JP2000297035A - Percutaneous absorption-type pharmaceutical preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation suppressed in causing adhesive transfer on the skin when peeled off, suppressed in the swelling/deformation of a medicament storage layer-forming film due to the solvent for the medicament in a medicament storage layer, and excellent in percutaneous absorbability of the medicament as well. SOLUTION: This pharmaceutical preparation is obtained by encapsulating 2-tert-butylamino-1-(2-chloro-4-hydroxyphenyl)ethan-1-ol or a pharmacologically acceptable salt thereof into a medicament storage layer formed either in a medicament storage layer-forming film itself or by the above film and an impermeable substrate laminated thereon and by laminating the other side of the above film with a fabric layer and a tack agent layer in this order.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to a method for transdermally administering 2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol or a pharmaceutically acceptable salt thereof. Regarding transdermal preparations for administration,
Specifically, the present invention relates to a practical transdermal absorption type preparation which provides good transdermal absorption when administered to the skin surface by providing a fabric layer between a drug storage layer forming film and an adhesive layer in a reservoir type preparation.

[0002]

2. Description of the Related Art In recent years, research and development for transdermal administration of various drugs have been actively conducted in order to maintain the effect and reduce side effects. Is generally low and it is extremely difficult to absorb the required amount of drug from the skin with a practical application area.

[0003] JP-A-10-152434 discloses a transdermal preparation of the present compound, which is a therapeutic agent for impending flow / premature delivery or a dysuria. This percutaneous absorption type preparation is a monolysis type consisting of a support and a drug-containing pressure-sensitive adhesive layer, and has a low solubility in the pressure-sensitive adhesive due to the structure in which the drug is incorporated in the pressure-sensitive adhesive. Most of the compound was in a crystalline form without being able to dissolve in the formulation. In the process of transferring a drug to the skin, a drug in a dissolved state can be transferred to the skin quickly, but a drug in a crystalline state must undergo a step of temporarily dissolving in an adhesive. Because of the rate limiting, the drug release from the preparation was low, and a sufficient amount of the compound could not be absorbed into the skin. The simplest method to improve this, that is, to enlarge the application area, or to increase the thickness of the pressure-sensitive adhesive layer is not necessarily effective because it causes adverse effects such as increased discomfort during application and a longer diffusion distance of the drug. I couldn't say.

[0004] When a drug having a low skin permeability is administered transdermally, as a method for improving its absorption, it is necessary to increase the solubility of the drug in the preparation, that is, to select another adhesive. If it is still insufficient, a method of increasing the drug release from the preparation by adding a solubilizer, and improving skin permeability by adding a transdermal absorption enhancer are generally used.

[0005] However, the above-mentioned monolysis-type preparation has various restrictions in using the above-mentioned means, since the drug is mixed in the adhesive as described above. For example, there is a problem that the dissolving agent or the percutaneous absorption enhancer is not compatible with the pressure-sensitive adhesive, or they are volatilized in the heating step. Therefore, a sufficient amount is not necessarily mixed in the pressure-sensitive adhesive to obtain a desired effect. Not always. In addition, it is necessary to increase the cohesive strength of the pressure-sensitive adhesive in order to hold the liquid component containing the dissolving agent and / or the transdermal absorption enhancer in the pressure-sensitive adhesive, and the pressure-sensitive adhesive has a carboxyl group, a hydroxyl group, and an amino group. In this case, the pressure-sensitive adhesive can be cross-linked by a cross-linking agent, but when the liquid component has the functional group capable of reacting with the cross-linking agent, the reaction of the liquid component with the cross-linking agent occurs preferentially, and Since the crosslinking reaction of the agent is inhibited, the liquid component is not retained in the pressure-sensitive adhesive, and at the same time, the desired medicinal effect cannot be obtained.

[0006]

Therefore, the present inventors formed the drug storage layer-forming film itself or the drug storage layer-forming film and the impermeable support laminated on the drug storage layer-forming film. Attention was paid to a percutaneous absorption-type preparation in which the present compound is encapsulated in a drug storage layer formed and a pressure-sensitive adhesive layer is further laminated on a film for forming a drug storage layer, that is, a percutaneous absorption-type preparation of a reservoir type preparation.

