CN105517543A - Patch containing bisoprolol and its packaging - Google Patents

Abstract

The present invention relates to a package including a support and a bisoprolol-containing adhesive layer formed on at least one surface of the support, the bisoprolol-containing adhesive layer having a water content of 10,000ppm or less, and a bisoprolol-containing adhesive patch in which the bisoprolol-containing adhesive patch is sealed in a moisture permeation resistant bag. The bisoprolol-containing adhesive patch of the present invention is excellent in the stability with time of bisoprolol contained in the pressure-sensitive adhesive layer. The package of the bisoprolol-containing adhesive patch of the present invention is excellent in usability and portability.

Description

Patch containing bisoprolol and its packaging

technical field

The present invention relates to a bisoprolol-containing patch and its package.

Background technique

In recent years, as means for administering drugs into the living body, patches in which a drug-containing adhesive sheet is attached to the skin have been used. For such a patch, an adhesive layer containing a transdermally absorbable drug is laminated on one side of a plastic support such as polyester or polyethylene, and the exposed surface of the adhesive layer is covered with a release liner. Pad covered. Usually, such a patch is individually packaged in a water-impermeable packaging material in order to prevent volatilization of the transdermally absorbable drug contained therein and the influence of humidity.

Bisoprolol, a highly selective antagonist of β1 receptors of the sympathetic nerve (β blocker), is used to improve essential hypertension, angina pectoris, arrhythmia, and its fumarate is given orally in the form of tablets medicine. However, in the case of oral administration, there are disadvantages such as poor persistence of effect, excessive increase in blood concentration temporarily observed after administration, and easy side effects. In order to improve the above problems, it is desired to use a patch of bisoprolol.

Regarding the above-mentioned patch containing bisoprolol, a packaging bag containing a patch is disclosed in Patent Document 1, wherein, in order to suppress the hydrolysis reaction of bisoprolol and improve its storage stability, the patch is accommodated in In the packaging bag, and the relative humidity at 25° C. in the inside of the above packaging bag is kept below 25%. However, the above-mentioned packaging bag needs a desiccant, and when it is formed into a packaging body, it is bulky and inconvenient to carry and use.

In addition, Patent Document 2 discloses a patch in which the moisture content of the adhesive layer is set to 1,000 ppm to 8,000 ppm for the purpose of preventing coloring of the adhesive layer and suppressing deterioration of donepezil release. . However, the above-mentioned patent documents do not suggest the improvement of the stability over time of bisoprolol contained in the patch, and do not suggest any possibility of application to a patch containing bisoprolol.

prior art literature

patent documents

Patent Document 1: International Publication No. 2005/072716

Patent Document 2: International Publication No. 2009/145177

Contents of the invention

The problem to be solved by the invention

An object of the present invention is to provide a bisoprolol-containing patch having excellent temporal stability of bisoprolol contained in an adhesive layer, and to provide a bisoprolol-containing patch having excellent usability and portability. The packaging body of the patch.

means of solving problems

The present inventors have carried out in-depth research in order to improve the stability over time of bisoprolol in the adhesive layer of the patch containing bisoprolol, and found that there is a significant difference between the stability over time and the water content of bisoprolol. In this connection, it was found that by appropriately controlling the moisture content of the adhesive layer, the hydrolysis reaction of bisoprolol over time can be suppressed without using a desiccant when packaging a patch containing bisoprolol, and the present invention has been completed. .

That is, the present invention is as follows.

(1) A bisoprolol-containing patch comprising a support and a bisoprolol-containing adhesive layer formed on at least one side of the support, the adhesive layer having a moisture content of 10,000 ppm the following.

(2) The bisoprolol-containing patch according to (1), wherein the moisture content of the adhesive layer is 200 ppm to 10,000 ppm.

(3) The bisoprolol-containing patch according to (1) or (2), wherein the adhesive layer contains one selected from the group consisting of an acrylic adhesive and a rubber adhesive. or two or more binders.

(4) The bisoprolol-containing patch according to any one of (1) to (3), further comprising a release liner temporarily attached to the adhesive surface of the adhesive layer.

(5) A package of a bisoprolol-containing patch, wherein the bisoprolol-containing patch according to any one of (1) to (4) is sealed in a moisture-permeable bag.

(6) The package as described in (5), wherein the moisture-permeable-resistant bag is a packaging material obtained by laminating an acrylonitrile-based resin layer and a water-impermeable layer so that the acrylonitrile-based resin layer is positioned between the above-mentioned bisoprolol-containing obtained by sealing the adjacent side of the patch.

(7) The package according to (5) or (6), wherein no desiccant is enclosed in the moisture permeability-resistant bag.

(8) The package according to any one of (5) to (7), wherein the moisture permeability-resistant bag is formed of a packaging material that does not contain a desiccant.

Invention effect

According to the present invention, it is possible to suppress the hydrolysis of bisoprolol in the adhesive layer over time without using a desiccant when packaging the patch containing bisoprolol, thereby achieving improved stability and reliability over time. The bisoprolol-containing patch can also provide a bisoprolol-containing patch package that is excellent in usability and portability. As a result, QOL (quality of life) and economic efficiency of patients are improved.

detailed description

The bisoprolol-containing patch of the present invention has a support and a bisoprolol-containing adhesive layer formed on at least one side of the support. In addition, in the following, the bisoprolol-containing patch of the present invention may be referred to as "the patch of the present invention" or simply "the patch".

The support that can be used in the present invention is not particularly limited, but is preferably a support that is substantially impermeable to drugs, that is, active ingredients such as bisoprolol, additives, and other components contained in the adhesive layer. A support that does not pass through the support and cause a loss of content from the back side. Specifically, for example, polyester, polyamide, polyvinylidene chloride, polyethylene, polypropylene, polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, ionomer resin, metal foil, etc., can be used. etc. or their laminated films, etc. The thickness of the support is usually 5 μm to 500 μm, preferably 10 μm to 200 μm.

Among these, in order to improve the adhesiveness (anchoring property) between the support body and the pressure-sensitive adhesive layer, it is preferable that the support body is a laminated film composed of a non-porous plastic film and a porous film made of the above materials. In this case, it is preferable that the adhesive layer is formed on the porous film side.

