WO2015034051A1 - Patch adhésif contenant du bisoprolol et son emballge - Google Patents

Patch adhésif contenant du bisoprolol et son emballge Download PDF

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Publication number
WO2015034051A1
WO2015034051A1 PCT/JP2014/073505 JP2014073505W WO2015034051A1 WO 2015034051 A1 WO2015034051 A1 WO 2015034051A1 JP 2014073505 W JP2014073505 W JP 2014073505W WO 2015034051 A1 WO2015034051 A1 WO 2015034051A1
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WO
WIPO (PCT)
Prior art keywords
bisoprolol
pressure
sensitive adhesive
adhesive layer
patch preparation
Prior art date
Application number
PCT/JP2014/073505
Other languages
English (en)
Japanese (ja)
Inventor
準 石倉
和宏 青柳
智 雨山
直子 漆原
智也 田中
中村　哲也
Original Assignee
日東電工株式会社
トーアエイヨー株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 日東電工株式会社, トーアエイヨー株式会社 filed Critical 日東電工株式会社
Priority to KR1020167005441A priority Critical patent/KR20160049532A/ko
Priority to CN201480048897.3A priority patent/CN105517543A/zh
Publication of WO2015034051A1 publication Critical patent/WO2015034051A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/10—Bag-type containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/16—Holders for containers

Definitions

  • the present invention relates to a patch preparation containing bisoprolol and a package thereof.
  • a patch preparation in which an adhesive sheet containing the drug is applied to the skin has been adopted.
  • 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 a release liner. It is covered.
  • a patch preparation is individually packaged with a packaging material that is impermeable to moisture in order to prevent volatilization of contained transdermal drug and the influence of humidity.
  • Bisoprolol a highly selective sympathetic ⁇ 1 receptor antagonist ( ⁇ -blocker), is used to improve essential hypertension, angina pectoris, and arrhythmias, and its fumarate is administered orally as a tablet. ing.
  • ⁇ -blocker highly selective sympathetic ⁇ 1 receptor antagonist
  • Patent Document 1 discloses that the patch preparation is contained in a packaging bag in order to suppress the hydrolysis reaction of bisoprolol and improve its storage stability, and at 25 ° C. inside the packaging bag.
  • a packaging bag containing a patch preparation in which the relative humidity is maintained at 25% or less is disclosed.
  • the packaging bag requires a desiccant, is bulky when a package is formed, and is inconvenient to carry and use.
  • Patent Document 2 discloses a patch preparation in which the moisture content of the pressure-sensitive adhesive layer is 1,000 ppm to 8,000 ppm for the purpose of preventing the pressure-sensitive adhesive layer from being colored and suppressing the degradation of donepezil release. ing.
  • the above-mentioned patent document does not suggest improvement of the temporal stability of bisoprolol contained in the patch preparation, nor does it suggest any possibility of application to the bisoprolol-containing patch preparation.
  • the inventors have found that the stability of bisoprolol over time has a significant correlation with the moisture content.
  • the present inventors have found that by controlling the water content of the pressure-sensitive adhesive layer appropriately, the hydrolysis reaction over time of bisoprolol can be suppressed without using a desiccant when packaging a bisoprolol-containing patch preparation. It came to do.
  • the present invention is as follows.
  • a bisoprolol-containing patch preparation comprising a support and a pressure-sensitive adhesive layer containing bisoprolol formed on at least one surface thereof, wherein the water content of the pressure-sensitive adhesive layer is 10,000 ppm or less.
  • the moisture-permeable bag is a packaging material in which an acrylonitrile-based resin layer and a moisture-impermeable layer are laminated, and the acrylonitrile-based resin layer is positioned on the proximal side of the bisoprolol-containing patch preparation.
  • the package according to (5) which is hermetically sealed.
  • the time-dependent hydrolysis of bisoprolol in the pressure-sensitive adhesive layer can be suppressed without using a desiccant when packaging a bisoprolol-containing patch preparation, so that the stability and reliability with time are improved.
  • a bisoprolol-containing patch preparation can be realized, and a package of a bisoprolol-containing patch preparation excellent in usability and portability can be provided. This increases the patient's quality of life (QOL) and economics.
  • the bisoprolol-containing patch preparation of the present invention has a support and a pressure-sensitive adhesive layer containing bisoprolol formed on at least one side of the support.
  • the bisoprolol-containing patch preparation of the present invention may be referred to as “the patch preparation of the present invention” or simply “the patch preparation”.
  • the support that can be used in the present invention is not particularly limited, but a material that is substantially impermeable to drugs or the like, that is, a component contained in an adhesive layer such as an active ingredient bisoprolol or an additive. Those that pass through the support and are lost from the back are not preferred.