However, in the above-mentioned reservoir-type preparation containing a solubilizer in the drug storage layer, the adhesive force between the pressure-sensitive adhesive layer and the drug storage layer-forming film is weak because a large amount of liquid components is contained.
During application or peeling, the drug storage layer side may be peeled off including the formed film. In addition, the adhesive often remains on the skin at the time of peeling (that is, adhesive residue), and when the drug storage layer forming film shows swelling properties with respect to the dissolving agent, the formulation itself is deformed. There is.

[0008] An object of the present invention is a transdermal absorption-type preparation for suppressing the occurrence of adhesive residue on the skin surface when peeled off, and the drug storage layer-forming film is swollen by the drug solvent in the drug storage layer. It is an object of the present invention to provide a percutaneous absorption-type preparation which can suppress deformation and which is excellent in percutaneous absorption of a drug.

[0009]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, by providing a cloth layer between the drug storage layer forming film and the adhesive layer, the above-mentioned adhesive residue The present inventors have found that a transdermal preparation exhibiting good transdermal absorbability in a small area when administered to the skin without causing deformation and having a small area can be obtained, thereby completing the present invention.

The transdermal preparation of the present invention has the following characteristics. (1) The drug storage layer formed on the drug storage layer forming film itself or the drug storage layer formed by the drug storage layer forming film and the impermeable support laminated on the drug storage layer forming film has a 2-t layer.
ert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethane-1-ol or a pharmaceutically acceptable salt thereof is encapsulated, and a fabric layer is formed on the other surface of the drug storage layer-forming film. And a transdermal preparation comprising an adhesive layer laminated in order. (2) The transdermal absorption preparation according to (1), wherein the drug storage layer further contains a solubilizer and / or a transdermal absorption enhancer. (3) the dissolving agent is an alcohol having 1 to 4 carbon atoms (2)
The percutaneous absorption type preparation according to the above. (4) The percutaneous absorption enhancer is at least one of esters of fatty acids having 12 to 18 carbon atoms, diesters of dicarboxylic acids having 6 to 10 carbon atoms, and glycerin esters of fatty acids having 8 to 10 carbon atoms. Percutaneous absorption preparation. (5) The drug storage layer forming film has a vinyl acetate content of 5 to 4
0% by weight of ethylene-vinyl acetate copolymer (1)
The percutaneous absorption type preparation according to the above. (6) basic p in the drug storage layer and / or the adhesive layer;
The transdermal preparation according to (1), further comprising an H regulator.

In the preparation of the present invention, the fabric layer functions as a backing material of the drug storage layer forming film by providing a fabric layer between the drug storage layer forming film and the adhesive layer of the conventional reservoir type preparation. Further, it is possible to suppress the deformation of the preparation due to the swelling of the drug storage layer forming film. Furthermore, since the adhesiveness between the fabric layer and the pressure-sensitive adhesive layer is good, peeling of the drug storage layer side is suppressed, and the pressure-sensitive adhesive is less likely to remain on the skin.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The drug storage layer may be formed of the drug storage layer forming film itself (that is, in a form surrounded by the drug storage layer forming film). And an impermeable support laminated on the storage layer forming film.

The film for forming the drug storage layer may be a heat-sealable polymer film, for example, a single layer of polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, or the like. Are exemplified.

In particular, an ethylene-vinyl acetate copolymer is preferred in that it has high permeability to polar solvents, and the vinyl acetate content of the ethylene-vinyl acetate copolymer is preferably 5 to 40% by weight. If the vinyl acetate content is less than 5% by weight, the membrane permeability of the dissolving agent will be low, and the transfer of the drug to the pressure-sensitive adhesive layer will be insufficient. Also, 4
If it exceeds 0% by weight, the strength of the film itself becomes insufficient.

The thickness of the drug storage layer forming film is 10 to 100
μm is preferable, and 20 to 50 μm is more preferable.

The impermeable support laminated on the drug storage layer-forming membrane is impermeable to the storage composition (also referred to as a drug-containing liquid composition) in the drug storage layer, and is provided around the preparation. It is preferable that the resin can be heat-sealed with the above-mentioned drug storage layer forming film in the part, and for example, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer and the like can be used. In order to prevent the contents in the layer from passing through the support and being lost from the back surface, the drug-containing liquid composition in the drug storage layer such as a drug such as a metal foil such as polyester or aluminum or a transdermal absorption enhancer or a solvent is used. On the other hand, it is preferable to laminate an impermeable film.