As the above-mentioned porous film, a porous film having improved anchorability with the pressure-sensitive adhesive layer is used, and specifically, paper, woven fabric, non-woven fabric, knitted fabric, and a mechanically perforated sheet are exemplified.

Among these, paper, woven fabric, and nonwoven fabric are particularly preferable from the standpoint of handleability and the like. From the viewpoints of improving anchorability, flexibility of the entire patch, and sticking workability, it is preferable to use a porous film having a thickness in the range of 10 μm to 200 μm. In the case of a thin patch such as a plaster type or an adhesive tape type, it is preferable to use a porous film having a thickness in the range of 10 μm to 100 μm.

Also, when using a woven fabric or a nonwoven fabric as the porous film, their basis weight is preferably 5 g/m ² to 30 g/m ² , more preferably 6 g/m ² to 15 g/m ² . As the most preferred support, polyester films (preferably polyethylene terephthalate films) with a thickness of 1.5 μm to 6 μm and polyester films with a weight per unit area of 6 g/m ² to 15 g/m ² can be cited. (Preferably polyethylene terephthalate) non-woven fabric laminated film.

In the patch of the present invention, the adhesive layer contains bisoprolol. Bisoprolol is already commercially available in the form of oral preparations, and in the case of tablets, it is contained in the form of salts such as bisoprolol fumarate. In the patch of the present invention, bisoprolol can be contained in the adhesive layer not only in the form of a free body (free base), but also in the form of a pharmaceutically acceptable salt. Compared with the free body, the salt form Since bisoprolol has lower skin permeability, bisoprolol is preferably contained in a free form in the adhesive layer from the viewpoint of skin permeability.

The content of bisoprolol in the patch of the present invention is preferably 0.5% by weight to 40% by weight, more preferably 0.5% by weight to 30% by weight, based on the total weight of the adhesive layer in terms of free body.

When the content of bisoprolol is 0.5% by weight or more, it can be expected to release a therapeutically effective amount of the drug. On the other hand, when the bisoprolol content is 40% by weight or less, a sufficient therapeutic effect can be obtained and it is economically advantageous, and when the bisoprolol content is 30% by weight or less, it is more economically advantageous.

In the patch of the present invention, as the adhesive forming the adhesive layer, from the viewpoint of controlling the moisture content of the adhesive layer and skin adhesiveness, it is preferably a hydrophobic adhesive, and it is preferable to form a non-aqueous adhesive. adhesive layer. Examples of the hydrophobic non-aqueous adhesive include: acrylic adhesives containing acrylic polymers; styrene-diene-styrene block copolymers (such as styrene-isoprene - Styrene block copolymer, styrene-butadiene-styrene block copolymer, etc.), polyisoprene, polyisobutylene, butyl rubber, polybutadiene and other rubber-based adhesives; silicone rubber , dimethyl siloxane type, diphenyl siloxane type and other polysiloxane adhesives; vinyl ether adhesives such as polyvinyl methyl ether, polyvinyl ethyl ether, polyvinyl isobutyl ether, etc. agent; vinyl ester adhesives such as vinyl acetate-ethylene copolymer; containing carboxylic acid components such as dimethyl terephthalate, dimethyl isophthalate, dimethyl phthalate and ethylene glycol Polyester-based adhesives such as polyol components, and more preferably acrylic-based adhesives and rubber-based adhesives. In the patch of the present invention, one or two or more selected from the group consisting of acrylic adhesives and rubber adhesives are preferably used.

Acrylic adhesives are also preferred from the viewpoint of moisture permeability and drug solubility. In order to impart sufficient skin adhesiveness to the adhesive layer, the acrylic adhesive is preferably contained in an amount of 30% by weight to 75% by weight, more preferably in an amount of 35% by weight to 70% by weight, and further It is preferable to contain 40 weight% - 65 weight%.

Examples of the acrylic adhesive include an acrylic adhesive mainly composed of a polymer of an alkyl (meth)acrylate containing an alkyl group having 2 to 18 carbon atoms as the first monomer. As this acrylic polymer, the homopolymer of (meth)acrylic-acid alkyl ester, or these copolymers are mentioned. Here, as the alkyl group having 2 to 18 carbon atoms in the above-mentioned alkyl (meth)acrylate, a linear or branched alkyl group having 4 to 12 carbon atoms is preferable. Specific examples of the alkyl (meth)acrylate include butyl (meth)acrylate, tert-butyl (meth)acrylate, pentyl (meth)acrylate, and hexyl (meth)acrylate. , Heptyl (meth)acrylate, Octyl (meth)acrylate, Isooctyl (meth)acrylate, Nonyl (meth)acrylate, Isononyl (meth)acrylate, Decyl (meth)acrylate , Undecyl (meth)acrylate, dodecyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, etc.

The above-mentioned alkyl (meth)acrylate is contained in a ratio of preferably 50% by weight or more, more preferably 60% by weight or more, of the monomer components to be polymerized.

In addition, the above-mentioned acrylic polymer may be a copolymer obtained by polymerizing a second monomer copolymerizable with the above-mentioned alkyl (meth)acrylate, and examples of the second monomer include: A monomer capable of becoming a functional group of a crosslinking point. Specifically, monomers having neither a carboxyl group nor a sulfonyl group, such as hydroxyethyl (meth)acrylate (for example, 2-hydroxyethyl (meth)acrylate), hydroxypropyl (meth)acrylate, esters, glycidyl (meth)acrylate, ethylene glycol diacrylate, hydroxyethyl (meth)acrylamide, etc.; monomers with carboxyl groups, such as (meth)acrylic acid, itaconic acid, maleic acid, Mesaconic acid, citraconic acid, glutaconic acid, etc. These second monomers can be used alone or in combination of two or more.