  • polyester, polyamide, polyvinylidene chloride, polyethylene, polypropylene, polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, ionomer resin, a single film such as a metal foil, or a laminate thereof A film or the like can be used.
  • the thickness of the support is usually 5 ⁇ m to 500 ⁇ m, preferably 10 ⁇ m to 200 ⁇ m.
  • the support in order to improve the adhesion (throwing property) between the support and the pressure-sensitive adhesive layer, is preferably a laminated film of a nonporous plastic film made of the above material and a porous film. . In this case, it is desirable to form the pressure-sensitive adhesive layer on the porous film side.
  • porous film one that improves anchoring property with the pressure-sensitive adhesive layer is adopted, and specifically, paper, woven fabric, non-woven fabric, knitted fabric, a mechanically perforated sheet, and the like are mentioned. It is done. Among these, paper, woven fabric, and non-woven fabric are particularly preferable from the viewpoint of handleability and the like.
  • a porous film having a thickness in the range of 10 ⁇ m to 200 ⁇ m is preferably used from the viewpoints of improvement of anchoring property, flexibility of the whole patch preparation, sticking operability, and the like.
  • a thin patch preparation such as a plaster type or an adhesive tape type
  • one having a thickness in the range of 10 ⁇ m to 100 ⁇ m is preferably employed.
  • the basis weight thereof is preferably 5 g / m 2 to 30 g / m 2 , more preferably 6 g / m 2 to 15 g / m 2 .
  • the most preferable support is a non-woven fabric made of a polyester film (preferably polyethylene terephthalate film) having a thickness of 1.5 ⁇ m to 6 ⁇ m and a polyester (preferably polyethylene terephthalate) having a basis weight of 6 g / m 2 to 15 g / m 2. And a laminated film.
  • the pressure-sensitive adhesive layer contains bisoprolol.
  • Bisoprolol is already marketed as an oral preparation, and in the case of a tablet, it is contained in the form of a salt such as bisoprolol fumarate.
  • bisoprolol can be contained in the adhesive layer not only in the free form (free base) but also in the form of a pharmaceutically acceptable salt. From the viewpoint of skin permeability, it is desirable that bisoprolol is contained in the pressure-sensitive adhesive layer as a free body.
  • the content of bisoprolol in the patch preparation of the present invention is preferably 0.5% to 40% by weight and more preferably 0.5% to 30% by weight based on the total weight of the pressure-sensitive adhesive layer in free form. % By weight.
  • the content of bisoprolol is 0.5% by weight or more, a therapeutically effective drug release can be expected.
  • the content of bisoprolol is 40% by weight or less, a sufficient therapeutic effect is obtained and economically advantageous, and when it is 30% by weight or less, it is more advantageous in terms of economics. .
  • the pressure-sensitive adhesive forming the pressure-sensitive adhesive layer is preferably a hydrophobic pressure-sensitive adhesive in order to control the moisture content of the pressure-sensitive adhesive layer and from the viewpoint of skin adhesiveness. It is preferable to form a layer.
  • the acrylic pressure-sensitive adhesive is preferable from the viewpoint of moisture permeability and drug solubility.
  • the acrylic pressure-sensitive adhesive is preferably 30% by weight to 75% by weight, more preferably 35% by weight to 70% by weight with respect to the total weight of the pressure-sensitive adhesive layer in order to give sufficient adhesiveness to the pressure-sensitive adhesive layer.
  • acrylic pressure-sensitive adhesive examples include acrylic acid-based pressure-sensitive adhesives mainly composed of a polymer containing (meth) acrylic acid alkyl ester having 2 to 18 carbon atoms in the alkyl group as a first monomer.
  • acrylic polymer examples include homopolymers of (meth) acrylic acid alkyl esters or copolymers thereof.
  • the alkyl having 2 to 18 carbon atoms in the (meth) acrylic acid alkyl ester is preferably a linear or branched alkyl having 4 to 12 carbon atoms.
  • the (meth) acrylic acid alkyl ester examples include (meth) acrylic acid butyl ester, (meth) acrylic acid t-butyl ester, (meth) acrylic acid pentyl ester, (meth) acrylic acid hexyl ester, (Meth) acrylic acid heptyl ester, (meth) acrylic acid octyl ester, (meth) acrylic acid isooctyl ester, (meth) acrylic acid nonyl ester, (meth) acrylic acid isononyl ester, (meth) acrylic acid decyl ester, Examples include (meth) acrylic acid undecyl ester, (meth) acrylic acid dodecyl ester, (meth) acrylic acid 2-ethylhexyl ester, and the like.
  • the (meth) acrylic acid alkyl ester is contained in the monomer component to be polymerized in a proportion of preferably 50% by weight or more, more preferably 60% by weight or more.