The thickness of the impermeable support is usually 5 to 50
0 μm, preferably in the range of 5 to 200 μm. In addition, these supports have adhesiveness with the drug storage layer forming film,
In order to improve the anchoring property, a surface on which the drug storage layer forming film is laminated may be subjected to a corona discharge treatment, a plasma treatment, an oxidation treatment, or the like.

The fabric layer needs to be formed between the drug storage layer forming film and the pressure-sensitive adhesive layer, and the fabric is heat-sealed or pressure-bonded to the forming film. The fabric is not particularly limited as long as it is porous, can be well adhered to the pressure-sensitive adhesive layer, and can be heat-fused or pressure-bonded to the drug storage layer-forming film. Examples thereof include woven fabric and nonwoven fabric. You. Examples of the material constituting the fabric layer include polyester, polypropylene, rayon, nylon, and cellulose. Further, a porous film may be laminated on the fabric layer, and such a laminate is also included in the fabric layer according to the present invention. As the porous film, it is preferable to use a film which can be used as the drug storage layer-forming film or a film having an air permeability (Gurley method) of 9000 sec / 100 cc or less. The laminate is usually used such that the pressure-sensitive adhesive layer comes into contact with the cloth. The fabric layer adheres strongly to the pressure-sensitive adhesive layer due to its excellent anchor effect. For example, even if the plasticizing of the pressure-sensitive adhesive becomes remarkable due to the dissolving agent, the drug storage layer side including the formed film is prevented from peeling off during application or peeling, and adhesive residue on the skin surface during peeling is suppressed. Further, since the fabric layer prevents the drug storage layer forming film from being swelled and deformed by a large amount of liquid components, even if the drug storage layer forming film is swellable with respect to the dissolving agent used, The deformation of the preparation of the present invention can be suppressed by the presence of the layer.

In the drug storage layer, 2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol or a pharmacologically acceptable salt thereof (hereinafter referred to as the present compound) is contained. It is enclosed.

The present compound contained in the drug storage layer has an asymmetric carbon in the molecule and has two types of optical isomers, a (-) form and a (+) form. The (-) form and the (±) form having activity are preferably used. The compound can be produced by a method known per se.

The pharmacologically acceptable salts of the compound bases include acid addition salts and alkali addition salts.
Examples of the acid addition salts include, for example, inorganic acid salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid , Methanesulfonic acid, p-toluenesulfonic acid,
Organic acid salts with mandelic acid, 10-camphorsulfonic acid, tartaric acid, succinic acid and the like. Examples of the alkali addition salt include salts with sodium, potassium, calcium and the like. As another organic acid salt for forming a salt, a specific fatty acid salt having enhanced lipophilicity of the present compound base can be used. Such fatty acids include:
From the viewpoint of having lipophilicity suitable for transdermal absorption and having a molecular size suitable for transdermal absorption, it has 8 to 18 carbon atoms.
Are preferred, and specific examples include caprylic acid, 2-octenoic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, sebacic acid and the like.

The compounding amount of the present compound in the composition enclosed in the drug storage layer is preferably 0.5 to 30% by weight. If the amount is less than 0.5% by weight, the therapeutic effect becomes insufficient and 3
Exceeding 0% by weight is not preferable from the viewpoint of drug utilization.

It is preferable that the drug storage layer further contains a solubilizer and / or a transdermal absorption enhancer.

The mixing ratio of the dissolving agent and the present compound is 10
The compound is preferably used in an amount of 1 to 50 parts by weight, more preferably 10 to 30 parts by weight, based on 0 parts by weight.

The mixing ratio of the percutaneous absorption enhancer to the present compound is preferably 10 to 1000 parts by weight, more preferably 20 to 100 parts by weight, per 100 parts by weight of the percutaneous absorption enhancer.
500 parts by weight.

When a solubilizer and a transdermal absorption enhancer are encapsulated in the drug storage layer, the mixing ratio of the two is such that the transdermal absorption enhancer is 3 to 200 parts by weight per 100 parts by weight of the solubilizer. preferable. When the amount is less than 3 parts by weight, a sufficient amount of the transdermal absorption enhancer cannot be contained in the pressure-sensitive adhesive, so that the desired enhancing effect cannot be obtained. This is not preferred because the relative amount of the dissolving agent of the formula (1) decreases, and the solubility of the compound decreases.