Moreover, the polymer containing the 3rd monomer other than a 2nd monomer may be sufficient as needed. These third monomers can be used to adjust the cohesion of the adhesive layer, and adjust the solubility and release of bisoprolol. Examples of the third monomer include vinyl esters such as vinyl acetate and vinyl propionate; vinyl ethers such as methyl vinyl ether and ethyl vinyl ether; N-vinyl-2-pyrrolidone , N-vinyl caprolactam and other vinyl amides; (meth)acrylic acid alkyl esters; (meth)acrylamide, dimethyl (meth)acrylamide and other monomers containing amide groups; (meth)acrylic acid Alkoxy-containing monomers such as methoxyethyl ester (e.g., 2-methoxyethyl acrylate), ethoxyethyl (meth)acrylate; styrene, vinylpyridine, vinylimidazole, vinyl Vinyl monomers such as morpholine; acrylamides (e.g., N-methylolacrylamide, N,N-dimethylaminopropylacrylamide); methoxynonaethylene glycol acrylate; acryloylmorpholine ; Phenoxy polyethylene glycol (meth) acrylate, etc. These third monomers can be used alone or in combination of two or more.

Among the above-mentioned acrylic polymers, it is preferable, for example, to combine the first monomer (especially 2-ethylhexyl acrylate), the second monomer (especially acrylic acid) and the third monomer from the viewpoint of being able to easily adjust the skin adhesive force. An acrylic polymer obtained by blending and copolymerizing monomers (especially N-vinyl-2-pyrrolidone) in a weight ratio of about 40 to 99.9:0.1 to 10:0 to 30.

In addition, if necessary, the above-mentioned acrylic adhesive can be subjected to physical crosslinking by radiation irradiation such as ultraviolet irradiation and electron beam irradiation; using isocyanate compounds such as trifunctional isocyanates, organic peroxides, organic metal salts, and metal alkoxides Chemical crosslinking treatment of various crosslinking agents such as metal chelates, multifunctional compounds (multifunctional external crosslinking agents; monomers for multifunctional internal crosslinking such as diacrylates and dimethacrylates, etc.).

On the other hand, rubber-based adhesives have particularly high drug release properties from the adhesive layer containing the adhesive, are easy to control drug release, have no possibility of remaining reactive functional groups, and have high drug stability. aspect is favorable. The content of the rubber-based adhesive is preferably 15% by weight to 60% by weight, more preferably 15% by weight to 55% by weight, based on the total weight of the adhesive layer.

The rubber-based adhesive is not particularly limited, and examples thereof include rubbers mainly composed of at least one selected from polyisobutylene, polyisoprene, butyl rubber, and styrene-diene-styrene copolymers. class of adhesives. Among them, polyisobutylene is preferably used from the standpoint of high drug stability and the ability to balance the necessary adhesive force and cohesive force. In this case, one kind of polyisobutylene can be used alone, or two or more polyisobutylenes with different molecular weights can be used. Polyisobutylene.

When a single polyisobutylene is contained in the adhesive layer, the content of the polyisobutylene is preferably 15% by weight to 60% by weight, more preferably 15% by weight to 55% by weight, based on the total weight of the adhesive layer. When the polyisobutylene content is less than 15% by weight relative to the total weight of the adhesive layer, it may be difficult to impart the necessary internal cohesion to the adhesive layer. On the other hand, when it exceeds 60% by weight, the adhesive layer may Reduced skin adhesiveness and viscosity.

Moreover, when single polyisobutylene is contained in an adhesive layer, the molecular weight of polyisobutylene is not specifically limited, It is preferable that a viscosity average molecular weight is 40,000-5,500,000, More preferably, it is 45,000-5,000,000. When the viscosity average molecular weight is less than 40,000, it may be difficult to impart the necessary internal cohesion to the adhesive layer. On the other hand, when it exceeds 5,500,000, the skin adhesiveness and viscosity of the adhesive layer may decrease.

In order to easily achieve both appropriate cohesive strength, appropriate softness, and skin adhesiveness, it is preferable to contain two or more types of polyisobutylene having different molecular weights in the adhesive layer. In this specification, "two or more types of polyisobutenes having different molecular weights" means polyisobutenes having peaks in molecular weight distribution measured by gel permeation chromatography (GPC) in two or more independent regions. In addition, there is usually one peak of the molecular weight distribution of each polyisobutylene. Therefore, "two or more types of polyisobutylenes having different molecular weights" includes, for example, two or more types of polyisobutylenes having different viscosity average molecular weights. The polyisobutene preferably consists of, for example, a first polyisobutene and a second polyisobutene having a relatively lower molecular weight than the first polyisobutene. The above-mentioned first polyisobutylene can impart appropriate cohesion to the adhesive layer, and the second polyisobutylene can impart appropriate softness and skin adhesiveness to the adhesive layer.

The molecular weights of the first polyisobutene and the second polyisobutene are not particularly limited, but the viscosity average molecular weight of the first polyisobutene 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 to 85,000, more preferably 45,000 to 65,000. When the viscosity-average molecular weight of the first polyisobutylene is less than 1,800,000, it may be difficult to impart the necessary internal cohesion to the adhesive layer. On the other hand, when the viscosity-average molecular weight of the first polyisobutylene exceeds 5,500,000, the skin of the adhesive layer may Decreased stickiness and stickiness. In addition, when the viscosity-average molecular weight of the second polyisobutylene is less than 40,000, the adhesive layer may exhibit a sticky feeling or stain the skin surface. The skin adhesiveness and viscosity of the mixture layer are reduced. In addition, the 1st polyisobutylene and the 2nd polyisobutylene can be used in combination of 2 or more types within the range of each molecular weight distribution.

It should be noted that, in this specification, the viscosity-average molecular weight refers to a value as follows: according to the flow time at 20° C. of the capillary of the Ubbelohde viscometer, by the Schulz-Blaschke (Schulz-Blaschke) formula The Staudinger index (J ₀ ) was calculated (the following formula (1)), and the value obtained by the following formula (2) was used using this J ₀ value.

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

η _SP =t/t ₀ -1

t: flow time of the solution (based on the Hagenbach-Couette correction formula)

t ₀ : the flow time of the solvent (based on the Hagenbach-Courette correction formula)

c: Concentration of solution (g/cm ³ )

J ₀ =3.06×10 ^-2 Mv ^0.65 ...(2)

Mv: viscosity average molecular weight

When the adhesive layer contains two or more polyisobutylenes having different molecular weights, the total content of the polyisobutylene is preferably 15% by weight to 60% by weight, more preferably 15% by weight to 55% by weight, based on the total weight of the adhesive layer. weight%. When the total polyisobutylene content is less than 15% by weight, it may be difficult to impart the necessary internal cohesion to the adhesive layer. On the other hand, when the total polyisobutylene content exceeds 60% by weight, the adhesive layer may stick to the skin. Sexuality and viscosity decrease.

