JPWO2008075665A1 - Transdermal absorption preparation and adhesive sheet for skin application - Google Patents

Abstract

The present invention relates to a skin patch having a pressure-sensitive adhesive composition layer formed on a support, the pressure-sensitive adhesive composition layer comprising a polyether polymer having a siloxane bond, and at least one pressure-sensitive adhesive composition layer. The present invention relates to a transdermally absorbable preparation characterized by containing a physiologically active substance. In particular, the pressure-sensitive adhesive composition layer is (A) a polyether polymer having at least one alkenyl group at the terminal, (B) a compound having 1 to 10 hydrosilyl groups in the molecule, (C) The present invention relates to a percutaneous absorption preparation obtained by curing a pressure-sensitive adhesive composition comprising a hydrosilylation catalyst. According to the present invention, the skin irritation is small as compared with conventional transdermal absorption preparations, wettability to skin, familiarity, sufficient adhesion to the skin, and sufficient amount of physiological activity. Provide a transdermally absorbable preparation that can contain a substance and has a good release of a physiologically active substance

Description

  The present invention relates to a treatment for a diseased part of the body or a transdermal absorption preparation for administering a physiologically active substance to the circulatory system or skin, and an adhesive sheet applied to the skin surface for use in protecting or treating the skin surface. More specifically, the present invention relates to a transdermally absorbable preparation excellent in solubility, skin adhesive properties and skin fixability of a physiologically active substance regardless of the type of the physiologically active substance.

  In recent years, percutaneous absorption preparations aimed not only at the skin disease site but also for systemic action have been remarkably developed based on the concept of drug delivery systems, and in particular, their usefulness as sustained-release preparations has been recognized. Conventionally, as this type of transdermally absorbable preparation, one in which an adhesive polymer layer containing a physiologically active substance is provided on a physiologically active substance-impermeable support is known, and is applied to the body surface. In this way, a physiologically active substance is administered to a diseased part or circulatory system of the body.

  As an adhesive base for this transdermally absorbable preparation, one having high safety, good balance of adhesive properties, and good release of a physiologically active substance is required. In particular, in a percutaneous absorption preparation intended for systemic action, it is known that release of a physiologically active substance from a carrier for holding a physiologically active substance is an important factor. As an adhesive composition layer of a transdermally absorbable preparation, an acrylic adhesive is used and a transdermal absorption accelerator is added or the skeleton is modified (Patent Document 1). There is a problem with safety such as irritation becoming stronger. As a base for transdermally absorbable preparations, silicone elastomers are particularly safe and are known to be effective as bases for implantable preparations and transdermally absorbable preparations (Patent Document 2). However, the silicone-based pressure-sensitive adhesive has a problem that the solubility of the physiologically active substance is low and a necessary amount of the physiologically active substance cannot be maintained.

  On the other hand, in addition to the above-mentioned percutaneous absorption preparation, as an adhesive sheet including a dressing used for protection or treatment of a skin damaged part, firstly, in order to prevent the skin from falling off, Skin adhesion is required, but the greater the skin adhesion, the stronger the physical irritation when peeling and removing from the skin surface, causing pain and exfoliation of the stratum corneum during peeling, There is a risk of damaging the user.

  As described above, it is necessary for a pressure-sensitive adhesive sheet for skin application to maintain a balance between skin adhesive force and skin irritation.

  Therefore, for the purpose of reducing this skin adhesive force, a method has been proposed in which a highly compatible oily liquid component is contained in the pressure-sensitive adhesive layer (for example, Patent Documents 3 and 4). This pressure-sensitive adhesive sheet gives a soft feeling to the pressure-sensitive adhesive layer, and improves the adhesion to the skin surface and the solubility of physiologically active substances, while the skin is stimulated by a soft pressure-sensitive adhesive layer during application to the skin surface. Can be reduced, and can be smoothly peeled off without causing keratinous damage during removal after use. However, since it is necessary to contain a relatively large amount of liquid component in order to give a soft feeling, the liquid component in the adhesive may bloom, and the skin irritation may be increased.

For administration of physiologically active substances to the skin such as the epidermis and dermis, creams, ointments and the like have been used as dosage forms (Patent Documents 5 and 6). Although it is well-familiar and has good contact efficiency with the skin, the content of bioactive substances and the amount of application on the skin (application thickness) are limited. There are problems such as stickiness due to smearing, and sticking to clothing and other things and not showing medicinal effects.
JP 2004-97730 A JP-A-60-169414 JP-A-3-220120 JP 2000-44904 A JP 56-150007 JP 58-103311

  The object of the present invention is that the skin irritation is small compared to conventional transdermal absorption preparations, the wettability and familiarity with the skin are good, the skin has sufficient adhesive force, and a sufficient amount of physiological It is an object of the present invention to provide a transdermally absorbable preparation which can contain an active substance and has a good bioactive substance release property. Another object of the present invention is to provide a pressure-sensitive adhesive sheet that reduces the amount of liquid component mixed, suppresses blooming of the organic liquid component, and reduces skin irritation caused by peeling and keratin peeling.

  As a result of intensive studies in view of such problems, the present invention has been completed. That is, the present invention is as follows.

  [1] In a skin patch in which a pressure-sensitive adhesive composition layer is formed on a support, the pressure-sensitive adhesive composition layer is made of a polyether polymer having a siloxane bond, and at least one of the pressure-sensitive adhesive composition layers is A transdermally absorbable preparation characterized by containing a physiologically active substance.

[2] In the percutaneous absorption preparation in which the pressure-sensitive adhesive composition layer is formed on the support, the pressure-sensitive adhesive composition layer (A) is a polyether polymer having at least one alkenyl group at the end,
(B) a compound having 1 to 10 hydrosilyl groups in the molecule,
(C) A transdermally absorbable preparation comprising a cured adhesive composition comprising a hydrosilylation catalyst, and containing a physiologically active substance in at least one of the adhesive composition layers.

  [3] The transdermally absorbable preparation of [1] or [2], wherein the pressure-sensitive adhesive composition layer contains (D) an organic liquid component.

  [4] The percutaneous absorption preparation according to any one of [1] to [3], wherein the pressure-sensitive adhesive composition layer contains a transdermal absorption enhancer.

  [5] The transdermally absorbable preparation of any one of [1] to [4], wherein the polyether polymer of the polymer (A) is polyoxypropylene.

  [6] Any one of [1] to [5], wherein the physiologically active substance is dissolved in the polymer (A), mixed with the compound (B) and the catalyst (C), and cured. A method for producing such a transdermally absorbable preparation.

  [7] The bioactive substance is dissolved in the organic liquid component (D), mixed with the polymer (A), the compound (B) and the catalyst (C), and then cured, [3 ] The manufacturing method of the transdermally absorbable preparation in any one of [5].

[8] A pressure-sensitive adhesive sheet for skin application in which a pressure-sensitive adhesive composition layer is formed on a support, wherein the pressure-sensitive adhesive composition layer (A) is a polyether-based polymer having at least one alkenyl group at its terminal. Compound (B) A compound having 1 to 10 hydrosilyl groups in the molecule (C) Hydrosilylation catalyst (D) A pressure-sensitive adhesive sheet for skin application formed by curing a mixture of organic liquid components.

  [9] In the adhesive sheet for skin application in which the adhesive composition layer is formed on the support, the total amount of hydroxyl groups of the compound (B) is 0.00 per mol of the total amount of alkenyl groups of the polymer (A). The pressure-sensitive adhesive sheet according to [8], having 4 to 4 moles of hydrosilyl group.

  [10] The pressure-sensitive adhesive sheet according to [8] or [9], wherein the polyether polymer of the polymer (A) is polyoxypropylene.

  [11] The pressure-sensitive adhesive sheet according to any one of [8] to [10], wherein the hydrosilylation catalyst (C) is a platinum-vinylsiloxane complex.

  [12] The pressure-sensitive adhesive sheet according to any one of [8] to [11], wherein the organic liquid component (D) is a fatty acid ester.

  [13] Any of [8] to [12], wherein the content ratio of the polymer (A) and the organic liquid component (D) is 1.0: 0.001 to 1.0: 1.5 Such an adhesive sheet.

  According to the transdermally absorbable preparation and the pressure-sensitive adhesive sheet of the present invention, the skin irritation is small compared to the conventional ones, the wettability and familiarity with the skin are good, the adhesive force is sufficient, and the skin for a long time. Fixing to is good. Moreover, according to the transdermally absorbable preparation of the present invention, a sufficient amount of physiologically active substance can be contained, and good release properties can be obtained.

  The present invention will be described in detail below.

  In the present invention, at least one pressure-sensitive adhesive composition layer is provided on a support.

  The support used in the transdermally absorbable preparation of the present invention is not particularly limited as long as it can hold the pressure-sensitive adhesive composition before curing, but the physiologically active substance contained in the pressure-sensitive adhesive composition is the support. Those which are lost from the back through the inside and do not cause a decrease in content are preferred. Specifically, urethane polymers such as polyether urethane, amide polymers such as polyether amide, acrylic polymers such as polyacrylate, olefin polymers such as polyethylene, polypropylene, and ethylene-vinyl acetate copolymer, polyethers Examples include ester polymers such as polyester. In addition, fluorine-based polymers such as polytetrafluoroethylene, silicon-based polymers such as polydimethylsiloxane and polydiphenylsiloxane, films such as polyvinyl chloride, polyvinylidene chloride, and polyvinyl alcohol, or foams obtained by foaming the above polymer materials A sheet, a nonwoven fabric, a metal foil, etc. can be illustrated.