A solubilizing agent is added to increase the solubility of the compound, and the dissolved drug permeates the skin, preferably through the intervention of a transdermal absorption enhancer. Therefore, it is preferable that the solubilizer dissolves the present compound and is mixed with the transdermal absorption enhancer described later. Examples of suitable solubilizers include alcohols having 1 to 4 carbon atoms.
Examples of the alcohol having 1 to 4 carbon atoms include methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-
Butyl alcohol is exemplified.

As the transdermal absorption enhancer, esters of fatty acids having 12 to 18 carbon atoms, 6 to 6 carbon atoms, in terms of increasing the transdermal absorbability of the present compound and having good compatibility with the above-mentioned solubilizers. diester of 10 dicarboxylic acids and carbon number 8 to
It is preferable to use at least one selected from glycerin esters of 10 fatty acids.

The fatty acid ester has 12 carbon atoms.
To 18 aliphatic monocarboxylic acid alkyl esters, for example, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid and the like and alcohols having 1 to 10 carbon atoms, for example, methyl alcohol, ethyl alcohol, n
-Propyl alcohol, isopropyl alcohol, n-
Butyl alcohol, isobutyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol,
Esters such as octyl alcohol, nonyl alcohol and isononyl alcohol are exemplified.

The diester of a dicarboxylic acid is preferably a dialkyl ester of an aliphatic dicarboxylic acid having 6 to 10 carbon atoms, and examples thereof include diesters of adipic acid, sebacic acid and an alcohol having 1 to 10 carbon atoms.

As the glycerin ester of a fatty acid, a glycerin ester of a fatty acid having 8 to 10 carbon atoms, for example, monoglyceride of caprylic acid, monoglyceride of capric acid,
And caprylic acid triglyceride.

Further, in order to improve the operability during the production of the composition enclosed in the drug storage layer, glycerin, propylene glycol, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylcellulose and the like may be added as necessary. It is possible to thicken.

When the present compound is an acid addition salt, it is preferable to include a basic pH adjuster in the drug storage layer and / or the pressure-sensitive adhesive layer. By adding a basic pH adjuster to the present compound in the form of an acid addition salt, for example, sodium hydroxide, triethanolamine, triisopropanolamine, etc., to release the salt of the present compound in the form of a salt, The present compound, which is a base having higher transdermal absorbability than a salt, can be obtained. It is preferable to add the basic pH adjuster in an amount necessary to neutralize the acid added to the present compound in the form of a base.

When the amount is less than this, the amount of base formed is small and transdermal absorbability is slightly inferior, but the drug stability in the preparation is excellent. It becomes basic and may cause skin irritation when applied to the skin.

The amount of the composition to be filled in the drug storage layer into the drug storage layer is preferably 50 μL / cm ² or less, and if it exceeds 50 μL / cm ² , the composition cannot be retained in the drug storage layer. The composition or the composition that has migrated from the drug storage layer to the pressure-sensitive adhesive layer is not sufficiently retained in the pressure-sensitive adhesive and separates (blooming) from the pressure-sensitive adhesive component, or the plasticization of the pressure-sensitive adhesive becomes remarkable. Adhesive residue may occur on the surface.

The pressure-sensitive adhesive layer and / or the drug storage layer may include, if necessary, p-acid such as citric acid, lactic acid, gluconic acid, etc., in addition to the basic pH adjuster and the transdermal absorption enhancer.
H regulators, solubilizers, stabilizers such as antioxidants such as ascorbic acid, tocopherol, and dibutylhydroxytoluene; plasticizers such as glycerin, propylene glycol, and polyethylene glycol; titanium oxide, zinc oxide, and hydrated silicon dioxide Various known additives such as fillers may be blended.

The pressure-sensitive adhesive layer may cover the entire surface of the percutaneously absorbable preparation, or may cover only the edge of the preparation in a frame shape with an appropriate width.

The polymer used for the pressure-sensitive adhesive layer is a pressure-sensitive adhesive polymer having tackiness at room temperature, and is preferably one that can dissolve the above-mentioned mixed solution of a solubilizer and a transdermal absorption enhancer. Preferred examples of the pressure-sensitive adhesive include an acrylic pressure-sensitive adhesive and a rubber-based pressure-sensitive adhesive.