In addition, when the pressure-sensitive adhesive layer contains two types of polyisobutylene having different molecular weights, the compounding weight ratio (a:b) of the first polyisobutylene (a) to the second polyisobutylene (b) is preferably 1:0.1 to 1: 3. More preferably 1:0.1 to 1:2.5, even more preferably 1:0.3 to 1:2. Of these two types of polyisobutylene, when the compounding weight ratio (b/a) of the second polyisobutylene (b) to the first polyisobutylene (a) is greater than 3, there is a possibility that the decrease in the internal cohesion of the adhesive layer may increase, On the other hand, when the blending weight ratio (b/a) of the second polyisobutylene (b) to the first polyisobutylene (a) is less than 0.1, the decrease in the skin adhesive force of the adhesive layer may increase.

As the adhesive contained in the adhesive layer, when a rubber-based adhesive is used, it is preferable to appropriately select and contain a tackifier known in the field of patch preparations. As the tackifier, for example, petroleum-based resins (for example, aromatic petroleum resins, aliphatic petroleum resins), terpene-based resins, rosin-based resins, coumarone-indene resins, styrene-based resins (for example, styrene resins, α-methylstyrene resins), hydrogenated petroleum resins (for example, alicyclic saturated hydrocarbon resins), and the like. Among them, alicyclic saturated hydrocarbon resins are preferable because they improve the storage stability of bisoprolol.

The tackifier can be used alone or in combination of two or more, and when two or more are used in combination, for example, resins having different types of resins and different softening points can be used in combination.

The content of the tackifier is preferably 10% by weight to 55% by weight, more preferably 10% by weight to 50% by weight, particularly preferably 10% by weight to 45% by weight, based on the total weight of the adhesive layer. When the content of the tackifier is less than 10% by weight, the viscosity and cohesion may be poor. On the other hand, when the content of the tackifier exceeds 55% by weight, the adhesive layer tends to harden and the skin adhesiveness tends to decrease.

In addition, the softening point of the tackifier is preferably 90°C to 150°C, more preferably 95°C to 145°C. When the softening point is 90° C. to 150° C., the compatibility with each component contained in the pressure-sensitive adhesive layer tends to be favorable and uniform mixing is easy. In addition, the softening point in this invention is the value measured by the ring and ball method.

An organic liquid component having fluidity at normal temperature (25° C.) may be contained in the adhesive layer. As the organic liquid component, it is a liquid organic component added in addition to bisoprolol as a drug, as long as it is an organic liquid component compatible with other constituents of the adhesive layer (for example, adhesive, thickener). Not particularly limited. As the organic liquid component, fatty acid alkyl esters and long-chain alcohols are preferably used from the viewpoint of greatly contributing to the acceleration of the absorption of bisoprolol and the improvement of the solubility of bisoprolol in the adhesive layer. The organic liquid components can be used alone or in combination of two or more.

Examples of the fatty acid alkyl esters include fatty acid alkyl esters of higher fatty acids having 12 to 16 carbon atoms, preferably 12 to 14 carbon atoms, and lower monohydric alcohols having 1 to 4 carbon atoms. Examples of preferable higher fatty acids include lauric acid (with 12 carbon atoms), myristic acid (with 14 carbon atoms), and palmitic acid (with 16 carbon atoms), and myristic acid is more preferable. As said monohydric alcohol, methanol, ethanol, propanol, isopropanol, butanol, etc. are mentioned, Preferably it is isopropanol. Therefore, as the fatty acid alkyl ester, isopropyl myristate is most preferable, and by using this compound, the absorption of bisoprolol can be promoted, the solubility can be improved, and the drug availability can be achieved at a high level.

In addition, examples of the aforementioned long-chain alcohol include saturated or unsaturated long-chain alcohols having 12 to 28 carbon atoms, preferably 12 to 24 carbon atoms, and saturated long-chain alcohols are preferably used from the viewpoint of storage stability. . Moreover, as said long-chain alcohol, a linear long-chain alcohol or a branched long-chain alcohol is mentioned, and these can be used in mixture. Examples of such straight-chain alcohols include 1-dodecanol, 1-tetradecyl alcohol, 1-hexadecanol, and stearyl alcohol. Among them, those with excellent compatibility with polyisobutylene and stabilization of bisoprolol From the aspect, 1-dodecanol is preferred. In addition, when it is difficult to obtain compatibility with polyisobutylene, for example, a branched long-chain alcohol having 16 to 28 carbon atoms, preferably 18 to 24 carbon atoms, can be used. Specifically, 2-hexyldecyl alcohol, isostearyl alcohol, 2-octyl dodecanol, 2-decyltetradecanol, etc., among them, are excellent in compatibility with polyisobutylene and can make peso From the viewpoint of improving the solubility of lore, 2-octyldodecanol is preferable.

As an organic liquid component, even if fatty acid alkyl ester is used alone, the above effects can be sufficiently obtained. However, when fatty acid alkyl ester and long-chain alcohol are used in combination, the permeability and solubility of bisoprolol and the skin of the adhesive layer may be affected. It is preferable from the point of view that the adhesiveness is further improved. The compounding weight ratio (c:d) of the fatty acid alkyl ester (c) to the long-chain alcohol (d) is preferably 1:0.01 to 1:0.5, more preferably 1:0.01 to 1:0.4, and still more preferably 1:0.05 ~1:0.4. Among these two organic liquid components, the permeability and solubility of bisoprolol can be observed when the compounding weight ratio (d/c) of the long-chain alcohol (d) to the fatty acid alkyl ester (c) is 0.01 or more , and the improvement of the skin adhesiveness of the adhesive layer, when the compounding weight ratio (d/c) of the long-chain alcohol (d) to the fatty acid alkyl ester (c) is greater than 0.5, the Since the compounding ratio is relatively reduced, it may be difficult to continuously promote percutaneous absorption at a high level.