  The support may be a single layer or a laminate composed of a plurality of layers, and in the case of a laminate, each layer may be made of the same material or different types of materials. For example, a film or nonwoven fabric having moisture permeability is preferably used. The thickness of the substrate is not particularly limited and can be appropriately selected depending on the purpose and application, and is exemplified by 10 to 5000 μm. When the thickness of the support is more than 5000 μm, the followability to the skin is lowered and the film is easily peeled off, which is not preferable because the physical irritation to the skin is increased. If the thickness of the support is less than 10 μm, it is not preferable from the viewpoint of durability. From the viewpoint of irritation to the skin and durability, it is preferably 10 to 2000 μm, more preferably 10 to 1000 μm.

  The pressure-sensitive adhesive composition laminated on the support is (A) a polyether polymer having at least one alkenyl group at the terminal, (B) a compound having 1 to 10 hydrosilyl groups in the molecule, ( C) A pressure-sensitive adhesive composition comprising a hydrosilylation catalyst is cured.

  The polymer (A) is a polyether polymer having at least one alkenyl group at the terminal. The alkenyl group is not particularly limited as long as it is a group containing a carbon-carbon double bond that is active for hydrosilylation reaction. The alkenyl group is preferably an aliphatic unsaturated hydrocarbon group having 2 to 20 carbon atoms, more preferably 2 to 6 carbon atoms (eg, vinyl group, allyl group, methylvinyl group, propenyl group, butenyl group, pentenyl group). Group, hexenyl group, etc.), preferably a cyclic unsaturated hydrocarbon group having 3 to 20 carbon atoms, more preferably 3 to 6 carbon atoms (eg, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, etc.) ), A methacryl group and the like.

Preferred alkenyl groups include those represented by the following formulas (1) and (2) because they can be easily synthesized. In the following formula, R ¹ and R ² are a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, preferably a hydrogen atom or a methyl group:
H ₂ C═C (R ¹ ) − (1)
^{HC (R 2) = CH- (} 2).

  The polymer (A) has an average of at least 1, preferably 1 to 5, more preferably 1 to 3, and still more preferably 1 to 2 alkenyl groups per molecule. Polymer (A) If the average number of alkenyl groups in one molecule is less than 1, the curability becomes insufficient, and if the number of alkenyl groups contained in one molecule is too large, the network structure becomes dense. For this reason, the adhesive properties tend to decrease.

As a typical example of the polyether polymer as the basic skeleton of the polymer (A), a general formula:
(-R ³ -O-)
The polyoxyalkylene type polymer which consists of a repeating unit represented by these is mentioned. Here, —R ³ — is a divalent alkylene group. Adhesive properties, skin irritation, the wettability to the skin, the main chain of the preferred polymer (A) is a polyoxypropylene (i.e., the -R ³ - is -CH ₂ CH (CH ₃₎ - is a) . Further, it is preferable from the viewpoint of workability in terms of availability. The polyether polymer may be composed of one type of repeating unit or may be composed of a plurality of repeating units. The polyether polymer may be a linear polymer or a branched polymer.

  All the parts other than the alkenyl group of the polymer (A) preferably comprise a polyether skeleton, but may contain other structural units. In that case, the total of the polyether skeleton in the polymer (A) is preferably 80% by weight or more, and more preferably 90% by weight or more.

  The molecular weight of the polymer (A) is preferably from 3,000 to 50,000, more preferably from 6,000 to 50,000, particularly preferably from 10,000 to 30,000 from the viewpoint of good workability at room temperature and obtaining good adhesive properties. When the number average molecular weight is less than 3,000, the obtained cured product tends to be brittle. Conversely, when the number average molecular weight exceeds 50,000, the viscosity tends to be high and workability tends to be lowered. The molecular weight is a polystyrene equivalent number average molecular weight measured by GPC. The bonding mode of the alkenyl group to the polyether polymer is not particularly limited, and examples thereof include a direct bond of an alkenyl group, an ether bond, an ester bond, a carbonate bond, a urethane bond, and a urea bond.

  The method for producing the polymer (A) is not particularly limited, and examples thereof include a method of introducing an alkenyl group after obtaining a polyether polymer. In this case, various known production methods can be applied to the polyether polymer, and a commercially available polyether polymer may be used. In addition, a method for introducing an alkenyl group into a polyether polymer is also known. For example, a monomer having an alkenyl group (eg, allyl glycidyl ether) and a monomer for synthesizing a polyether polymer are copolymerized. And a functional group that is reactive to the functional group into a polyether polymer in which a functional group (eg, hydroxyl group, alkoxide group) has been previously introduced into a desired portion (end of main chain, etc.) And a method of reacting a compound having both a group and an alkenyl group (eg, acrylic acid, methacrylic acid, vinyl acetate, acrylic acid chloride, etc.).

  The compound (B) is a compound having an average of two or more hydrosilyl groups in one molecule. The hydrosilyl group means a group having a Si—H bond. In the present invention, when two hydrogen atoms (H) are bonded to the same silicon atom (Si), it is calculated as two hydrosilyl groups. The chemical structure of the compound (B) other than the hydrosilyl group is not particularly limited. The number average molecular weight of the compound (B) calculated from the SiH value obtained by titration is preferably 400 to 3000, more preferably 500 to 1000. This is because if the number average molecular weight is too low, it tends to volatilize at the time of heat-curing, and it tends to be difficult to obtain a sufficient cured product, and if it is too high, the curing rate tends to be slow.

  The number of hydrosilyl groups contained in one molecule of the compound (B) is 1 to 10, preferably 2 to 8. If the average number of hydrosilyl groups is 2 or more, a plurality of polymer (A) molecules can be cross-linked during curing, exhibiting a cohesive force preferable as a percutaneous absorption preparation, and affixed to the skin and peeled off. It is difficult for glue residue to occur. However, if the number of hydrosilyl groups is too large, the cross-linking becomes too dense, and the adhesive physical properties such as skin adhesive strength and tackiness of the transdermally absorbable preparation tend to be lowered. In addition, the density of the crosslinking affects the density between the polyether parts as the main chain of the polymer (A), and further affects the moisture permeability of the entire transdermally absorbable preparation. Therefore, the number of hydrosilyl groups in the compound (B) should be selected in consideration of the balance with the adhesive properties. Moreover, a compound (B) may be used independently and may be used together 2 or more types.

  The compound (B) is preferably compatible with the polymer (A). From the viewpoint of easy availability of raw materials and compatibility with the polymer (A), examples of suitable compounds (B) include organohydrogensiloxanes modified with organic groups. A typical example of the organohydrogensiloxane is a compound represented by the following formula (3).

  The value of a in the above formula (3) matches the number of hydrosilyl groups in the molecule. The value of a + b is not particularly limited but is preferably 2-50. R is a hydrocarbon group having 2 to 20 carbon atoms in the main chain. The compound of the above formula (3) can be obtained by modifying an unmodified methyl hydrogen silicone and introducing R. Unmodified methylhydrogen silicone corresponds to the compound in which R is all H in the above (3), and “Silicon market outlook—Manufacturer strategy and application development” issued by CMC Co., Ltd. (1990.1.31). As described in "-", it is used as a raw material for various modified silicones. Examples of the organic compound for introducing R include α-olefin, styrene, α-methylstyrene, allyl alkyl ether, allyl alkyl ester, allyl phenyl ether, allyl phenyl ester, and the like. The number of hydrosilyl groups in the molecule after modification can be adjusted by the amount of the organic compound added for modification.

  The ratio of the amount of the polymer (A) and the compound (B) in the pressure-sensitive adhesive composition for forming the pressure-sensitive adhesive composition layer is such that the compound (B) is based on the total amount of alkenyl groups derived from the polymer (A). Expressed by the total amount of derived hydrosilyl groups. Depending on the size of the total amount of hydrosilyl groups per mole of the total amount of alkenyl groups in the pressure-sensitive adhesive composition, the level of crosslinking density after curing is determined. Considering the balance between imparting appropriate tackiness and reducing the adhesive residue, etc., the total amount of hydrosilyl groups per 1 mol of the total amount of alkenyl groups is preferably 0.1 to 5.0 mol, more preferably 0. 4 to 4.0 moles.

The hydrosilylation catalyst that is the catalyst (C) is not particularly limited, and any catalyst that promotes the hydrosilylation reaction can be used. Specifically, chloroplatinic acid, a platinum-vinylsiloxane complex (for example, platinum-1,3-divinyl-1,1,3,3, -tetramethyldisiloxane complex or platinum-1,3,5,7- Tetravinyl-1,3,5,7-tetramethylcyclotetrasiloxane complex), platinum-olefin complexes (e.g.
Pt _x (ViMe ₂ SiOSiMe ₂ Vi) _y , Pt [(MeViSiO) ₄ ] _z (where x, y, and z represent positive integers)) and the like. Among these, from the viewpoint of the activity of the catalyst, a platinum complex catalyst not containing a strong acid conjugate base as a ligand is preferable, a platinum-vinylsiloxane complex is more preferable, and platinum-1,3-divinyl-1,1 is preferable. 3,3, -tetramethyldisiloxane complex or platinum-1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasiloxane complex is particularly preferred.

The amount of the catalyst (C) is not particularly limited, but is preferably 10 ⁻⁸ to 10 ⁻¹ mol, more preferably 10 ⁻⁶ to 10 mol, per 1 mol of the total amount of alkenyl groups of the polymer (A). ^-2 moles. If it is in the said range, it will become easy to achieve appropriate hardening rate, stable sclerosis | hardenability, ensuring of a required pot life, etc.

  In this invention, it is preferable to contain an organic liquid component (D) in an adhesive composition layer. Addition of organic liquid component reduces pain and skin irritation when peeling adhesive tape for skin application and transdermal absorption preparation from the skin surface, and improves diffusibility of physiologically active substances due to plasticization of adhesive In some cases, it may contribute to improving the release of a physiologically active substance on the skin surface.