Examples of the acrylic pressure-sensitive adhesive include a homopolymer of an alkyl acrylate or an alkyl methacrylate or a copolymer thereof. Here, the alkyl in the alkyl acrylate or alkyl methacrylate is a linear or branched alkyl having 1 to 18 carbon atoms, and specifically, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl , Isooctyl, 2-ethylhexyl, nonyl, isononyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl and the like. Preferably, it is a linear or branched alkyl having 4 to 12 carbon atoms. Further, as the acrylic pressure-sensitive adhesive used in the present invention, a copolymer of the above-mentioned alkyl acrylate and / or alkyl methacrylate and one or more of the following monomers is also preferably used. be able to.

The monomer having a carboxyl group (for example, acrylic acid, itaconic acid, maleic acid,
Maleic anhydride), those having a sulfonic acid group (for example, styrene sulfonic acid, allyl sulfonic acid, sulfopropyl acrylate, acryloyloxynaphthalene sulfonic acid, acrylamidomethylpropane sulfonic acid), hydroxy lower alkyl acrylate (for example, acrylic acid) Hydroxymethyl, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate), acrylamide, acrylamide derivatives (for example, dimethylacrylamide, N-butylacrylamide, N-methylolacrylamide, N
-Methylolpropane acrylamide), aminoalkyl acrylate (eg, aminoethyl acrylate), alkylaminoalkyl acrylate (eg, dimethylaminoethyl acrylate, tert-butylaminoethyl acrylate), alkoxy acrylate Alkyl esters (eg, methoxyethyl acrylate, ethoxyethyl acrylate), tetrahydrofurfuryl acrylate, esters of acrylic acid and methoxydiethylene glycol, esters of acrylic acid and methoxypolyethylene glycol, acrylic acid and methoxypolypropylene glycol And lower alkyl esters of hydroxy methacrylate (for example, hydroxymethyl methacrylate, Hydroxyethyl acrylic acid, hydroxypropyl methacrylate, methacrylic acid hydroxybutyl) methacrylamide, methacrylamide derivatives (e.g., dimethyl methacrylamide, N- methacrylamide, N- methylolmethacrylamide, N-
Methylol propane methacrylamide), aminoalkyl methacrylate (eg, aminoethyl methacrylate), alkylaminoalkyl methacrylate (eg, dimethylaminoethyl methacrylate, tert-butylaminoethyl methacrylate), alkoxy methacrylate Alkyl esters (eg, methacrylic acid methoxyethyl ester, methacrylic acid ethoxyethyl ester), methacrylic acid tetrahydrofurfuryl ester, methacrylic acid and methoxydiethylene glycol, methacrylic acid and methoxypolyethylene glycol, methacrylic acid and methoxypolypropylene glycol With esters, methacrylonitrile, acrylonitrile, vinyl acetate, propionic acid Alkenyl, vinyl pyrrolidone, methyl vinyl pyrrolidone, vinyl pyridine, vinyl piperidone,
Vinyl pyrimidine, vinyl pyrazine, vinyl pyrazine, vinyl pyrrole, vinyl imidazole, vinyl caprolactam, vinyl oxazole, vinyl morpholine,
Styrene and the like.

In the case where a copolymer comprising the above monomer and an alkyl acrylate and / or alkyl methacrylate is used as the acrylic pressure-sensitive adhesive, alkyl acrylate and / or alkyl methacrylate 30 to 30% are used. It is preferable to copolymerize at a rate of 99.5% by weight, preferably 50 to 90% by weight, and 0.5 to 70% by weight of the above monomer, preferably 10 to 50% by weight.

Further, by using the acrylic pressure-sensitive adhesive having a crosslinked structure, sufficient cohesive force can be provided even when the dissolving agent or the transdermal absorption enhancer significantly plasticizes the pressure-sensitive adhesive layer. be able to. The cross-linking treatment can be performed when a monomer containing a carboxyl group or a hydroxyl group is used as a component of the acrylic pressure-sensitive adhesive. As the cross-linking agent, a metal alcoholate made of titanium or aluminum, a metal Chelate compounds, polyfunctional isocyanates (especially trifunctional isocyanates) and the like can be mentioned. These crosslinking agents are usually added in a range of 0.05 to 5 parts by weight based on 100 parts by weight of the acrylic polymer.

