adhesive laminated on one side of the support,
A bisoprolol-containing patch preparation in which the stress relaxation rate of the pressure-sensitive adhesive layer is 20 to 90% and the displacement stress of the pressure-sensitive adhesive layer is 1.0 to 6.5 N / 30 mm width.
The stress relaxation rate of the pressure-sensitive adhesive layer is 40 to 90%, and the deviation stress of the pressure-sensitive adhesive layer is 1.0 to 4.0 N / 30 mm width.
The bisoprolol-containing patch preparation according to claim 1.
The adhesive preparation containing bisoprolol according to claim 1 or 2, wherein the adhesive comprises a rubber-based adhesive.
4. The bisoprolol-containing patch preparation according to claim 3, wherein the rubber-based adhesive is polyisobutylene and / or a styrene-isoprene-styrene block copolymer.
The bisoprolol-containing patch preparation according to claim 4, wherein the polyisobutylene is a polyisobutylene having a viscosity average molecular weight of 40,000 to 5,500,000.
The polyisobutylene includes a first polyisobutylene (a) having a viscosity average molecular weight of 1,800,000 to 5,500,000, and a second polyisobutylene (b) having a viscosity average molecular weight of 40,000 to 85,000. The blending ratio (a: b) of the first polyisobutylene (a) and the second polyisobutylene (b) is from 1: 0.1 to 1: 3 by weight. Bisoprolol-containing patch preparation.
The bisoprolol-containing patch preparation according to claim 4, wherein the styrene-isoprene-styrene block copolymer has a styrene ratio of less than 30% by weight.
The bisoprolol-containing patch preparation according to claim 4 or 7, wherein the content of the styrene-isoprene-styrene block copolymer in the pressure-sensitive adhesive layer is 5 to 50% by weight.