  • the acrylic polymer may be a copolymer polymerized by containing a second monomer copolymerizable with the (meth) acrylic acid alkyl ester, and the second monomer.
  • Examples of the body include monomers having a functional group that can serve as a crosslinking point when a crosslinking agent is used.
  • monomers having neither a carboxyl group nor a sulfonyl group such as hydroxyethyl (meth) acrylate (for example, 2-hydroxyethyl (meth) acrylate), hydroxypropyl (meth) acrylate, glycidyl (meth) acrylate Ethylene glycol diacrylate, hydroxyethyl (meth) acrylamide and the like; monomers having a carboxyl group, such as (meth) acrylic acid, itaconic acid, maleic acid, mesaconic acid, citraconic acid, glutaconic acid and the like. These 2nd monomers can be used 1 type or in combination of 2 or more types.
  • a polymer obtained by containing a third monomer in addition to the second monomer may be used.
  • These third monomers can be used for adjusting the cohesive force of the pressure-sensitive adhesive layer and adjusting the solubility and release of bisoprolol.
  • the third monomer include vinyl esters such as vinyl acetate and vinyl propionate; vinyl ethers such as methyl vinyl ether and ethyl vinyl ether; vinyl amides such as N-vinyl-2-pyrrolidone and N-vinyl caprolactam.
  • These third monomers can be used alone or in combination of two or more.
  • a first monomer particularly 2-ethylhexyl acrylate
  • a second monomer particularly acrylic acid
  • a copolymer obtained by blending a third monomer particularly N-vinyl-2-pyrrolidone in a weight ratio of about 40 to 99.9: 0.1 to 10: 0 to 30 is preferable.
  • the acrylic pressure-sensitive adhesive may be subjected to physical crosslinking by radiation irradiation such as ultraviolet irradiation or electron beam irradiation, isocyanate compound such as trifunctional isocyanate, organic peroxide, organic metal salt, metal alcoholate, metal You may perform the chemical crosslinking process using various crosslinking agents, such as a chelate compound and a polyfunctional compound (Polyfunctional external crosslinking agent, multifunctional internal crosslinking monomers, such as diacrylate and dimethacrylate, etc.).
  • radiation irradiation such as ultraviolet irradiation or electron beam irradiation
  • isocyanate compound such as trifunctional isocyanate
  • organic peroxide organic metal salt
  • metal alcoholate metal You may perform the chemical crosslinking process using various crosslinking agents, such as a chelate compound and a polyfunctional compound (Polyfunctional external crosslinking agent, multifunctional internal crosslinking monomers, such as diacrylate and dimethacrylate, etc.).
  • the rubber-based pressure-sensitive adhesive has particularly high drug release properties from the pressure-sensitive adhesive layer containing the pressure-sensitive adhesive, and it is easy to control the drug release, and there is no possibility that a reactive functional group remains. This is advantageous because of its high stability.
  • the content of the rubber-based pressure-sensitive adhesive is preferably 15% by weight to 60% by weight and more preferably 15% by weight to 55% by weight with respect to the total weight of the pressure-sensitive adhesive layer.
  • the rubber-based pressure-sensitive adhesive is not particularly limited, and examples thereof include a rubber-based pressure-sensitive adhesive mainly composed of at least one selected from polyisobutylene, polyisoprene, butyl rubber, and styrene-diene-styrene copolymer.
  • polyisobutylene is preferably used from the viewpoint of high drug stability and achieving both necessary adhesive strength and cohesive strength.
  • polyisobutylene may be used alone or with a molecular weight of Two or more different polyisobutylenes may be used.
  • the content of 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 pressure-sensitive adhesive layer. % By weight. If the content of polyisobutylene relative to the total weight of the pressure-sensitive adhesive layer is less than 15% by weight, it may be difficult to impart the necessary internal cohesive force to the pressure-sensitive adhesive layer, while if it exceeds 60% by weight, the pressure-sensitive adhesive There is a risk that the skin adhesion and tack of the layer may be reduced.
  • the molecular weight of polyisobutylene is not particularly limited, but the viscosity average molecular weight is preferably 40,000 to 5,500,000, and 45,000 to More preferably, it is 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.
  • polyisobutylene having different molecular weights it is preferable to contain two or more types of polyisobutylene having different molecular weights in order to easily achieve appropriate cohesion, moderate flexibility and skin adhesiveness.
  • 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. Therefore, “two or more polyisobutylenes having different molecular weights” contain, for example, two or more polyisobutylenes having different viscosity average molecular weights.
  • the polyisobutylene is preferably composed of, for example, a first polyisobutylene and a second polyisobutylene having a molecular weight relatively lower than that of the first polyisobutylene.