As described above, the organic liquid component often functions effectively as a permeation enhancer, and in this case, increasing the content of the organic liquid component improves the skin permeability of bisoprolol. That is, by including a large amount of organic liquid components in the adhesive layer, the skin permeability becomes higher and the skin permeability is easily controlled, so it can be said that it is an ideal adhesive composition for a patch. In addition, by containing an organic liquid component in the adhesive layer, appropriate flexibility and skin adhesiveness can be imparted to the adhesive layer.

In the case of using an organic liquid component, in order to prevent the organic liquid component from seeping out from the adhesive layer, the content of the organic liquid component is preferably 5% by weight to 70% by weight, more preferably 10% by weight, relative to the total weight of the adhesive layer. % to 65% by weight, more preferably 20% to 50% by weight.

In the patch of the present invention, components other than the above may be appropriately added to the adhesive layer. For example, in order to further improve the solubility of bisoprolol in the adhesive layer and obtain better skin irritation, it is possible to mix in the adhesive layer other than the above-mentioned organic ingredients containing liquid or pasty. Dissolving aid. As long as the dissolution aid is excellent in compatibility with the adhesive, fully dissolves bisoprolol, has little possibility of bisoprolol exudation (bleeding) from the adhesive layer, and has no effect on the adhesive properties and drug release properties. A dissolution aid that does not cause adverse effects is sufficient. Specifically, fatty acids such as oleic acid, myristic acid, and capric acid; organic acids such as dicarboxylic acids such as adipic acid and sebacic acid; esters with alcohols such as ethanol and 2-propanol; glycerin , propylene glycol and other polyols or their diesters and triesters; esters of polyols and organic acids such as glycerol triacetate; polyethers such as polyethylene glycol, polypropylene glycol and polyethylene oxide hydrogenated castor oil; and Crotamiton, etc.

Moreover, in order to improve the cohesive force of an adhesive layer, you may make an adhesive layer contain a suitable filler as needed. Such a filler is not particularly limited, and examples thereof include inorganic fine particles such as silicon dioxide, titanium oxide, zinc oxide, magnesium oxide, iron oxide, aluminum hydroxide, talc, kaolin, bentonite, barium sulfate, and calcium carbonate, and lactose. , carbon black, polyvinylpyrrolidone, polyester, polyolefin, polyurethane, polyamide, cellulose, acrylic resin and other organic particles, and polyester, polyolefin, polyurethane, polyamide, cellulose, acrylic Fibers of resin, glass, etc.

In addition, by containing an appropriate softener in the adhesive layer as needed, appropriate skin adhesive force and tackiness can be imparted to the adhesive layer. Such a softener is not particularly limited, and examples thereof include liquid rubbers such as liquid polybutene and liquid polyisoprene, and liquid hydrocarbons such as liquid paraffin, squalane, and squalene among the organic liquid components. In addition, if necessary, a cover tape or the like may be attached so as to cover a part or the entire surface of the patch of the present invention to enhance skin adhesiveness and supplement the adhesiveness to the skin.

In the present invention, when the first polyisobutylene is used as the binder, a large amount of organic liquid components can be contained, and as a result, the effect of promoting absorption and improving the solubility of the drug by the organic liquid components can be sufficiently obtained. . Thereby, the reduction of the cohesive force can be suppressed, and it can be made into a patch without adhesive residue etc. In addition, as the tackifier, by using a tackifier having a high softening point within the temperature range of the above-mentioned softening point, not only the cohesive force can be improved, but also the skin adhesiveness can be simultaneously improved. In addition, the thickness of an adhesive layer is 10 micrometers - 300 micrometers normally, Preferably it is 10 micrometers - 250 micrometers, More preferably, it is 15 micrometers - 250 micrometers.

In order to improve the temporal stability of bisoprolol, the moisture content of the pressure-sensitive adhesive layer is 10,000 ppm or less, preferably 200 ppm to 10,000 ppm.

From the viewpoint of the possibility of moisture control during patch preparation, the lower limit of the preferred range of the moisture content of the adhesive layer may be, for example, 200ppm, 300ppm, 400ppm, 500ppm, 600ppm, 700ppm, 800ppm, 900ppm, 1,000ppm , 1,500ppm, 2,000ppm, 2,500ppm, 3,000ppm, 3,500ppm or 4,000ppm. From the viewpoint of the stability of bisoprolol, the upper limit of the preferred range of the moisture content of the adhesive layer may be, for example, 10,000 ppm, 9,500 ppm, 9,000 ppm, 8,500 ppm, 8,000 ppm, 7,500 ppm, 7,000 ppm, 6,500 ppm, 6,000ppm, 5,500ppm, or 5,000ppm. Here, the moisture content of the adhesive layer refers to the ratio of the weight of water contained in the adhesive layer (weight of water relative to the total weight of the adhesive layer) measured by Karl Fischer coulometric titration. ratio) in this specification is a value measured under the measurement conditions described in Examples described later.

The moisture content of the adhesive layer of the patch fluctuates depending on the relative humidity of the external environment (atmosphere), and converges to the equilibrium moisture content at the temperature and humidity over time. That is, when the relative humidity of the external environment (atmosphere) is high, the pressure-sensitive adhesive layer absorbs or adsorbs moisture, and the moisture content of the pressure-sensitive adhesive layer increases. Conversely, when the relative humidity of the external environment (atmosphere) is low, the adsorption of moisture to the adhesive layer is suppressed, and moisture is released from the adhesive layer, thereby reducing the moisture content of the adhesive layer. Therefore, by adjusting the temperature and/or relative humidity of the external environment (atmosphere), the moisture content of the adhesive layer can be controlled. In addition, the adjustment of the temperature and relative humidity of an external environment (atmosphere) can be performed suitably by well-known air-conditioning equipment.

For example, in the manufacturing process of a patch containing bisoprolol, the atmosphere in the stamping and packaging stages is maintained at temperature = 20 ± 10°C and relative humidity = 30 ± 10%. In such an environment, the patch By maintaining for 30 minutes to 48 hours, the moisture content of the adhesive layer can be controlled within the above-mentioned range.