  Although it does not specifically limit as an organic liquid component used for this invention, It has compatibility with each component and what can melt | dissolve and disperse | distribute uniformly in an adhesive composition layer is preferable.

As such an organic liquid component,
a) Polyhydric alcohols such as ethylene glycol, diethylene glycol, dipropylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, butanediol, triethylene glycol, glycerin;
b) Oils and fats such as olive oil, camellia oil, soybean oil, castor oil, lanolin;
c) fatty acids such as oleic acid;
d) Polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tetraoleate, polyoxyethylene Liquid surfactants such as lauryl ether, polyoxyethylene laurate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate;
e) Methyl caproate, methyl caprylate, methyl caprate, methyl laurate, methyl myristate, methyl stearate, methyl oleate, ethyl laurate, ethyl myristate, ethyl oleate, isopropyl myristate, isopropyl palmitate, Butyl palmitate, isostearyl laurate, isostearyl palmitate, octyl palmitate, octyl stearate, octyldodecyl myristate, isotridecyl myristate, diisopropyl adipate, octyl palmitate, octyl stearate, diethyl sebacate, caprylic glyceride , Other fatty acid esters such as pelargonic glyceride, capric glyceride, triethyl citrate, tributyl acetyl citrate;
f) Hydrocarbons such as liquid paraffin, squalane, squalene;
g) Organic solvents such as ethanol, ethyl acetate, dimethyl sulfoxide, isosorbitol, dimethyl decyl sulfoxide, methyl octyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dodecylpyrrolidone;
Etc. These organic liquid components can be used by mixing one or more kinds as necessary.

  Among the above organic liquid components, a preferable organic liquid component is a fatty acid ester because of excellent diffusibility of a physiologically active substance.

  Although content of these organic liquid components is not specifically limited, For example, it is 0.001-1.5 with respect to the weight 1 of a polymer (A), Preferably it is 0.001-1.0. When the content of the liquid component is outside this weight ratio, practical skin adhesion and low skin irritation cannot be obtained, and the release of the physiologically active substance is not sufficient.

  The percutaneous absorption enhancer used in the present invention improves the solubility and diffusibility of the physiologically active substance in the pressure-sensitive adhesive, acts on the skin surface, and has a keratin softening property, a keratin permeability, a pore opening property, etc. By fulfilling the function, the transdermal absorbability of the physiologically active substance can be improved.

  Although it does not specifically limit as a percutaneous absorption promoter used for this invention, The thing which can disperse | distribute uniformly in an adhesive layer is preferable. In addition, among the above organic liquid components, those acting as a transdermal absorption enhancer may be used singly or mixed with other transdermal absorption enhancers as those exhibiting both characteristics. It doesn't matter.

  Examples of such a percutaneous absorption enhancer include monovalent or polyvalent alcohols, monovalent or divalent carboxylic acids, hydroxycarboxylic acids, esters, pyrrolidone derivatives, surfactants, hydrocarbons, monocyclic mono-monomers. Terpenes, urea derivatives, specific compounds and the like are used.

  The monovalent alcohol is preferably an alcohol having 18 or less carbon atoms from the viewpoint of promoting transdermal absorption. For example, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, nonyl alcohol, iso Nonyl alcohol, lauryl alcohol, oleyl alcohol, cetyl alcohol and the like can be mentioned.

  Examples of the polyhydric alcohol include ethylene glycol, diethylene glycol, dipropylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, butanediol, triethylene glycol, and glycerin.

  The monovalent carboxylic acid is preferably a carboxylic acid having 20 or less carbon atoms from the viewpoint of promoting transdermal absorption. Examples thereof include aliphatic monocarboxylic acids such as capric acid, nonanoic acid, caprylic acid, lauric acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, oleic acid, linoleic acid, and linolenic acid.

  Examples of the divalent carboxylic acid include oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, suberic acid, adipic acid, sebacic acid, phthalic acid, isophthalic acid, terephthalic acid and the like.

  Examples of the hydroxycarboxylic acid include malic acid and tartaric acid.

  As said ester, the ester which consists of said monohydric and polyhydric alcohol and monohydric and bivalent carboxylic acid or hydroxycarboxylic acid is used suitably. For example, methyl caprate, methyl nonanoate, methyl caprylate, methyl laurate, methyl myristate, methyl pentadecylate, methyl palmitate, methyl margarate, methyl stearate, methyl oleate, methyl linoleate, methyl linolenate, Ethyl caprate, ethyl nonanoate, ethyl caprylate, ethyl laurate, ethyl myristate, ethyl pentadecylate, ethyl palmitate, ethyl margarate, ethyl stearate, ethyl oleate, ethyl linoleate, ethyl linolenate, capric acid Propyl, propyl nonanoate, propyl caprylate, propyl laurate, propyl myristate, propyl pentadecylate, propyl palmitate, propyl margarate, propyl stearate, propylene oleate , Propyl linoleate, propyl linolenate, isopropyl caprate, isopropyl nonanoate, isopropyl caprylate, isopropyl laurate, isopropyl myristate, isopropyl pentadecylate, isopropyl palmitate, isopropyl margarate, isopropyl stearate, isopropyl oleate, linole Isopropyl, linolenate, butyl caprate, butyl nonanoate, butyl caprylate, butyl laurate, butyl myristate, butyl pentadecylate, butyl palmitate, butyl margarate, butyl stearate, butyl oleate, butyl linoleate And butyl linolenate.

  Examples of the pyrrolidone derivative include 1-dodecylazacycloheptan-2-one, 1-geranylazacycloheptan-2-one, 1-farnesylazacycloheptan-2-one 2-pyrrolidone, 1-methyl-2-pyrrolidone, Examples include 5-methyl-2-pyrrolidone, 1,5-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid and the like.

  As the surfactant, a nonionic surfactant, an anionic surfactant, a cationic surfactant, or an amphoteric surfactant is used.

  Examples of the nonionic surfactant include polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan alkyl esters such as sorbitan monolaurate, sorbitan monopalmitate; polyoxyethylene lauryl ether, polyoxyethylene hexyl In addition to polyoxyethylene alkyl ethers such as decyl ether; fatty acid alkanolamides such as lauric acid diethanolamide, tetraoleic acid polyoxyethylene sorbitol, polyoxyethylene fatty acid amide, alkylamine oxide and the like.

  Examples of the anionic surfactant include those having at least one of a carboxylic acid group, a sulfonic acid group, a sulfate ester group, and a phosphate ester group in the molecule.

  Examples of those having a carboxylic acid group include, for example, fatty acid soaps, ether carboxylic acids (salts), carboxylates such as condensates of amino acids and fatty acids, and the like, and those having a sulfonic acid group include, for example, alkylsulfonic acid Salts, sulfosuccinic acid, ester sulfonates, alkylallyl and alkylnaphthalene sulfonates, N-acyl sulfonates, etc .; those having sulfate ester groups include, for example, sulfated oils, ester sulfates, ether sulfates, Alkyl allyl ether sulfates, amide sulfates, etc .; those having a phosphate group include, for example, alkyl phosphates, amide phosphates, ether phosphates, alkyl allyl phosphates, and the like.

  Examples of the cationic surfactant include fatty acid amines, alkyl quaternary ammonium salts, aromatic quaternary ammonium salts, pyridium salts, imidazolium salts, and the like.

  Examples of the amphoteric surfactants include carboxybetaines such as lauryldimethylaminoacetic acid betaine, as well as sulfobetaines, aminocarboxylates, and imidazoline derivatives.

  Examples of the hydrocarbon include liquid paraffin, squalane and squalene.

  Examples of the monocyclic monoterpenes include P-menthane, limonene, α-terpinene, terpinolene 1-menthol, 1-carpeol, α-terhineol 1-menton, d-carvone, cineol, and urea derivatives such as urea and allantoin. Is mentioned.

  Examples of the specific compound include panthenol, tocopherol, tocopheryl acetate, tocopheryl linoleate, crotamiton, pyrothiodecane, polyvinylpyrrolidone, and EDTA.

  These percutaneous absorption enhancers can be used by mixing one or more kinds as necessary. Moreover, although it is preferable to use the said transdermal absorption promoter, use of a compound other than the above is not denied.

  The content of these percutaneous absorption enhancers is not particularly limited, but is, for example, 0.001 to 1.5, preferably 0.001 to 1.0, with respect to 1 by weight of the polymer (A). It is. If the content of the transdermal absorption enhancer is outside this weight ratio, practical skin adhesion and low skin irritation may not be obtained, and also in terms of release of physiologically active substances. It may not be enough.

  The pressure-sensitive adhesive composition layer in the transdermally absorbable preparation and the adhesive sheet for skin application of the present invention is formed by curing the above-mentioned pressure-sensitive adhesive composition. Here, the term “curing” refers to heating the pressure-sensitive adhesive composition mixed with the polymer material to cause the polymer (A) and the compound (B) to undergo a hydrosilylation reaction by heating. Examples of the curing conditions include leaving at 40 to 180 ° C. for 1 to 60 minutes. If it is desired to complete the curing, it may be further left at 40 to 80 ° C. for several days.

  The viscosity at the time of curing is preferably 10 to 1000 Pa · s. This viscosity can be controlled by the ratio of the amounts of the components (A) to (C) and the kind and amount of the storage stabilizer for the compound (B) described above.

  The pressure-sensitive adhesive composition for forming the pressure-sensitive adhesive composition layer may contain components other than the above (A) to (D) and the percutaneous absorption enhancer. These components include tackifiers, storage stabilizers for compound (B), and other components.