  • the first polyisobutylene can impart an appropriate cohesive force to the pressure-sensitive adhesive layer, and the second polyisobutylene can provide an appropriate flexibility 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 skin adhesion and sufficient release of bisoprolol,
  • the viscosity average 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.
  • 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 lowered. Further, if the viscosity average molecular weight of the second polyisobutylene is less than 40,000, the pressure-sensitive adhesive layer may feel sticky or may contaminate the skin surface, while if it exceeds 85,000, the pressure-sensitive adhesive. There is a risk that the skin adhesion and tack of the layer may be reduced.
  • the 1st and 2nd polyisobutylene can be used in combination of 2 or more type within the range of each molecular weight distribution.
  • the viscosity average molecular weight is a Staudinger index (J 0 ) calculated from the flow time at 20 ° C. of the capillary of the Ubbelohde viscometer by the Schulz-Blaschke equation (the following equation (1)), It refers to a value determined by the following equation (2) using the J 0 value.
  • the total content of polyisobutylene is preferably 15% by weight to 60% by weight, more preferably 15% by weight with respect to the total weight of the pressure-sensitive adhesive layer. % By weight to 55% 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 60% by weight, Tack may be reduced.
  • the blending weight ratio (a: b) of the first polyisobutylene (a) and the second polyisobutylene (b) is preferably The ratio is 1: 0.1 to 1: 3, more preferably 1: 0.1 to 1: 2.5, and still more preferably 1: 0.3 to 1: 2.
  • the blending weight ratio (b / a) of the second polyisobutylene (b) to the first polyisobutylene (a) exceeds 3
  • the internal cohesive force of the pressure-sensitive adhesive layer decreases.
  • it is less than 0.1 the skin adhesive force of the pressure-sensitive adhesive layer may be greatly reduced.
  • a tackifier known in the field of patch preparations.
  • tackifiers include petroleum resins (for example, aromatic petroleum resins and aliphatic petroleum resins), terpene resins, rosin resins, coumarone indene resins, styrene resins (for example, styrene resins, ⁇ -Methylstyrene resin), hydrogenated petroleum resin (for example, alicyclic saturated hydrocarbon resin) and the like.
  • alicyclic saturated hydrocarbon resins are preferable because the storage stability of bisoprolol is improved.
  • the tackifier can be used singly or in combination of two or more. When two or more types are used in combination, for example, resins having different types and softening points may be combined.
  • the content of the tackifier is preferably 10% to 55% by weight, more preferably 10% to 50% by weight, particularly preferably 10% to 45% by weight, based on the total weight of the pressure-sensitive adhesive layer. . If the content of the tackifier is less than 10% by weight, tack and cohesive force may be poor. On the other hand, if the content exceeds 55% by weight, the pressure-sensitive adhesive layer becomes hard and the skin adhesiveness tends to be lowered.
  • the softening point of the tackifier is preferably 90 ° C to 150 ° C, more preferably 95 ° C to 145 ° C.
  • the softening point in the present invention is a value measured by the ring and ball method.
  • the pressure-sensitive adhesive layer may contain an organic liquid component having fluidity at room temperature (25 ° C.).
  • the organic liquid component is a liquid organic component that is added in addition to the drug bisoprolol and is particularly compatible with other components of the pressure-sensitive adhesive layer (for example, pressure-sensitive adhesive, tackifier). It is not limited.
  • As the organic liquid 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. You may use an organic liquid component individually by 1 type or in combination of 2 or more types.
  • fatty acid alkyl ester examples include fatty acid alkyl esters formed from 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.
  • Preferred higher fatty acids include lauric acid (carbon number 12), myristic acid (carbon number 14), and palmitic acid (carbon number 16), and myristic acid is more preferable.
  • the monohydric alcohol include methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, and the like, preferably isopropyl alcohol. Therefore, isopropyl myristate is most preferable as the fatty acid alkyl ester, and by using this compound, absorption enhancement of bisoprolol, improvement in solubility, and drug utilization can be achieved at a high level.
  • Examples of the 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 preferable from the viewpoint of storage stability. used. Moreover, as said long chain alcohol, a linear or branched long chain alcohol is mentioned, These can be mixed and used. Examples of such linear alcohols include 1-dodecanol, 1-tetradecanol, 1-hexadecanol, stearyl alcohol, etc. Among them, 1-dodecanol is excellent in compatibility with polyisobutylene and stability of bisoprolol. Is preferable.
  • a branched long-chain alcohol having 16 to 28 carbon atoms preferably 18 to 24 carbon atoms
  • Specific examples include 2-hexyldecanol, isostearyl alcohol, 2-octyldodecanol, and 2-decyltetradecanol.