In the adhesive preparation of the present invention, in order to protect the adhesive surface of the adhesive layer until use, a release liner may be laminated on the adhesive surface. The release liner is not particularly limited, and for example, polyester, polychloride, etc. that have been subjected to easy-release treatment by coating silicone resin, fluorine-containing resin, etc. on the contact surface with the adhesive layer can be used. Films such as vinyl, polyvinylidene chloride, polyethylene terephthalate, high-grade paper, cellophane, etc., or laminated films of high-grade paper, cellophane, etc. and polyolefin, etc. The thickness of the release liner is preferably 10 μm to 200 μm, more preferably 25 μm to 150 μm.

For the purpose of the present invention, as the release liner, a release liner made of polyester (particularly polyethylene terephthalate) resin is preferable from the viewpoint of barrier properties, price, and the like. Also in this case, a release liner having a thickness of about 25 μm to about 100 μm is preferable from the viewpoint of handleability.

The shape of the patch of the present invention is not particularly limited, and includes, for example, a tape shape and a sheet shape.

The patch of the present invention can be produced by, for example, dissolving an adhesive composition containing an adhesive, bisoprolol, if necessary a thickener, an organic liquid component, etc., in a suitable solvent such as toluene, and dissolving the obtained The solution is applied on a release liner, dried to form a pressure-sensitive adhesive layer, and then a support is laminated on the pressure-sensitive adhesive layer, thereby producing. In addition, for example, it can be produced by directly applying the above-mentioned binder solution on a support, followed by drying to form a binder layer on the support. In addition, when forming the adhesive layer, if the solution of the adhesive composition is applied thickly at once, it may be difficult to dry uniformly, so in order to make the thickness of the adhesive layer sufficient , can be divided into two or more coatings.

In addition, in order to prevent the components contained in the adhesive layer from oozing out from the side of the patch, the peripheral part of the patch may be pressurized so that the thickness of the adhesive layer in the peripheral part may be reduced.

The patch of the present invention is preferably enclosed in a moisture-permeable-resistant bag until it is used, and stored or transported as a package. As a method of forming the package, for example, a method of packaging one patch or a plurality of overlapping patches with a packaging material constituting a moisture-permeable bag, and heat-sealing the periphery thereof to seal the package . As the above-mentioned packaging material, for example, a sheet-like or film-like packaging material can be mentioned, and from the viewpoint of controlling the moisture content of the adhesive layer, ease of packaging, and airtightness, it is preferable to show water-impermeability and be heat-sealable. packaging materials. Specifically, plastics having heat sealability such as polyethylene, ionomer resins, ethylene-vinyl acetate copolymers, ethylene-vinyl alcohol copolymers, polyacrylonitrile-based copolymers, and polyvinyl alcohol-based copolymers are preferably used. A packaging material obtained by laminating an air-impermeable or water-impermeable film such as a polyester film or metal foil on a sheet. By using an air-impermeable or water-impermeable film, it is possible to control the moisture content of the adhesive layer as described above without enclosing a desiccant in the package or making the packaging material itself contain a desiccant.

As the above-mentioned packaging material, a packaging material having a thickness of 10 μm to 200 μm is generally used.

It should be noted that, as the above-mentioned packaging material, it is more preferable to use a barrier for the innermost layer (when the bisoprolol-containing patch is enclosed in a moisture-permeable-resistant bag, the layer positioned on the side adjacent to the bisoprolol-containing patch) Highly durable acrylonitrile resin. From the viewpoint of the uniformity of properties of the acrylonitrile resin layer, the acrylonitrile resin is preferably a copolymer having acrylonitrile as the main structural unit, and the copolymer preferably contains at least acrylonitrile and a rubber component such as butadiene, and /or a copolymer having an alkyl (meth)acrylate having 1 to 6 carbon atoms in the alkyl group as a structural unit. In addition, in the copolymer, the content of acrylonitrile is preferably 50% by weight to 90% by weight, and a particularly preferred copolymer is a copolymer having 50% by weight to 90% by weight of acrylonitrile, 2% by weight to 12% by weight of A copolymer obtained by copolymerizing a rubber component such as diene, and a monomer component composed of 8% by weight to 38% by weight of an alkyl (meth)acrylate having an alkyl group having 1 to 6 carbon atoms. In addition, the copolymerization form of the copolymer may be random copolymerization, block copolymerization, or graft copolymerization, and it is preferably a rubber that can effectively combine the characteristics of polyacrylonitrile with excellent non-absorptivity to physiologically active components and excellent impact absorption. As for the characteristic graft copolymerization form of the components, random copolymerization and block copolymerization may be appropriately performed as long as the above-mentioned characteristics are not hindered.

In addition, the composition analysis of the acrylonitrile-type resin in this invention was performed by the following method.

That is, CHN elemental analysis was performed on a sample obtained by cutting out the acrylonitrile-based resin layer from the packaging material, and the acrylonitrile content was calculated from the nitrogen content. In addition, the rubber component and the carbon number of the alkyl group having ¹ to 6 ^carbon atoms (methyl ) molecular structure and weight ratio of the alkyl acrylate component, and obtain the weight ratio of the above three components.

The thickness of the acrylonitrile-based resin layer can be appropriately set according to the type of patch, etc., and is not particularly limited. From the viewpoint of securing appropriate flexibility and rigidity as a packaging material for the patch, the thickness is preferably 5 μm to 100 μm, more preferably 5 μm to 80 μm, and most preferably 5 μm to 50 μm.

In addition, if the adhesive component and the like flow out from the side of the patch, the operability of taking it out from the package may deteriorate, so it is preferable to emboss the packaging material or make the release liner part smaller than the patch The packaging form is designed by dry-type edge processing with a slightly larger body and blister molding to reduce the contact area.

The patch of the present invention can be used by breaking the package or the like immediately before use to take out the patch, peeling off the release liner, and sticking the exposed adhesive surface on the skin surface.

The usage of the patch of the present invention varies depending on the patient's age, body weight, symptoms, and the like.