The rubber-based pressure-sensitive adhesive has a viscosity average molecular weight of 300,0
Those containing from 00 to 2,500,000 high molecular weight rubber-based polymers are preferably used. The high-molecular-weight rubber-based polymer is an essential component for imparting a suitable cohesive force to the rubber-based pressure-sensitive adhesive, and is preferably contained in the rubber-based pressure-sensitive adhesive in an amount of 10% by weight or more, more preferably 20% by weight.
That is all. Examples of the high molecular weight rubber-based polymer include polyisobutylene, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, and the like.One or more of these may be used. It can be used as a mixture.

In order to impart appropriate tackiness to the rubber-based pressure-sensitive adhesive, a rosin-based resin, a polyterpene resin, a coumarone-indene resin, a petroleum-based resin, a terpene-phenol resin, a xylene resin, A tackifier such as an alicyclic saturated hydrocarbon resin may be blended.

Preferred examples of the rubber-based pressure-sensitive adhesive include a high-molecular-weight polyisobutylene having a viscosity-average molecular weight of 300,000 to 2,500,000.
It is preferable to contain 0000 to 200,000 medium molecular weight polyisobutylene and / or low molecular weight polyisobutylene or polybutene having a viscosity average molecular weight of 500 to 4,000. Here, high molecular weight polyisobutylene was added to 1
0 to 80% by weight, preferably 20 to 70% by weight, and 0 to 90% by weight, preferably 10 to 90% by weight of a medium molecular weight polyisobutylene.
It is preferable to blend the low molecular weight polyisobutylene or polybutene in the range of 0 to 80% by weight, preferably 10 to 60% by weight. In the present invention, the viscosity average molecular weight is calculated from the Flory viscosity equation.

The thickness of the pressure-sensitive adhesive layer is from 10 to 100 μm so that sufficient skin adhesion that can withstand long-time application can be obtained.
It is preferable that

The pressure-sensitive adhesive layer may contain the above-mentioned transdermal absorption enhancer. The amount of the transdermal absorption enhancer is 100 parts by weight or less based on 100 parts by weight of the pressure-sensitive adhesive polymer. When the amount is more than 100 parts by weight, the adhesive component and the transdermal absorption enhancer may not be retained in the adhesive and may be separated (blooming) on the surface of the adhesive, resulting in poor skin adhesion.

The transdermal preparation of the present invention preferably covers and protects the exposed surface of the pressure-sensitive adhesive layer with a release liner. The release liner is not particularly limited as long as it can be easily peeled off from the pressure-sensitive adhesive layer at the time of use. For example, a release treatment is performed by applying a silicone resin, a fluororesin, or the like to a surface in contact with the pressure-sensitive adhesive layer. For example, a film of polyester, polyvinyl chloride, polyvinylidene chloride, polyethylene terephthalate, or the like, a paper of high quality paper, glassine paper, or the like, or a laminated film of high quality paper or glassine paper and a polyolefin is used. The release liner has a thickness of usually 10 to 200 μm, preferably 50 to 100 μm.

FIGS. 1 and 2 show examples of cross-sectional views of the transdermal preparation of the present invention.

The method for producing the transdermal preparation of the present invention is not particularly limited, and examples thereof include the following. After applying the adhesive on the release liner and drying,
The fabric is laminated and thermally fused with the drug storage layer forming film. Thereafter, the impermeable support is heat-sealed at a suitable inner diameter and seal width except for the drug storage layer solution inlet, and cut off along the outer periphery of the heat-sealed portion. Next, after injecting the drug storage layer solution containing the present compound from the injection port, the injection port is completely sealed by heat sealing to obtain the transdermal preparation of the present invention.

When the drug storage layer is formed on the drug storage layer forming film itself, the drug storage layer forming film is laminated on one side of the impermeable support in advance, and the formed film side and the adhesive The layer, the fabric, and the film formed by laminating the drug storage layer forming film in this order are heat-sealed except for the injection port. Next, similarly to the above, after injecting the drug storage layer solution from the injection port, the injection port is completely sealed by heat sealing to obtain the transdermally absorbable preparation of the present invention.

For the prevention and treatment of urgency flow, premature birth, dysuria, etc.
Dose of the transdermal preparation of the present invention in
Depending on age, weight, symptoms, etc.
Containing 0.1 to 500 mg of the compound at a time.
The formulation is 1-100 cm of skin ^TwoOnce a day-7 days
About once.