  • 2-octyldodecanol is excellent in compatibility with polyisobutylene and dissolves bisoprolol. It is preferable at the point which can improve property.
  • 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: 0.5, more preferably 1: 0.01 to 1: 0. .4, more preferably 1: 0.05 to 1: 0.4.
  • the organic liquid component often acts effectively as a permeation enhancer, and in that case, the skin permeability of bisoprolol is improved by increasing the content of the organic liquid component. That is, by containing a large amount of an organic liquid component in the pressure-sensitive adhesive layer, the composition has a higher skin permeability and can easily control the skin permeability. Therefore, it can be said to be an ideal pressure-sensitive adhesive composition as a patch preparation. Moreover, moderate softness
  • flexibility and skin adhesiveness can be provided to an adhesive layer by containing an organic liquid component in an adhesive layer.
  • the content of the organic liquid component is preferably 5% by weight to 70% by weight with respect to the total weight of the pressure-sensitive adhesive layer. More preferably, it is 10 wt% to 65 wt%, and further preferably 20 wt% to 50 wt%.
  • the pressure-sensitive adhesive layer comprises a liquid or paste-like organic component other than the above as necessary.
  • a dissolution aid can be blended.
  • Such a solubilizing agent has excellent compatibility with the pressure-sensitive adhesive, sufficiently dissolves bisoprolol, has a low risk of bleeding out of the pressure-sensitive adhesive layer (bleed), and does not adversely affect the adhesive properties and drug release properties. Anything is acceptable.
  • esters of fatty acids such as oleic acid, myristic acid and capric acid, organic acids such as dicarboxylic acids such as adipic acid and sebacic acid, and alcohols such as ethanol and 2-propanol; glycerin and propylene glycol Polyhydric alcohols such as diesters and triesters thereof; Esters of polyhydric alcohols and organic acids such as triacetin; Polyethers such as polyethylene glycol, polypropylene glycol, polyoxyethylene hydrogenated castor oil; Other crotamitons, etc. Is mentioned.
  • an appropriate filler can be contained in the pressure-sensitive adhesive layer as desired.
  • 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.
  • an appropriate softening agent or tack can be imparted to the pressure-sensitive adhesive layer by adding an appropriate softening agent to the pressure-sensitive adhesive layer.
  • the softening agent 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 organic liquid components.
  • 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.
  • the first polyisobutylene when used as the pressure-sensitive adhesive, it becomes possible to contain a large amount of an organic liquid component. As a result, the effect of promoting the absorption of the drug by the organic liquid component and the effect of improving the solubility are sufficient. Can get to. As a result, it is possible to suppress a reduction in cohesive force and to obtain a patch preparation with no adhesive residue or the like. Further, by using a tackifier that is higher in the temperature range of the softening point described above, not only the cohesive force but also the skin adhesion can be improved at the same time.
  • the thickness of the pressure-sensitive adhesive layer is usually 10 ⁇ m to 300 ⁇ m, preferably 10 ⁇ m to 250 ⁇ m, and more preferably 15 ⁇ m to 250 ⁇ m.
  • the moisture content of the pressure-sensitive adhesive layer is 10,000 ppm or less, preferably 200 ppm to 10,000 ppm.
  • the lower limit value of the preferable range of the moisture content of the pressure-sensitive adhesive layer is, for example, 200 ppm, 300 ppm, 400 ppm, 500 ppm, 600 ppm, 700 ppm, 800 ppm, 900 ppm, 1,000 ppm from the viewpoint of the possibility of moisture control during the manufacture of the patch preparation. 1,500 ppm, 2,000 ppm, 2,500 ppm, 3,000 ppm, 3,500 ppm or 4,000 ppm.
  • the upper limit value of the preferable moisture content of the pressure-sensitive adhesive layer is, 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, 6,000 ppm, 5,500 ppm or 5,000 ppm.
  • the moisture content of the pressure-sensitive adhesive layer means the ratio of the weight of water contained in the pressure-sensitive adhesive layer (the ratio of the weight of water to the total weight of the pressure-sensitive adhesive layer) measured by the Karl Fischer coulometric titration method. In this specification, it is a value measured under the measurement conditions described in the examples described later.
  • the moisture content of the adhesive layer of the patch preparation varies depending on the relative humidity of the external environment (atmosphere) and converges to the equilibrium moisture content at that temperature and humidity with the passage of time. That is, when the relative humidity in the external environment (atmosphere) is high, the pressure-sensitive adhesive layer absorbs and 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 moisture content of the pressure-sensitive adhesive layer decreases due to the suppression of moisture adsorption to the pressure-sensitive adhesive layer and the release of moisture from the pressure-sensitive adhesive layer. .
  • the moisture content of the pressure-sensitive adhesive layer can be controlled by adjusting the temperature and / or relative humidity of the external environment (atmosphere).