In order to achieve the administration of an effective amount of bisoprolol while using the above-mentioned maximum value of the permeation rate of bisoprolol in human skin, the sticking area of the patch of the present invention can be considered. The sticking area of the patch is preferably 3 cm ² to 50 cm ² , more preferably 3 cm ² to 48 cm ² , and still more preferably 4 cm ² to 45 cm ² .

When the sticking area of the patch is less than 3 cm ² , it may make the sticking operation difficult, and when the sticking area of the patch is larger than 50 cm ² , it may bring pressure to the patient during sticking. In the case where a strong drug effect is required, two or more tablets can also be pasted at the same time.

The bisoprolol-containing patch of the present invention is controlled so that the maximum release rate of bisoprolol from immediately after sticking to the skin until 24 hours has elapsed is 30 μg/cm ² /hour or less, and after sticking to the skin The release rate of bisoprolol after 24 hours was 10 μg/cm ² /hour or less.

Example

The present invention will be described in more detail through examples below, but the present invention is not limited to these examples. In the following description, "part" or "%" means "part by weight" or "% by weight".

[Example 1]

15.1 parts of high molecular weight polyisobutylene (viscosity average molecular weight = 4,000,000), 26.1 parts of medium molecular weight polyisobutylene (viscosity average molecular weight = 55,000), 27.4 parts of alicyclic saturated hydrocarbon resin (tackifier), isopropyl myristate ( 30.0 parts of organic liquid components) and 1.4 parts of bisoprolol (free body) were mixed in toluene to prepare a viscous toluene solution of the adhesive composition. The obtained solution was coated on a polyethylene terephthalate (PET) release liner (thickness: 75 μm) so that the thickness after drying was 160 μm, and it was dried in a hot air circulation dryer. Drying was carried out at 100° C. for 5 minutes to form an adhesive layer.

This pressure-sensitive adhesive layer was attached to the nonwoven fabric side of a support body of a laminated film of a PET film and a PET nonwoven fabric (weight per unit area=12 g/m ² ) having a thickness of 2 μm, and punched out to 36 cm ² (6 cm x 6 cm), and pressurize (4.9 MPa) the peripheral part of the patch to obtain a patch containing bisoprolol.

In the manufacturing process of the patch containing bisoprolol, the atmosphere during the above-mentioned punching process is kept at temperature = 20 ± 10 ° C and relative humidity = 30 ± 10%, and the patch is adjusted by keeping it in this environment for 24 hours. The moisture content of the adhesive layer of the agent.

Use a packaging material made by laminating PET film (thickness = 12 μm) / aluminum foil (thickness = 9 μm) / acrylonitrile resin film (thickness = 30 μm) by dry lamination at temperature = 20 ± 10 ° C and relative humidity = The obtained bisoprolol-containing patch was sealed in an atmosphere of 30±10% to obtain a bisoprolol-containing patch package (9 cm×9 cm).

[Example 2]

Under an inert gas atmosphere, make 70.0 parts of 2-ethylhexyl acrylate, 5.0 parts of hydroxyethylacrylamide, 25.0 parts of N-vinyl-2-pyrrolidone, and 0.2 parts of azobisisobutyronitrile as a polymerization initiator in Solution polymerization was carried out at 60°C in ethyl acetate to prepare an acrylic adhesive solution. 65.0 parts of this acrylic adhesive solution, 30.0 parts of isopropyl myristate as an organic liquid component, and 5.0 parts of bisoprolol (free body) were mixed to prepare a viscous ethyl acetate of an adhesive composition. solution. The obtained solution was coated on a polyethylene terephthalate (PET) release liner (thickness 75 μm) so that the thickness after drying was 45 μm, and it was dried in a hot air circulation dryer at 100 °C for 5 minutes to form an adhesive layer.

This adhesive layer was attached to the nonwoven fabric side of a support body of a laminated film of a PET film and a PET nonwoven fabric (weight per unit area = 12 g/m ² ) having a thickness of 2 μm, and punched out to a thickness of 36 cm. ² (6cm x 6cm) in size to obtain a patch containing bisoprolol.

In the manufacturing process of the patch containing bisoprolol, the atmosphere during the above-mentioned punching process is kept at temperature = 20 ± 10 ° C and relative humidity = 30 ± 10%, and the patch is adjusted by keeping it in this environment for 24 hours. The moisture content of the adhesive layer of the agent.

Use a packaging material made by laminating PET film (thickness = 12 μm) / aluminum foil (thickness = 9 μm) / acrylonitrile resin film (thickness = 30 μm) by dry lamination at temperature = 20 ± 10 ° C and relative humidity = The obtained bisoprolol-containing patch was sealed in an atmosphere of 30±10% to obtain a bisoprolol-containing patch package (9 cm×9 cm).

[Comparative example 1]

60.0 parts of the acrylic adhesive solution used in the preparation of the patch of Example 2 above, 30.0 parts of the above-mentioned isopropyl myristate as an organic liquid component, 5.0 parts of polyvinylpyrrolidone and the above-mentioned bisoprolol (free Body) 5.0 parts were mixed to prepare a viscous ethyl acetate solution of the adhesive composition. The obtained solution was coated on a polyethylene terephthalate (PET) release liner (thickness 75 μm) so that the thickness after drying was 45 μm, and it was dried in a hot air circulation dryer at 100 °C for 5 minutes to form an adhesive layer. This pressure-sensitive adhesive layer was attached to the nonwoven fabric side of a support body of a laminated film of a PET film and a PET nonwoven fabric (weight per unit area=12 g/m ² ) having a thickness of 2 μm, and punched out to 36 cm ² (6 cm x 6 cm), and pressurize the periphery of the patch in the same manner as in Example 1 above to obtain a bisoprolol-containing patch.

The obtained bisoprolol-containing patch was packaged by dry lamination in a packaging material obtained by laminating PET film (thickness = 12 μm) / aluminum foil (thickness = 9 μm) / acrylonitrile-based resin film (thickness = 30 μm). Sealing was performed to obtain a bisoprolol-containing patch package (9 cm×9 cm).

In addition, in the manufacturing process of the bisoprolol-containing patch of this comparative example, the adjustment of the moisture content of the patch at the time of punching processing and the time of packaging was not performed.