  Tackifiers include phenol resin, modified phenol resin, terpene phenol resin, xylene phenol resin, cyclopentadiene-phenol resin, xylene resin, petroleum resin, phenol-modified petroleum resin, rosin ester resin, low molecular weight polystyrene resin, terpene Resin etc. are mentioned. When these are used to improve the adhesive properties, they may be used alone or in combination of two or more. The amount used in the case of using these tackifiers is preferably 10 to 100 parts by weight, more preferably 15 to 50 parts by weight with respect to 100 parts by weight of the total amount of the polymer (A) and the compound (B). . If the amount used is too large, the moisture permeability of the pressure-sensitive adhesive composition layer decreases, which is not preferable.

Examples of the storage stabilizer for the compound (B) include compounds containing an aliphatic unsaturated bond, organic phosphorus compounds, organic sulfur compounds, nitrogen-containing compounds, tin compounds, and organic peroxides. Specifically, 2-benzothiazolyl sulfide, benzothiazole, thiazole, dimethylacetylene dicarboxylate, diethylacetylene dicarboxylate, 2,6-di-t-butyl-4-methylphenol, butylhydroxyanisole, vitamin E, 2- (4-morphodinyldithio) benzothiazole, 3-methyl-1-buten-3-ol, acetylenically unsaturated group-containing organosiloxane, acetylene alcohol, 3-methyl-1-butyn-3-ol , 2-methyl-3-butyn-2-ol, diallyl fumarate, diallyl maleate, diethyl fumarate, diethyl maleate, dimethyl maleate, 2-pentenenitrile, 2,3-dichloropropene, and the like. It is not limited to these. The storage stabilizer suppresses the conversion of hydrosilyl groups (Si-H groups) to Si-OH groups in the compound (B) (due to standing for a long time or mixing of moisture), thereby reducing the pot life of coating. Can be improved. The amount of the storage stabilizer is preferably 10 ⁻⁶ to 10 ⁻¹ mol with respect to 1 mol of the total amount of hydrosilyl groups contained in the pressure-sensitive adhesive composition due to the compound (B) and the compound (C). .

  In addition, water-soluble organic polymers and water-absorbing polymers for improving the water resistance, sweat resistance, water absorption, etc. of the pressure-sensitive adhesive composition layer are added to the pressure-sensitive adhesive composition for forming the pressure-sensitive adhesive composition layer. In addition, other plasticizers, softeners, fillers, pigments, surfactants, ultraviolet absorbers, antioxidants, antibacterial agents, and the like may be blended. At this time, it is preferable not to use an organic solvent, but the use thereof is not denied.

  The physiologically active substance in the present invention is not particularly limited and can be used. As specific physiologically active substances, the following compounds can be exemplified.

  1. β-adrenergic agonists such as albuterol, bambuterol, vitorterol, carbuterol, clenbuterol, chlorprenalin, denopamine, dioxetedrine, dopexamine, ephedrine, epinephrine, etafedrine, ethyl norepinephrine, isonoterine, promoterol, Naral, mabuterol, metaproterenol, methoxyphenamine, oxyfedrine, pyrbuterol, prenalterol, procaterol, protokilol, reproterol, limiterol, ritodrine, soterenol, terbuterol and xamoterol.

  2. β-adrenergic blocking agents such as acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befnolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucmolol, befetolol, bufuralol, bunitrolol, bupranolol, butidolol hydrochloride, butofrolol hydrochloride Carteolol, carvedilol, seriprolol, cetamolol, chloranolol, zilevorol, epanolol, esmolol, indenolol, labetalol, levobanolol, mepindolol, metipranolol, metoprolol, moprolol, nadoxolol, nifenalol, nipprelolol, oxyprenolol, oxyprenolol Practolol, prone Roll, propranolol, sotalol, Sul Fina roll, talinolol, tertatolol, timolol, toliprolol and xibenolol.

  3. Analgesics such as chlorobutanol; narcotic analgesics such as alfentanil, allylprozin, alphaprozin, anilellidine, benzylmorphine, benzitolamide, buprenorphine, butorphanol, clonitazene, codeine, methylcodeine bromide, codeine phosphate phosphate, codeine sulfate , Desomorphin, Dextromoramide, Dezocine, Diampromide, Dihydrocodeine, Enol acetate dihydrocodeine, Dihydromorphine, Dimenoxadol, Dimefeptanol, Dimethylthianbutene, Dioxafetil butyrate, Dipipanone, Epeptosine, Ethoheptadine, Ethylmethylthianbutene, Ethylmorphene Ethone Fentanyl, hydrocodone, hydromorphone, hydroxypentidine, isomethadone, ketobe Don, levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone hydrochloride, methopone, morphine, morphine derivative, mylofine, nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretam , Pentazocine, phenadoxone, phenazosin, pheoperidine, pimidine, pyritramide, proheptadine, promedol, properidine, propyram, propoxyphene, sufentanil and thyridine and non-narcotic analgesics such as acetaminophen, acetylsalicylic salicylic acid and alclofenac.

  4). Anti-anginal drugs such as acebutolol, alprenolol, aminodarone, amlodipine, arotinolol, atenolol, bepridil, bevantolol, bukumolol, bufetrol, bufuralol, bunitrolol, bupranolol, carazolol, carteolol, carvedilol, ceriprolol, maleic acid Cinepasset, diltiazem, epanolol, felodipine, galopamil, imolamine, indenolol, isosorbide dinitrate, isradipine, limaprost, mepindolol, metoprolol, molsidomine, nadolol, nicardipine, nifedipine, nifenarol, nilvadipine, nipradilol Oxyfedrine, ozagrel, penbutolol, Nitric acid pentaerythritol, pindolol, professional story roll, propranolol, sotalol, terodiline, timolol, toliprolol and verapamil.

5). Antiarrhythmic drugs such as acebutol, acecaine, adenosine, azimarin, alprenolol, amiodarone, amoproxan, aprindine, arotinolol, atenolol, bevanthrol, bretylium tosylate, bubumolol, bufetrol, bunaphthol, bunitrolol, buprinolol, butidoline hydrochloride Capobenic acid, carazolol, carteolol, cifenline, chloranolol, disopyramide, encainide, esmolol, flecainide, galopamil, hydroquinidine, indecainide, indenolol, ipratropium bromide, lidocaine, loradimine, lorcainide, meventurinol, methiprenololidine, , Nifenalol, oxyprenolol, pen Troll, pindolol, Pirumenoru, practolol, Purajimarin, procainamide hydrochloride, pro neta roll, propafenone, propranolol, Pirinorin, quinidine sulfate, quinidine, sotalol, talinolol, timolol, tocainide, verapamil, Bikuijiru and xibenolol 6. Antidepressants: Bicyclic systems such as vinedaline, caroxazone, citalopram, dimetazan, indalpine, fencamine, indeloxazine hydrochloride, nefopam, nomifensine, oxytryptane, oxypertin, paroxetine, sertraline, thiazesim, trazodone and zometapine; hydrazide / hydrazine , For example, benmoxine, iproclozide, iproniazide, isocarboxazide, niaramide, octamoxine and phenelzine; pyrrolidones such as cotinine, rolicipurine and rolipram; Tricyclic systems such as azinazolam, amitriptyline, amitriptyline, amoxapine, buttriptyline, clomipramine, demexeptiline, desipramine, dibenzepine, dimetracrine, dothiepine, doxepin, fluacidine, imipramine, imipramine N-oxide, iprindol, lofepramine, Metapramine, nortriptyline, noxiptylline, opipramol, pizotirin, propizepine, protriptyline, quinupramine, tianeptine and trimipramine; and others such as adrafinil, benactidine, bupropion, butacetin, deanol, aceanolate deanol, acetamidobenzoyl dool, Etoperidone, febalmamate, femoxeti , Fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypersinin, levofacetoperan, medifoxamine, minaprine, moclobemide, oxafurozan, piberalin, prolinetan, piriscideanol, rubidium chloride, sulpiride, sultopride, teniloxazine, tozalinone, tofenacin , Troxatone, tranylcypromine, L-tryptophan, risperidone, viloxazine and dimerzine.

  7). Antiestrogens such as dermadinone acetate, ethamoxytrifitol, tamoxifen and toremifene.

  8). Anti-gonadotropins such as danazol, gestrinone and paroxypropion.