  • adjustment of the temperature and relative humidity of the external environment (atmosphere) can be appropriately performed with a known air conditioner.
  • the atmosphere of the punching process and the packaging stage is maintained at a temperature of 20 ⁇ 10 ° C. and a relative humidity of 30 ⁇ 10%.
  • the water content of the pressure-sensitive adhesive layer can be controlled within the above range.
  • a release liner may be laminated on the adhesive surface in order to protect the adhesive surface of the adhesive layer until use.
  • the release liner is not particularly limited.
  • polyester, polyvinyl chloride, which has been subjected to an easy release treatment by applying a silicone resin, a fluorine resin, or the like to the contact surface with the pressure-sensitive adhesive layer A film such as polyvinylidene chloride and polyethylene terephthalate, paper such as high-quality paper and glassine paper, or a laminate film of high-quality paper or glassine paper and polyolefin is used.
  • the thickness of the release liner is preferably 10 ⁇ m to 200 ⁇ m, more preferably 25 ⁇ m to 150 ⁇ m.
  • the release liner is preferably made of a polyester (particularly, polyethylene terephthalate) resin from the viewpoint of barrier properties, cost, and the like. Further, in this case, those having a thickness of about 25 ⁇ m to 100 ⁇ m are preferable from the viewpoint of handleability.
  • the shape of the patch preparation of the present invention is not particularly limited and includes, for example, a tape shape and a sheet shape.
  • the adhesive preparation of the present invention is prepared by, for example, dissolving a pressure-sensitive adhesive composition containing a pressure-sensitive adhesive, bisoprolol, if necessary, a tackifier, an organic liquid component, etc. in an appropriate solvent such as toluene, and applying the obtained solution onto a release liner. It can be produced by drying, forming a pressure-sensitive adhesive layer, and laminating a support on the pressure-sensitive adhesive layer.
  • the pressure-sensitive adhesive solution can be directly applied to a support and dried to form a pressure-sensitive adhesive layer on the support.
  • the patch preparation of the present invention is preferably enclosed in a moisture-permeable bag until use and stored or transported as a package.
  • a method for forming such a package for example, there is a method in which a single patch preparation or a plurality of patch preparations are packaged with a packaging material constituting a moisture-permeable bag body and the periphery is sealed by heat sealing.
  • the packaging material include a sheet-like or film-like material. From the viewpoints of controlling the moisture content of the pressure-sensitive adhesive layer, ease of packaging, and airtightness, the packaging material exhibits moisture impermeability and can be heat-sealed. Is desirable.
  • a plastic sheet having heat sealing properties such as polyethylene, ionomer resin, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, polyacrylonitrile copolymer, polyvinyl alcohol copolymer, It is preferable to use a packaging material in which a gas or moisture impermeable film such as a polyester film or a metal foil is laminated.
  • a gas or moisture impermeable film By using a gas or moisture impermeable film, the moisture content of the pressure-sensitive adhesive layer can be controlled as described above without having to enclose the desiccant in the package or containing the desiccant in the packaging material itself. it can.
  • the packaging material one having a thickness of 10 ⁇ m to 200 ⁇ m is usually used.
  • an acrylonitrile-based resin having a high barrier property is used for the innermost layer (the layer located on the proximal side of the bisoprolol-containing patch preparation when the bisoprolol-containing patch preparation is sealed in a moisture-permeable bag). More preferred.
  • the acrylonitrile-based resin is preferably a copolymer having acrylonitrile as a main structural unit from the viewpoint of uniformity of properties of the acrylonitrile-based resin layer, and the copolymer has at least acrylonitrile, butadiene, etc. as the structural unit.
  • the rubber component and / or a copolymer containing an alkyl (meth) acrylic acid alkyl ester having 1 to 6 carbon atoms is preferable.
  • the content of acrylonitrile is preferably 50% by weight to 90% by weight, and particularly preferable copolymer is 50% by weight to 90% by weight of acrylonitrile, and 2% by weight of a rubber component such as butadiene.
  • It is a copolymer obtained by copolymerizing a monomer component having a composition of ⁇ 12 wt% and (meth) acrylic acid alkyl ester having an alkyl group having 1 to 6 carbon atoms of 8 wt% to 38 wt%.
  • the copolymer may be in random copolymerization, block copolymerization, or graft copolymerization, but is characterized by the characteristics of polyacrylonitrile having excellent non-adsorptivity to physiologically active components and rubber having excellent shock absorption.
  • a graft copolymerization form capable of efficiently having the characteristics of the components is preferable, and random copolymerization or block copolymerization may be appropriately added as long as the characteristics are not inhibited.