[Comparative example 2]

55.0 parts of the acrylic adhesive solution used in the preparation of the patch of Example 2 above, 30.0 parts of the above-mentioned isopropyl myristate as an organic liquid component, 10.0 parts of the above-mentioned polyvinylpyrrolidone, and the above-mentioned bisoprolol (Free body) 5.0 parts were mixed to prepare a viscous ethyl acetate solution of the adhesive composition. The obtained solution was coated on a release liner (thickness 75 μm) made of polyethylene terephthalate (PET) so that the thickness after drying was 45 μm, and it was dried in a hot air circulation dryer at 100 °C for 5 minutes to form an adhesive layer. This pressure-sensitive adhesive layer was attached to the nonwoven fabric side of a support body of a laminated film of a PET film and a PET nonwoven fabric (weight per unit area=12 g/m ² ) having a thickness of 2 μm, and punched out to 36 cm ² (6 cm x 6 cm), and pressurize the periphery of the patch in the same manner as in Example 1 above to obtain a bisoprolol-containing patch.

The obtained bisoprolol-containing patch was packaged by dry lamination in a packaging material obtained by laminating PET film (thickness = 12 μm) / aluminum foil (thickness = 9 μm) / acrylonitrile-based resin film (thickness = 30 μm). Sealing was performed to obtain a bisoprolol-containing patch package (9 cm×9 cm).

In addition, in the manufacturing process of the bisoprolol-containing patch of this comparative example, the adjustment of the moisture content of the patch at the time of punching processing and the time of packaging was not performed.

[Test Example 1] Moisture content of adhesive layer

In an environment controlled to a temperature of 23 ± 2°C and a relative humidity of 40 ± 5%, the packages of the above-mentioned examples and comparative examples were unsealed, and each patch containing bisoprolol that was taken out was punched out into ^7.5cm2 , so as to produce a test piece. Then, the release liner was removed from the test piece, and then it was put into a moisture vaporizer. It should be noted that the above treatment is completed within 1 minute after the package is unsealed.

The test piece was heated at 140°C in the moisture vaporization device, and the resulting moisture was introduced into the titration flask with nitrogen as a carrier, and the moisture content of the adhesive layer was measured by Karl Fischer coulometric titration (the weight of moisture) Ratio (ppm) relative to the total weight of the adhesive layer).

[Test Example 2] Stability of Bisoprolol

The packages of Examples 1, 2 and Comparative Examples 1, 2 were stored in a thermostat controlled at 50±5° C. for one month. From the patches before storage and after one month of storage, the patches of Example 1 were extracted with tetrahydrofuran, and the patches of Example 2, Comparative Examples 1 and 2 were extracted with methanol, and were analyzed by high performance liquid chromatography (HPLC). The resulting extract was analyzed. For the related substances detected in HPLC and presumed to be generated by the decomposition or modification of bisoprolol, the area ratio of the total peak area of the above-mentioned related substances to the peak area of bisoprolol is calculated, expressed as related substances content(%).

(Measurement conditions of HPLC)

Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm is filled with octyl silylated silica gel for liquid chromatography with a particle size of 3 μm

Column temperature: 40°C

mobile phase:

Mobile phase A (phosphate buffer (pH2.5))

Mobile phase B (phosphate buffer (pH2.5)/acetonitrile=1/4)

Elution conditions: Concentration gradient control by changing the mixing ratio of mobile phase A and mobile phase B

Flow rate: 1.2mL/min

Detector: UV spectrophotometer (wavelength: 225nm)

Table 1 shows the results of Test Examples 1 and 2.

[Table 1]

As shown in Table 1, for the patches of Examples 1 and 2 of the present invention, the moisture content of the adhesive layer is 395ppm and 6,740ppm respectively, and the content of related substances immediately after the preparation of the sample is as low as 0.5%. After being stored at 50° C. for one month, the content of related substances also remained at a level as low as below 1.0%.

On the other hand, in the patch preparations of Comparative Examples 1 and 2, the moisture content in the adhesive layer exceeded 10,000 ppm, and after storage at 50°C for one month, the content of related substances was 2.0% or more, showing that Bisoprolol has poor stability.

Although this invention was demonstrated in detail with reference to the specific aspect, it is clear for those skilled in the art that various changes and correction can be added without deviating from the mind and range of this invention.

In addition, this application is based on the Japanese patent application (Japanese Patent Application No. 2013-185598) for which it applied on September 6, 2013, The whole is taken in here by reference.

Industrial applicability

According to the present invention, it is possible to provide a device capable of suppressing hydrolysis of bisoprolol in an adhesive layer over time and improving stability and reliability over time even without using a desiccant when packaging a patch containing bisoprolol Patches containing bisoprolol. In addition, it is possible to provide a bisoprolol-containing patch package that is excellent in usability and portability.

Claims (8)

1. the patch containing bisoprolol, it has supporter and is formed in the adhesive phase containing bisoprolol at least one side of this supporter, and the moisture content of this adhesive phase is 10, below 000ppm.

2. the patch containing bisoprolol as claimed in claim 1, wherein, the moisture content of described adhesive phase is 200ppm ~ 10,000ppm.

3. the patch containing bisoprolol as claimed in claim 1 or 2, wherein, described adhesive phase contains one or more the binding agent in the group being selected from and being made up of acrylic adhesives and rubber adhesive.

4. the patch containing bisoprolol according to any one of claims 1 to 3, it also possesses the release liner on the adhesive surface being temporarily pasted onto described adhesive phase.

5. a package body for the patch containing bisoprolol, wherein, is sealed with the patch containing bisoprolol according to any one of Claims 1 to 4 in the bag of resistance to poisture-penetrability.

6. package body as claimed in claim 5, wherein, the mode that the described bag of resistance to poisture-penetrability is positioned at the adjacent side of the described patch containing bisoprolol with this vinyl cyanide resin bed by the packaging material that vinyl cyanide resin bed and impermeable stratum are laminated seals and obtains.

7. the package body as described in claim 5 or 6, wherein, does not enclose desiccant in the described bag of resistance to poisture-penetrability.

8. the package body according to any one of claim 5 ~ 7, wherein, the described bag of resistance to poisture-penetrability is formed by the packaging material not containing desiccant.