  9. Antihypertensive agents: arylethanolamine derivatives such as amosulalol, bufuralol, direvalol, labetalol, pronetalol, sotalol and sulfinalol; aryloxypropanolamine derivatives such as acebutolol, alprenolol, arotinolol, atenolol, betaxolol, bevantolol , Bisoprolol, bopindolol, bunitrolol, bupranolol, butofilolol, carazolol, cartezolol, carvedilol, ceriprolol, cetamolol, epanolol, indenolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nipprelolol, oxiprenolol, penbutrol Pindolol, propranolol, talinolol, te Laolol, timolol and triprolol; benzothiadiazine derivatives such as althiazide, bendroflumethiazide benzthiazide, benzylhydrochlorothiazide, butiazide, chlorothiazide, chlorthalidone, cyclopenthiazide, cyclothiazide, diazoxide, epithiazide, ethiazide, fenquizone, hydrochlorothiazide , Hydroflumethiazide, methylclothiazide, methicrane, metrazone, paraflutizide, polythiazide, tetrachloromethiazide and trichloromethiazide; N-carboxyalkyl (peptide / lactam) derivatives such as alacepril, captopril, cilazapril, delapril, enalapril, enara Prirat, Hoshinopril, Lisinopril, Mobiletipril, Perindopril Quinapril and ramipril; dihydropyridine derivatives such as amlodipine, felodipine, isradipine, nicardipine, nifedipine, nilvadipine, nisoldipine and nitrendipine; guanidine derivatives such as betanidin, debrisoquine, guanabenz, guanacrine, guanazodine, guanazudin, guanazudin, Guanoxane; hydrazine and phthalazine series, such as budralazine, cadralazine, dihydralazine, endralazine, hydralcarbazine, hydralazine, pheniprazine, pyrrazine, and todralazine; imidazole derivatives, such as clonidine, lofexidine, phentolamine, thiamenidine and tronidine; quaternary ammonium compounds , Odor Azamethonium chloride, chloroisondamine chloride, hexamethonium, bis (methyl sulfate) pentacinium, pentamethonium bromide, pentolinium tartrate, phenactopinium chloride and trimethidiunam methosulfate; quinazoline derivatives such as alfuzosin, bunazosin, doxazosin, prazosin Terazosin and trimazosin; reserpine derivatives, vietaserpine, deserpidine, resinnamine, reserpine and syrosingopine; sulfonamide derivatives such as ambuside, clopamide, furosemide, indapamide, kinetazone, trypamide and xipamide; and others such as adimarin, γ-aminobutyric acid, Bufeniode, chlorthalidone, cicletaine, cyclosidomine, cryptenamine tannate, fenoldopam, furosek Nan, Indamine, Ketanserin, Metobutamate, Mecamylamine, Methyldopa, Methyl 4-pyridyl ketone thiosemicarbalzone, Metrazone, Minoxidil, Musolimine, Pardiline, Penpidine, Pinacidil, Piperoxane, Primaperone, Protoveratrines, Laubacin, Recimetol, Rilmenidene, Saralasin, sodium nitroprusside, ticrinaphen, trimetaphane, camsylate, tyrosinase and urapidil.

  10. Anti-inflammatory (non-steroidal) agents: aminoaryl carboxylic acid derivatives such as enfenamic acid, etofenamate, flufenamic acid, isonyxine, meclofenamic acid, mefanamic acid, niflumic acid, talniflumate, telofenamate and tolfenamic acid; aryl Acetic acid derivatives such as acemetacin, alclofenac, ampenac, bufexamac, synmetacin, clopilac, diclofenac sodium, etodolac, felbinac, fenclofenac, fenclolac, fenclozic acid, fenthiazac, glucametacin, ibufenac, indomethacin, isofezolac , Isoxepak, Ronazolac, Methazic acid, Oxamethasine, Progouritacin, Sulindac, Thiaramid, Tolmeti Arylbutyric acid derivatives such as bumadizone, butybufen, fenbufen and xembusine; arylcarboxylic acid derivatives such as cridanac, ketorolac and tinolidine; arylpropionic acid derivatives such as aluminoprofen, beoxaprofen, bucuroxy acid, carprofen , Fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuprofaxam, indoprofen, ketoprofen, loxoprofen, miloprofen, naproxen, oxaprozin, picketprofen, pirprofen, pranoprofen, protidic acid, suprofen and thiaprofenic acid; Pyrazoles such as diphenamisole and epilysole; pyrazolones such as apazone, Nspiperilone, feprazone, mofebutazone, morazon, oxyphenbutazone, phenibutazone, pipebuzone, propifenazone, lamifenazone, sukibzone and thiazolinobutazone; salicylic acid derivatives such as acetaminosalol, aspirin, benolylate, bromosaligenate, calcium acetylsalicylate, diflunisalicylate, Ethersalate, fendosaur, gentisic acid, glycol salicylate, imidazolic salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphthyl salicylate, olsalazine, palsalimide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamine o-acetic acid, salicylsulfuric acid, salsayl Rate and sulfasalazine; thiazinecarbox Mido series such as droxicam, isoxicam, piroxicam and tenoxicam; and others such as epsilon-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, diphene Pyramide, ditazole, emorzone, guayazulene, nabumetone, nimesulide, orgothein, oxaceptol, paraniline, perisoxal, pifoxime, proquazone, valdecoxib, ketorolac, proxazole and tenidap.

  11. Antitumor agents: 2-aminolevulinic acid and alkylating agents: alkyl sulfonates such as busulfan, improsulfan and piperosulfan; aziridines such as benzodepa, carboxone, metuledepa and uredepa; ethyleneimine and methylmelamines such as Artretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; nitrogen mustard systems such as chlorambucil, chlornafazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine , Mechlorethamine hydrochloride, melphalan, nobenbiquine, phenesterine, prednisotin, trophosphamide and uracil mustard; nitrosourea, eg , Carmustine, chlorozotocin, hotemustine, lomustine, nimustine and ranimustine; and others, such as dacarbazine, mannomustine, mitoblonitol, mitractol, and pipobroman; antibiotics such as aclacinomycin, actinomycin F1, anthromycin, azaserine, bruomycin, Mycin, carubicin, cardinophilin, chromomycin, dactinomycin, daunorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, mitomycin, mycophenolic acid, nogaramycin, olivomycin, pepromycin, pricamycin, porphy Romycin, puromycin, streptonigrin, streptozocin, tubercidine, ubenimex, zino Antimetabolites: folic acid analogs such as denopterin, methotrexate, pteropterin and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiapurine and thioguanine; and pyrimidine analogs such as ancitabine, Azacitidine, 6-azauridine, carmofur, cytarabine, doxyfluridine, enositabine, furoxyuridine, fluroouracil and tegafur; enzymes such as L-asparaginase; and others such as acegraton, ansacrine, bestlabsyl, bisplatin, carboplatin, cisplatin, defophamide , Demecorsin, diadicone, erfornitine, ellipticine acetate, etoglucide, etoposide, gallium nitrate, hydro Siurea, interferon-α, interferon-β, interferon-γ, interleukin-2, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenmet, pirarubicin, podophyllic acid, 2-ethidrazide, procarbateni Poside, tenuazonic acid, triadiquone, 2,2 ', 2 "-trichlorotriethylamine, urethane, vinblastine, vincristine and vindesine; antitumor (hormonal) agents: androgens such as, for example, carsterone, drmostanolone propionate, epithiostanol, Anti-adrenal systems such as aminoglutethimide, mitotane and trilostane; antiandrogens such as flutamide and niluta De; and antiestrogen-based, for example, tamoxifen and toremifene.

  12 Antiparkinson agents such as amantadine, benserazide, bietanautin, biperidene, bromocriptine, budipine, carbidopa, deprenyl, dexetimide, dietadine, droxidopa, etopropazine, ethylbenzhydramine, levodopa, naxagolide, pergolide, pyrrolidiprodine, primoditin And trihexyphenidyl hydrochloride.

  13. Antiprostatic hypertrophy agents such as guestnolone caproate, mepaltricin.

  14 Antipsychotics: butyrophenones such as benperidol, bromperidol, droperidol, fluanizone, haloperidol, melperone, moperone, pipamperon, sniperone, timiperone and trifluperidol; phenothiazines such as acetophenazine, butaperazine, carfenazine, chlorproe Tagine, Chlorpromazine, Crospyrazine, Cyamemazine, Dixylazine, Fluphenazine, Imicropazine, Mepazine, Mesoridazine, Methoxypromazine, Metophenazate, Oxaflumazine, Perazine, Pericazine, Perimethazine, Perphenazine, Piperacetazine, Pipothiazine, Prochlorperazine, Promazine Sulforidazine, thiopropazate, thioridazine, trifluoperazine and triflupro Gins; thioxanthenes such as chlorprothixene, clopenthixol, flupentixol and thiothixene; other tricyclics such as benzquinamide, carpipramine, clocapramine, clomaclan, clothiapine, clozapine, opipramol, protipendil, tetrabenazine And other such as alizaprid, amisulpride, bramate, fluspirylene, morindon, penfluridol, pimozide, spirylene and sulpiride.

  15. Antispasmodic agents such as aribendol, ambusetamide, aminopromazine, apotropine, methylbebonium sulfate, bietamivelin, butavelin, butropium bromide, N-butylscopolammonium bromide, caroverine, simetropium bromide, cinnamedrine, clevopride, conidium oxyacid, hydrochloric acid Coniine, cyclonium iodide, diphemerin, diisopromine, dioxafetil butyrate, diponium bromide, drophenine, emepronium bromide, etavelin, fecremin, phenalamide, phenovelin, fenpiplan, fenpiberinium bromide, fentonium bromide, flavoxate, furopropion, Gluconic acid, guaiactinamine, hydramidazine, hymechromone, leiopyrrole, mebevelin, moxaverine, nafiberine, oct Miramine, octaverine, pentapiperide, phenamaside hydrochloride, phloroglucinol, pinaberium bromide, piperylate, pipoxolan hydrochloride, pramiberin, prifinium bromide, propridine, propiban, propilomazine, prozapine, racephemin, rosiverine, spasmolitol, strontium iodide, sultroponium iodide Thiemonium iodide, tiquidium bromide, tiropramide, trepibutone, trichromyl, triphorium, trimebutine, N, N-1-trimethyl-3,3-diphenylpropylamine, tropendyl, trospium chloride and xennitropium bromide.

  16. Anti-anxiety drugs: arylpiperazines such as buspirone, gepirone and ipsapilone; benzodiazepine derivatives such as alprazolam, bromazepam, camazepam, chlordiazepoxide, clobazam, chlorazepate, cothiazepam, cloxazolam, diazepam, ethyllofazepam, fluzopameptam Frutoprazepam, halazepam, ketazolam, lorazepam, loxapine, medazepam, methaclazepam, mexazolam, nordazepam, oxazepam, oxazolam, pinazepam, prazepam and tofisopam; carbamates such as cyclalbamate, emylcamate, probamate Others, for example, Alpiden, Ben Kutamin, captodiamine, chlormezanone, Echihokishin, Furuorezon, glutamic acid, hydroxyzine, Mekuroraruurea, main phenoxy salon, Okisanamido, phenazine glycolate doll, Surikuron.