  • composition analysis of the acrylonitrile-type resin in this invention is based on the following method. That is, the CHN elemental analysis is performed on the sample obtained by scraping the acrylonitrile-based resin layer from the packaging material, and the acrylonitrile content is calculated from the nitrogen content. Further, according to the spectra of 1 H-NMR and 13 C-NMR (in heavy dimethyl sulfoxide (DMSO), 80 ° C.), the rubber component and the molecule of the (meth) acrylic acid alkyl ester component in which the alkyl group has 1 to 6 carbon atoms The structure and weight ratio are determined, and the weight ratio of the three components is determined.
  • DMSO heavy dimethyl sulfoxide
  • the thickness of the acrylonitrile-based resin layer is appropriately set according to the type of the patch preparation, and is not particularly limited. However, the non-permeability and non-adsorption property to the physiologically active ingredient in the patch preparation are satisfactorily exhibited, and moisture From the viewpoint of ensuring appropriate flexibility and rigidity as a packaging material for a patch preparation while having impermeability, it is preferably 5 ⁇ m to 100 ⁇ m, more preferably 5 ⁇ m to 80 ⁇ m, and most preferably 5 ⁇ m to 50 ⁇ m.
  • the adhesive component flows out from the side of the patch preparation, there is a concern that the handling properties such as removal from the package may deteriorate, so embossing may be applied to the packaging material or the aforementioned release liner part may be applied. It is preferable to devise packaging forms such as dry edge processing that is slightly larger than the preparation body, or blister molding that is processed so that the contact area is small.
  • the patch preparation of the present invention can be used by taking out the patch preparation by tearing the above-mentioned package immediately before use, etc., peeling off the release liner and sticking the exposed adhesive surface to the skin surface.
  • the usage of the patch preparation of the present invention varies depending on the age, weight, symptoms, etc. of the patient.
  • the application area of the patch preparation of the present invention can be considered in order to achieve administration of an effective amount of bisoprolol while adopting the maximum value of the permeation rate of bisoprolol described above to human skin.
  • the patch area of the patch preparation is preferably 3 cm 2 to 50 cm 2 , more preferably 3 cm 2 to 48 cm 2 , still more preferably 4 cm 2 to 45 cm 2 . If the application area of the patch preparation is smaller than 3 cm 2 , the application operation may be difficult, and if it is larger than 50 cm 2 , the patient may be stressed at the time of application. When a strong medicinal effect is required, two or more sheets can be attached simultaneously.
  • the maximum value of bisoprolol release rate immediately after skin application until 24 hours is 30 ⁇ g / cm 2 / hour or less, and the bisoprolol release rate after 24 hours after skin application is 10 ⁇ g / cm. 2 / hour or less.
  • part or % means “part by weight” or “% by weight”.
  • alicyclic saturated hydrocarbon resin tackifier
  • the obtained solution was applied on a polyethylene terephthalate (PET) release liner (thickness 75 ⁇ m) so that the thickness after drying was 160 ⁇ m, and this was applied at 100 ° C. for 5 minutes in a hot air circulating dryer. It dried and the adhesive layer was formed.
  • the peripheral part of the patch preparation was pressurized (4.9 MPa) to obtain a bisoprolol-containing patch preparation.
  • the moisture content of the layer was adjusted.
  • Example 2 Under an inert gas atmosphere, 70.0 parts of 2-ethylhexyl acrylate, 5.0 parts of hydroxyethylacrylamide, and 25.0 parts of N-vinyl-2-pyrrolidone, and azobisisobutyronitrile as a polymerization initiator An acrylic pressure-sensitive adhesive solution was prepared by solution polymerization of 0.2 parts in ethyl acetate at 60 ° C. 65.0 parts of this acrylic pressure-sensitive adhesive solution, 30.0 parts of isopropyl myristate as an organic liquid component, and 5.0 parts of bisoprolol (free body) are mixed, and a viscous ethyl acetate solution of the pressure-sensitive adhesive composition is mixed. Prepared.
  • the obtained solution was applied on a polyethylene terephthalate (PET) release liner (thickness 75 ⁇ m) so that the thickness after drying was 45 ⁇ m, and this was applied in a hot air circulating dryer at 100 ° C. for 5 minutes. It dried and formed the adhesive layer.
  • the moisture content of the layer was adjusted.
  • the peripheral part of the patch preparation was pressurized in the same manner as in Example 1 to obtain a bisoprolol-containing patch preparation.
  • the water content of the patch preparation during punching and packaging was not adjusted.
  • the obtained solution was applied on a polyethylene terephthalate (PET) release liner (thickness 75 ⁇ m) so that the thickness after drying was 45 ⁇ m, and this was applied in a hot-air circulating dryer at 100 ° C. for 5 minutes. It dried and the adhesive layer was formed.
  • PET polyethylene terephthalate
  • the peripheral part of the patch preparation was pressurized in the same manner as in Example 1 to obtain a bisoprolol-containing patch preparation.
  • the water content of the patch preparation during punching and packaging was not adjusted.
  • Test Example 1 Moisture content of pressure-sensitive adhesive layer Each bisoprolol taken out of the package of each of the above Examples and Comparative Examples in an environment controlled at a temperature of 23 ⁇ 2 ° C and a relative humidity of 40 ⁇ 5% Each of the contained patch preparations was punched out to 7.5 cm 2 to prepare a test piece. Thereafter, the release liner was removed from the test piece and put into a moisture vaporizer. In addition, said process was completed within 1 minute after opening of a package. The test piece was heated at 140 ° C.
  • Table 1 shows the results of Test Examples 1 and 2.
  • the moisture content of the pressure-sensitive adhesive layer was 395 ppm and 6,740 ppm, respectively, and the content of related substances immediately after sample preparation was 0.5%.
  • the content of related substances was maintained at a low level of 1.0% or less even after storage at 50 ° C. for 1 month.
  • the moisture content in the pressure-sensitive adhesive layer exceeds 10,000 ppm, and after storing at 50 ° C. for 1 month, the content of related substances is 2.0%. This is the result, indicating that the stability of bisoprolol in the patch preparation is poor.
  • the packaging body of the bisoprolol containing medicated patch excellent in usability and portability can be provided.

Abstract

Cette invention concerne : un patch adhésif contenant du bisoprolol qui comprend un corps formant support et une couche adhésive qui est formée sur au moins une surface du corps formant support et contient du bisoprolol, la couche adhésive ayant une teneur en humidité de 10 000 ppm ou moins ; et un emballage de patch adhésif contenant du bisoprolol, qui est obtenu par scellage du patch adhésif contenant du bisoprolol dans un sachet manifestant une résistance à la perméation de vapeur d'eau. Le patch adhésif contenant du bisoprolol selon l'invention permet d'obtenir une excellente stabilité à long terme du bisopropol qui est contenu dans la couche adhésive. De plus, le patch adhésif contenant du bisoprolol selon l'invention offre une excellent facilité d'utilisation et portabilité.
PCT/JP2014/073505 2013-09-06 2014-09-05 Patch adhésif contenant du bisoprolol et son emballge WO2015034051A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1020167005441A KR20160049532A (ko) 2013-09-06 2014-09-05 비소프롤롤 함유 부착 제제 및 그 포장체
CN201480048897.3A CN105517543A (zh) 2013-09-06 2014-09-05 含有比索洛尔的贴剂及其包装体

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JP2013185598A JP2015051947A (ja) 2013-09-06 2013-09-06 ビソプロロール含有貼付製剤およびその包装体
JP2013-185598 2013-09-06

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KR (1) KR20160049532A (fr)
CN (1) CN105517543A (fr)
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JP6654365B2 (ja) * 2015-06-17 2020-02-26 日東電工株式会社 貼付製剤

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10505342A (ja) * 1994-08-27 1998-05-26 エルティーエス ローマン テラピイー システム ゲーエムベーハー 加水分解に対する保護を備えた経皮性治療システム
WO2005072716A1 (fr) * 2004-01-30 2005-08-11 Hisamitsu Pharmaceutical Co., Inc. Sachet d'emballage contenant du plâtre
JP2007099759A (ja) * 2005-09-09 2007-04-19 Nitto Denko Corp ビソプロロール含有貼付製剤

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Publication number Priority date Publication date Assignee Title
CN101262858B (zh) * 2005-09-09 2014-04-09 日东电工株式会社 含有比索洛尔的胶粘药物制剂
US8703178B2 (en) * 2007-03-08 2014-04-22 Nitto Denko Corporation Percutaneous administration device of bisoprolol
WO2009145177A1 (fr) * 2008-05-30 2009-12-03 日東電工株式会社 Préparation de patch contenant du donézépil et conditionnement
JP5776079B2 (ja) * 2010-02-26 2015-09-09 日東電工株式会社 ビソプロロール含有貼付製剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10505342A (ja) * 1994-08-27 1998-05-26 エルティーエス ローマン テラピイー システム ゲーエムベーハー 加水分解に対する保護を備えた経皮性治療システム
WO2005072716A1 (fr) * 2004-01-30 2005-08-11 Hisamitsu Pharmaceutical Co., Inc. Sachet d'emballage contenant du plâtre
JP2007099759A (ja) * 2005-09-09 2007-04-19 Nitto Denko Corp ビソプロロール含有貼付製剤

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JP2015051947A (ja) 2015-03-19

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