  17. Calcium regulators such as calcifediol, calcitonin, calcitriol, clodronic acid, dihydrotaxosterol, elcatonin, etidronic acid, ipriflavone, pamidronic acid, paratyloid hormone and teriparatide acetate.

  18. Cardiotonic agents such as acephylline, acetyl digititoxin, 2-amino-4-picoline, anrinone, benfurosyl semisuccinate, bucladecin, cerberoside, camfotamide, combaratoxin, simarin, denopamine, deslanoside, digitaline, digitalis, digitoxin , Digoxin, dobutamine, dopamine, dopexamine, enoximone, erythrofrein, phenalkamine, guitarine, gitoxin, glycosamine, heptaminol, hydrastinine, ibopamine, lanotodises, metamibum, milrinone, neriifolin, oleandrin, ouabaline, Prosilaridin, resibehogenin, silalene, silarenin, strophanthin, sulmazole, theobromine and xamotero .

  19. Chelating agents such as deferodimine, sodium dithiocarb, disodium calcium edetate, disodium edetate, sodium edetate, trisodium edetate, penicillamine, trisodium calcium pentenoate, pentectinic acid, succimale and trientine.

  20. Dopamine receptor agonists such as bromocriptine, dopexamine, fenoldopam, ibopamine, lisuride, naxagolide and pergolide.

  21. Enzyme inducer (liver), for example flumesinol.

  22. Estrogens: Non-steroidal estrogens such as benzestrol, bropaloestrol, chlorotrianisene, dienestrol, diethylstilbestrol, diethylstilbestrol dipropionate, dimestrol, phosfestol, hexestrol, meta Lenstril and metestrol; and steroidal estrogens such as colpolmon, conjugated estrogen hormone, equilenin, equilin, estradiol, estradiol benzoate, 17β-cypionate estradiol, estriol, estrone, ethinyl estradiol, mestranol, mexestrol, mita Trienediol, clobetasone butyrate, quinestradiol and quinestrol.

  23. Glucocorticoids, such as 21-acetoxyprefunenolone, arclomethasone, algestone, amicinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, brobetazone, crocortron, clopredonol, corticosterone, cortisone, cortibazole, deflazacort, Desonide, Desoxymethazone, Dexamethasone, Diflorazone, Diflucortron, Difluprednate, Enoxolone, Fluazacort, Fluchloronide, Flumethasone, Flunisolide, Fluocinolone Atonide, Fluocinonide, Fluocortin Butyl, Flucortron, Fluperolone acetate, Fluperolone acetate Fluprednidone, fluprednisolone, fluland lenolide, formocortal, harshi Nido, halomethasone, halopredone acetate, hydrocortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone phosphate, 21-hydrocortisone sodium succinate, hydrocortisone tebutate, madipredone, medorizone, meprednisone, methiol prednisolone, mometasone flanate, parameterzone, predonical Bait, prednisolone, 21-diethylaminoacetate prednisolone, sodium prednisolone phosphate, sodium prednisolone succinate, 21-m-sulfobenzoic acid prednisolone sodium, 21-stearoylglycolate prednisolone, tebutonic acid prednisolone, 21-trimethylacetate prednisolone, prednisone, Prednival, prednylidene, 21-diethylaminoacetic acid Down, thixotropic Col tar, Torianshinoron, birds Ann Shino Ron acetonide, birds Ann Shino Ron Veneto acetonide and birds Ann Shino Ron hexacetonide.

  24. Mineralcorticoids such as aldosterone, deoxycorticosterone, deoxycorticosterone acetate and fludrocortisone.

  25. Monoamine oxidase inhibitors, such as deprenyl, iproclozide, iproniazide, isocarboxazide, moclobemide, octomoxine, pargyline, phenelzine, phenoxypropazine, pivalylbenzhydrazine, prodipine, troxatone and tranylcypromine.

  26. Muscle relaxants (skeletal), for example, afroqualon, alcuronium, atracurium besylate, baclofen, benzocamine, benzoquinonium chloride, C-carevacine, carisoprodol, chlormezanone, chlorphenesin carbamate, chlorproetadine, cloxoxazone, Kuraray, cyclalbamate, cyclobenzaprine, dantrolene, decamethonium bromide, diazepam, eperisone, fazazinium bromide, flumetramide, galamine triethiodide, hexacarbacolin bromide, hexafluorenium bromide, idrosilamide, methyl laurexium sulfate, leptodactillin, Memantine, mefenesin, mefenoxalon, metaxalone, metcarbamol, metocrine iodide, nimetazepam, orphenadrine, panclonide bromide , Fenprobamate, pheniramidol, pipeclium bromide, promoxolane, quinine sulfate, styramate, succinylcholine bromide, succinylcholine iodide, succinylcholine iodide, succinonium bromide, tetrazepam, thiocorchicoside, tizanidine, tolperisone, tubocurarine chloride, Vecuronium bromide, Pridinol mesylate and Zoxolamine.

  27. Narcotic antagonists such as amifenazole, cyclazocine, levalorphan, nazide, nalmufen, nalorphine, narolphine dinicotinate, naloxone and naltrexone.

  28. Progestogens, for example, allylestrenol, anagandone, chlormadinone acetate, dermadinone acetate, demegestone, desogestrel, dimethisterone, didrogesterone, ethisterone, ethinodiol, flurogestone acetate, guestden, caprolate guestnolone, haloprogesterone, 17-hydroxy-16-methyleneprogesterone , 17α-hydroxyprogesterone, caproic acid 17α-hydroxygesterone, linestrenol, medrgestone, medroxyprogesterone, megestrol acetate, melengestrol, norethindrone, norethinodolyl, norgesterone, norgestimate, norgestrel, norgestrienone, norbinisterone, penta Guestron, progesterone, promegestone, ki Ngestrone and Trengestone and their esters.

  29. Vasodilators (coronary arteries), e.g., amotrifen, bendazole, benfurosyl hemisuccinate, benzodiolone, croacidin, chromonal, clobenfurol, clonitrate, dilazep, dipyridamole, dropreniramine, efroxate, erythritol, erythritol tetranitrate, etaphenone, phengerelin, phlegreline, Phen, hexestrol bis (β-diethylaminoethyl ether), hexobenzine, itramine tosylate, kerin, lidofrazine, mannitol hexanitrate, medivazine, nicorandil, nitroglycerin, pentaerythritol tetranitrate, pentrinitrol, perhexiline, pimefilin, prenylamine, Propatyl nitrate, pyridophylline, trapidyl, trichromyl, trimetazidine, li Acid trolnitrate and bisnadine and peripheral vasodilators such as aluminum nicotinate, bamethane, bencyclane, betahistine, bradykinin, brobincamine, buhoniod, bufuromezil, butalamine, cetiezil, cyclonicate, cinepazide, cinnarizine, cyclandrate, diisopropylamine dichloramine , Eledoisin, phenoxydil, flunaricin, herolicate, ifenprodil, inositol niacate, isoxyspurine, kallidin, kallikrein, moxycilite, nafuronyl, nicametate, nicergoline, nicofuranose, nicotinyl alcohol, nilidrin, pentifylline, pentoxyphyllin, pentoxyphyllin Protaglandin E1, slotoctyl and xanthinal niacin.

  30. Benzodiazepine antagonists such as flumazenil.

  31. Bronchodilators: Ephedrine derivatives such as albuterol, bambuterol, vitorterol, carbuterol, clenbuterol, chlorprenalin, dioxededrine, ephedrine, epinifrine, eprodinol, etafedrine, ethyl norepinephrine, fenoterol, isotoprenaline, proetherol Renol, N-methylephedrine, pyrbuterol, procaterol, protokyol, reproterol, limiterol, soterenol, terbutaline and tulobuterol; quaternary ammonium compounds such as methylbebonium sulfate, curtropium bromide, ipratropium bromide and oxitropium bromide; xanthine Derivatives, for example, acefylline, acefylline Perazine, ambuphylline, aminophylline, bamifilin, choline theophylline, doxophilin, daphylline, enprofilin, etamiphilin, etophylline, guaytylin, proxyphylline, theobromine, 1-theobromine acetic acid and theophylline; and others such as, for example, fencepyrido, medivadin, methoxyphe Namin and tretoquinol.

  32. In addition, incontinence treatments such as oxybutynin, osteoporosis treatments such as risedronate, antihistamines such as ketofetin acetate, diabetes treatments such as tolbutamide, and ventilation treatments such as colchicine.

  These can be used in combination of two or more as required.

  If there is at least one pressure-sensitive adhesive composition layer containing these physiologically active substances, a plurality of pressure-sensitive adhesive composition layers may be laminated.

  The method for mixing these physiologically active substances into the pressure-sensitive adhesive composition is not particularly limited. Usually, after the physiologically active substance is dissolved in the polymer (A), it is mixed with the compound (B) and the catalyst (C). In order to further improve the solubility of the physiologically active substance, after dissolving the physiologically active substance in the organic liquid component, the polymer (A), the compound (B) and the catalyst (C And a manufacturing method in which this is cured.

  The method for laminating the pressure-sensitive adhesive composition layer on the support is not particularly limited. For example, a method in which the pressure-sensitive adhesive composition is coated on one surface of the support and then cured under the above-described conditions, or a release agent in advance. There is a method in which the above pressure-sensitive adhesive composition is applied to a sheet (peeling sheet) that has been coated and cured, and then the support is bonded. As the release agent, various release agents such as silicone, olefin and fluorine are known and can be used as appropriate. Of these, olefin-based and solvent-free addition-curable silicone-based release agents are preferable from the viewpoint of ensuring cost and releasability.

  The thickness of the pressure-sensitive adhesive composition layer is not particularly limited, and may be, for example, 10 to 5000 μm.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the examples, and various applications are possible without departing from the technical idea of the present invention. is there.

(Synthesis of polymer (A))
An oxypropylene polymer glycol having a number average molecular weight of 3000 was obtained by a polymerization method using caustic alkali. According to the method of Synthesis Example 1 of JP-A-5-117521, propylene oxide is polymerized using a double metal cyanide complex catalyst (zinc hexacyanocobaltate) using the oxypropylene polymer glycol as an initiator, and the number average molecular weight 28,000 polymers were obtained. The polymer is converted to an allyl group using a 28% methanol solution of sodium methylate and allyl chloride, and then desalted and purified to have approximately two allyl group ends in one molecule. A polyoxyalkylene polymer (polymer (A)) was obtained. The allyl terminal group amount of the obtained polymer was 0.12 mmol / g.

(Synthesis of Compound (B))
In the presence of a platinum catalyst, 0.6 equivalent of α-methylstyrene of the total hydrosilyl group amount is added to methyl hydrogen silicone represented by the following formula (4) (wherein x is an average of 5), and 1 molecule A compound (compound (B)) having an average of 2.5 hydrosilyl groups therein was obtained. The hydrosilyl group content of this compound was 3.2 mmol / g.

Example 1
Platinum-1,3 as a hydrosilylation catalyst is added by adding 2.3 parts by weight of the compound (B) and 0.03 parts by weight of ubiquinone (ubidecalenone) as a physiologically active substance to 100 parts by weight of the polymer (A). -A pressure-sensitive adhesive composition was obtained by sufficiently mixing 0.1 part by weight of divinyl-1,1,3,3-tetramethyldisiloxane complex (3% by weight platinum isopropanol solution) and 0.03 part by weight of dimethyl maleate. It was. The pressure-sensitive adhesive composition was coated on the treated surface of release paper that had been subjected to silicone release treatment at room temperature so that the thickness after curing was 50 μm, and cured at 130 ° C. for 3 minutes to form a pressure-sensitive adhesive layer. Formed. Next, on the cured pressure-sensitive adhesive layer, a moisture-permeable polyurethane sheet (DSU-214-CDB, manufactured by Seadam Co., Ltd., 30 μm) (basis weight 35 g / m ² ) (basis weight 35 g / m ² ) as a support is 5 kg / cm ² at 120 ° C., speed Lamination was performed under the condition of 2 m / min. In this way, a transdermal absorption preparation was prepared.

(Comparative Example 1)
100 parts by weight of an acrylic copolymer obtained by copolymerizing 65 parts by weight of 2-ethylhexyl acrylate, 30 parts by weight of 2-methoxyethyl acrylate, and 5 parts by weight of acrylic acid is dissolved in 200 parts by weight of toluene and homogeneous. An adhesive solution was prepared. This solution was mixed with 0.03 part by weight of ubiquinone with respect to 100 parts by weight of the acrylic copolymer, and coated on the release sheet subjected to the release treatment so that the thickness after drying was 50 μm. After drying at 3 ° C. for 3 minutes, it was transferred to a moisture-permeable polyurethane sheet (same as in the above example) as a support to obtain a transdermally absorbable preparation.

(Comparative Example 2)
Stearyl alcohol 4 parts by weight, oleic acid 8 parts by weight, octyl stearate 6 parts by weight, sorbitan monooleate 2 parts by weight, propylene glycol 5 parts by weight, benzoic acid 0.2 parts by weight, potassium hydroxide 0.4 parts by weight, 74.4 parts by weight of purified water was added to 0.03 part by weight of ubiquinone and stirred with a homogenizer to obtain an O / W type cream.

  Example 1 and Comparative Examples 1 and 2 were affixed to the skin of the hands of three volunteers and reapplied or painted every 24 hours, and wrinkles on the skin after 6 weeks were photographed to observe the state of wrinkles. The results are shown in Table 1.

(Wrinkle improvement evaluation)
Evaluation criteria: ○: Wrinkles are visually improved before and after application.

            Δ: Wrinkles are slightly improved visually before and after application.

            X: Wrinkles are not changed before and after application.

(Skin irritation)
The transdermal absorption preparation cut to a width of 20 mm was applied to the back of the volunteer, and a roller having a weight of 1 kg was reciprocated once for pressure bonding. After 6 hours, the percutaneous absorption preparation was peeled off, and the amount of exfoliated skin was measured using the percutaneous absorption preparation after peeling. That is, the sample peeled from the back of the volunteer is immersed in keratin staining solution (GentianViolet 1%, BrilliantGreen 0.5%, distilled water 98.5%) manufactured by Wako Pure Chemical Industries, Ltd. for about 30 minutes to stain skin keratin. went. Thereafter, the sample was thoroughly washed with distilled water and then dried for 24 hours. The pressure-sensitive adhesive layer surface of the dried sample was observed using a microscope, image analysis was performed, and the keratin exfoliated area ratio was obtained.

  From the above results, the present invention is less irritating to the skin than conventional adhesives and creams, can contain a sufficient amount of a physiologically active substance, and has a good release of the physiologically active substance. It is clear to provide an absorption formulation.

(Example 2)
With respect to 100 parts by weight of the polymer (A), 2.3 parts by weight of the compound (B) and a platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (hydrosilylation catalyst) 3 wt% platinum isopropanol solution) 0.1 parts by weight, dimethyl maleate 0.03 parts by weight, isopropyl myristate 30 parts by weight, and estradiol 1 part by weight were sufficiently mixed to obtain an adhesive composition. This pressure-sensitive adhesive composition was coated on a polyester film (thickness 25 μm) so that the thickness after curing was 50 μm, and then heated at 130 ° C. for 5 minutes to obtain the transdermally absorbable preparation of the present invention.

(Example 3)
For 100 parts by weight of the polymer (A), 4.2 parts by weight of the compound (B) and a platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (hydrosilylation catalyst) 3 wt% platinum isopropanol solution) 0.1 parts by weight, dimethyl maleate 0.03 parts by weight, isopropyl myristate 30 parts by weight, and estradiol 1 part by weight were sufficiently mixed to obtain an adhesive composition. This pressure-sensitive adhesive composition was coated on a polyester film (thickness 25 μm) so that the thickness after curing was 50 μm, and then heated at 130 ° C. for 5 minutes to obtain the transdermally absorbable preparation of the present invention.

Example 4
10.7 parts by weight of compound (B) with respect to 100 parts by weight of polymer (A), platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (hydrosilylation catalyst) 3 wt% platinum isopropanol solution) 0.1 parts by weight, dimethyl maleate 0.03 parts by weight, isopropyl myristate 30 parts by weight, and estradiol 1 part by weight were sufficiently mixed to obtain an adhesive composition. This pressure-sensitive adhesive composition was coated on a polyester film (thickness 25 μm) so that the thickness after curing was 50 μm, and then heated at 130 ° C. for 5 minutes to obtain the transdermally absorbable preparation of the present invention.

(Example 5)
10.7 parts by weight of compound (B) with respect to 100 parts by weight of polymer (A), platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (hydrosilylation catalyst) 3 wt% platinum isopropanol solution) 0.1 part by weight, 0.03 part by weight of dimethyl maleate and 1 part by weight of estradiol were sufficiently mixed to obtain an adhesive composition. This pressure-sensitive adhesive composition was coated on a polyester film (thickness 25 μm) so that the thickness after curing was 50 μm, and then heated at 130 ° C. for 5 minutes to obtain the transdermally absorbable preparation of the present invention. Table 2 shows the results of the adhesion test on the examples and comparative examples.

(Adhesion test)
Each strip-shaped preparation sample cut to a width of 25 mm was affixed to a SUS304 plate, and a rubber roller having a weight of 2 kg was reciprocated once under the condition of a speed of 2 m / min, and left for 1 hour. The stress at the time of peeling each tape from the SUS304 plate at an angle of 180 ° at a speed of 300 mm / min was used as a measurement value of the adhesive strength.

  From the above results, it is clear that the present invention provides a pressure-sensitive adhesive sheet that can contain a sufficient amount of a physiologically active substance and controls the adhesive force by adding an organic liquid component and has low skin irritation. It is.

(Example 6)
With respect to 100 parts by weight of the polymer (A), 2.3 parts by weight of the compound (B) and a platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (hydrosilylation catalyst) 3 wt% platinum isopropanol solution) 0.1 parts by weight, 0.03 parts by weight of dimethyl maleate, 20 parts by weight of polyoxyethylene sorbitol tetraoleate, and 2.5% by weight of estradiol are added and mixed thoroughly. Thus, a pressure-sensitive adhesive composition was obtained. This pressure-sensitive adhesive composition was coated on a polyester film (thickness 25 μm) so that the thickness after curing was 50 μm, and then heated at 130 ° C. for 5 minutes to obtain the transdermally absorbable preparation of the present invention.

(Example 7)
With respect to 100 parts by weight of the polymer (A), 2.3 parts by weight of the compound (B) and a platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (hydrosilylation catalyst) 3 wt% platinum isopropanol solution) 0.1 parts by weight, dimethyl maleate 0.03 parts by weight, estradiol was added to 2.5% by weight, and mixed well to obtain a pressure-sensitive adhesive composition. This pressure-sensitive adhesive composition was coated on a polyester film (thickness 25 μm) so that the thickness after curing was 50 μm, and then heated at 130 ° C. for 5 minutes to obtain the transdermally absorbable preparation of the present invention. Table 3 shows the results of the bioactive substance release test for each of the obtained preparations.

(Bioactive substance release test)
The release test was performed using a Franz diffusion cell. As a permeable membrane, a urethane film having a thickness of 25 μm cut into a circle having a diameter of 3 cm was used, and a 50% ethanol solution was used as a reservoir solution. The sample was cut into a 1 cm diameter circle and used. Using a Franz diffusion cell, the concentration of the physiologically active substance released from the sample into the reservoir solution was quantified by liquid chromatography. The results are shown in Table 3.

  From the above results, it is clear that the present invention provides a percutaneous absorption preparation having a release characteristic of a physiologically active substance and having a further excellent release characteristic by using a percutaneous absorption enhancer. .

(Example 8)
With respect to 100 parts by weight of the polymer (A), 2.3 parts by weight of the compound (B) and a platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (hydrosilylation catalyst) After adding flurbiprofen to 0.1 parts by weight of a 3% by weight platinum isopropanol solution and 0.03 parts by weight of dimethyl maleate so that the content with respect to the pressure-sensitive adhesive composition is 2.5% by weight. And sufficiently mixed to obtain a pressure-sensitive adhesive composition. This pressure-sensitive adhesive composition was coated on a polyester film (thickness 25 μm) so that the thickness after curing was 50 μm, and then heated at 130 ° C. for 5 minutes to obtain the transdermally absorbable preparation of the present invention.

Example 9
With respect to 100 parts by weight of the polymer (A), 2.3 parts by weight of the compound (B) and a platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (hydrosilylation catalyst) 3 wt% platinum isopropanol solution) 0.1 part by weight, 0.03 part by weight of dimethyl maleate, 30 parts by weight of isopropyl myristate, flurbi in an amount of 2.5% by weight based on the pressure-sensitive adhesive composition Profen was made into the above solution of isopropyl myristate, and the whole was mixed well to obtain a pressure-sensitive adhesive composition. This pressure-sensitive adhesive composition was coated on a polyester film (thickness 25 μm) so that the thickness after curing was 50 μm, and then heated at 130 ° C. for 5 minutes to obtain the transdermally absorbable preparation of the present invention.

(Example 10)
With respect to 100 parts by weight of the polymer (A), 2.3 parts by weight of the compound (B) and a platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (hydrosilylation catalyst) 3 wt% platinum isopropanol solution) 0.1 part by weight, 0.03 part by weight of dimethyl maleate, 20 parts by weight of polyoxyethylene sorbit tetraoleate, and content of flurbiprofen in the pressure-sensitive adhesive composition is 2 After adding so that it might become 5 weight%, it fully mixed and obtained the adhesive composition. This pressure-sensitive adhesive composition was coated on a polyester film (thickness 25 μm) so that the thickness after curing was 50 μm, and then heated at 130 ° C. for 5 minutes to obtain the transdermally absorbable preparation of the present invention.

(Example 11)
With respect to 100 parts by weight of the polymer (A), 2.3 parts by weight of the compound (B) and a platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (hydrosilylation catalyst) 3 wt% platinum isopropanol solution) 0.1 parts by weight and dimethyl maleate 0.03 parts by weight, ketoprofen was added so that the content with respect to the pressure-sensitive adhesive composition was 5.0% by weight. It mixed and the adhesive composition was obtained. This pressure-sensitive adhesive composition was coated on a polyester film (thickness 25 μm) so that the thickness after curing was 50 μm, and then heated at 130 ° C. for 5 minutes to obtain the transdermally absorbable preparation of the present invention.

(Comparative Example 3)
After 100 parts by weight of DURO-TAK387-2052 (acrylic pressure-sensitive adhesive, manufactured by NSC), flurbiprofen was added so that the content with respect to the pressure-sensitive adhesive composition was 2.5% by weight. It mixed and the adhesive composition was obtained. This pressure-sensitive adhesive composition was applied on a polyester film (thickness 25 μm) to a thickness of 50 μm, and then heated at 130 ° C. for 5 minutes to obtain a transdermal absorption preparation.

(Comparative Example 4)
After adding flurbiprofen so that content with respect to an adhesive composition may be 2.5 weight% with respect to 100 weight part of MD7-4502 (silicone adhesive, Toray Dow Corning Silicone Co., Ltd.) To obtain a pressure-sensitive adhesive composition. This pressure-sensitive adhesive composition was applied on a polyester film (thickness 25 μm) to a thickness of 50 μm and then heated at 130 ° C. for 5 minutes. Flurbiprofen precipitated in a crystalline state, and a uniform preparation was obtained. I couldn't.

(Comparative Example 5)
To 100 parts by weight of DURO-TAK387-2052 (acrylic adhesive, manufactured by NSC), add ketoprofen so that the content of the adhesive composition is 5.0% by weight, and then mix thoroughly. A pressure-sensitive adhesive composition was obtained. This pressure-sensitive adhesive composition was applied on a polyester film (thickness 25 μm) to a thickness of 50 μm, and then heated at 130 ° C. for 5 minutes to obtain a transdermal absorption preparation.

(Comparative Example 6)
After adding ketoprofen to 100 parts by weight of MD7-4502 (silicone-based pressure-sensitive adhesive, manufactured by Toray Dow Corning Silicone) so that the content of the pressure-sensitive adhesive composition is 5.0% by weight, mix thoroughly. Thus, a pressure-sensitive adhesive composition was obtained. This pressure-sensitive adhesive composition was applied on a polyester film (thickness 25 μm) to a thickness of 50 μm and then heated at 130 ° C. for 5 minutes. Flurbiprofen precipitated in a crystalline state, and a uniform preparation was obtained. I couldn't.

(Determination of solubility of bioactive substances)
The percutaneously absorbable preparations obtained in Examples 8 to 11 and Comparative Examples 3 to 6 were visually determined as follows.

  ○: The physiologically active substance is uniformly dispersed.

  (Triangle | delta): Although bioactive substance is disperse | distributing uniformly, it is opaque.

  X: Dispersion of physiologically active substance is poor and non-uniform.

(Bioactive substance release test)
The above method was used.

(Adhesion test)
The above method was used.

(Skin irritation)
Each strip-shaped preparation sample cut to a width of 5 mm was affixed to the skin, and a rubber roller having a weight of 2 kg was brought into close contact by reciprocating at a speed of 2 m / min, and left for 72 hours. Each tape was peeled from the skin at a speed of 300 mm / min at an angle of 180 °, and then the condition of the skin was observed and evaluated as follows.

  ○: No change with surrounding skin.

  ×: Discolored to red compared to surrounding skin, or peeling of the skin is observed.

  From the above results, the present invention has a skin irritation smaller than that of conventional adhesives, can contain a sufficient amount of a physiologically active substance, and has a good release of the physiologically active substance. It is clear to provide

Claims (13)

  In a skin patch having a pressure-sensitive adhesive composition layer formed on a support, the pressure-sensitive adhesive composition layer comprises a polyether polymer having a siloxane bond, and at least one of the pressure-sensitive adhesive composition layers is a physiologically active substance. A transdermally absorbable preparation comprising: In the percutaneous absorption preparation in which the pressure-sensitive adhesive composition layer is formed on the support, the pressure-sensitive adhesive composition layer (A) is a polyether polymer having at least one alkenyl group at the end,
(B) a compound having 1 to 10 hydrosilyl groups in the molecule,
The transdermally absorbable preparation according to claim 1, wherein the adhesive composition comprising (C) a hydrosilylation catalyst is cured, and at least one layer of the adhesive composition layer contains a physiologically active substance.   The transdermally absorbable preparation according to claim 1 or 2, wherein the pressure-sensitive adhesive composition layer contains (D) an organic liquid component.   The transdermal absorption preparation according to any one of claims 1 to 3, wherein the pressure-sensitive adhesive composition layer contains a transdermal absorption enhancer.   The percutaneously absorbable preparation according to any one of claims 1 to 4, wherein the polyether polymer of the polymer (A) is polyoxypropylene.   The physiologically active substance is dissolved in the polymer (A), mixed with the compound (B) and the catalyst (C), and then cured, which is described in any one of claims 1 to 5. A method for producing a transdermally absorbable preparation.   The physiologically active substance is dissolved in the organic liquid component (D), and then mixed with the polymer (A), the compound (B) and the catalyst (C), and then cured. The manufacturing method of the transdermal absorption preparation of any one of these. A pressure-sensitive adhesive sheet for skin application having a pressure-sensitive adhesive composition layer formed on a support, wherein the pressure-sensitive adhesive composition layer (A) is a polyether polymer (B) having at least one alkenyl group at its terminal. ) A pressure-sensitive adhesive sheet for skin application, which is obtained by curing a compound comprising (C) a hydrosilylation catalyst (D) organic liquid component having 1 to 10 hydrosilyl groups in the molecule.   In the adhesive sheet for skin application in which the adhesive composition layer is formed on the support, the total amount of hydroxyl groups of the compound (B) is 0.4 to 4 per 1 mol of the total amount of alkenyl groups of the polymer (A). The pressure-sensitive adhesive sheet according to claim 8, which has a molar amount of hydrosilyl group.   The pressure-sensitive adhesive sheet according to claim 8 or 9, wherein the polyether polymer of the polymer (A) is polyoxypropylene.   The pressure-sensitive adhesive sheet according to any one of claims 8 to 10, wherein the hydrosilylation catalyst (C) is a platinum-vinylsiloxane complex.   The pressure-sensitive adhesive sheet according to any one of claims 8 to 11, wherein the organic liquid component (D) is a fatty acid ester.   The content ratio of the polymer (A) and the organic liquid component (D) is 1.0: 0.001 to 1.0: 1.5, according to any one of claims 8 to 12. Adhesive sheet.