[0053]

EXAMPLES Examples of the present invention will be shown below, and the present invention will be described more specifically. In the following, parts and% mean parts by weight and% by weight, respectively.

Tables 1 and 2 show a list of these compositions.

[0055]

[Table 1]

[0056]

[Table 2]

(Preparation of Adhesive Solution A) High molecular weight polyisobutylene (viscosity average molecular weight 2,100,000, VIS
TANEX MML-140, manufactured by Exxon Chemical Co.) 50
Parts, medium molecular weight polyisobutylene (viscosity average molecular weight 60,
000, HIMOL 6H, 30 parts by Nippon Petrochemical Co., Ltd.) and an alicyclic petroleum resin (softening point 100 ° C., Alcon P)
(-100, Arakawa Chemical Co., Ltd.) was dissolved in hexane to prepare a rubber-based pressure-sensitive adhesive solution A.

(Preparation of Pressure-Sensitive Adhesive Solution B) An acrylic pressure-sensitive adhesive solution B was prepared by copolymerizing 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid in ethyl acetate under an inert gas atmosphere.

Example 1 To the pressure-sensitive adhesive solution A, isopropyl myristate was added so as to have a compounding amount of 40% with respect to the pressure-sensitive adhesive solid content, mixed, and dried on a release liner (peeled 75 μm-thick polyester film). Coating and drying were performed so that the thickness afterwards became 40 μm. The polyester non-woven fabric (basis weight 8g /
m ² ), and a 50 μm-thick ethylene-vinyl acetate copolymer film (vinyl acetate content: 14%) was heat-sealed. Seal width 4m
The solution was heat-sealed while leaving the drug storage layer solution inlet so as to obtain m, and cut along the outer periphery of the heat-sealed portion.

Then, (-)-2-te was added to a mixed solution of ethyl alcohol and isopropyl myristate (mixing ratio 7: 3).
Liquid for drug storage layer to which rt-butylamino-1- (2-chloro-4-hydroxyphenyl) ethane-1-ol (hereinafter referred to as (-)-the present compound base) is added to a concentration of 20%. After injecting 50 μL from the injection port, the injection port was completely sealed by heat sealing to obtain a percutaneous absorption-type preparation of the present invention.

Example 2 In Example 1, a polyisocyanate compound (Coronate HL, manufactured by Nippon Polyurethane Co.) was added to the adhesive solution B in an amount of 0.15% based on the solid content of the adhesive. A transdermal preparation of the present invention was obtained in the same manner as in Example 1, except that the compound was added in an amount of 20% to a mixed solution of isopropyl myristate-caprylic acid monoglyceride (mixing ratio 6: 2: 2).

Example 3 In Example 2, the drug storage layer solution was changed to ethyl alcohol-
Example 2 except that 20% of (-)-the present compound base was added to a mixed solution of diisopropyl sebacate (mixing ratio 7: 3).
In the same manner as in the above, a transdermal preparation of the present invention was obtained.

Example 4 In Example 1, the drug storage layer solution was changed to ethyl alcohol-
Example 1 except that 20% of (-)-the present compound base was added to a mixed solution of isopropyl myristate (mixing ratio 20: 1).
In the same manner as in the above, a transdermal preparation of the present invention was obtained.

Example 5 A transdermal preparation of the present invention was obtained in the same manner as in Example 1 except that the vinyl acetate content of the ethylene-vinyl acetate copolymer was changed to 5%.

Example 6 In Example 1, the drug storage layer solution was mixed with an isopropyl alcohol-isopropyl myristate mixed solution (mixing ratio: 7:
A transdermal preparation of the present invention was obtained in the same manner as in Example 1, except that 15% of (-)-the present compound base was added to 3).

Example 7 In Example 1, the drug storage layer solution was changed to ethyl alcohol-
A mixture of isopropyl myristate (mixing ratio 20: 1) to which 15% and 3% of (-)-tartrate salt of the present compound and sodium hydroxide are added, respectively, and a vinyl acetate content of an ethylene-vinyl acetate copolymer Was changed to 33% to obtain a transdermal preparation of the present invention in the same manner as in Example 1.

Comparative Example 1 (Reservoir Type Preparation) A transdermal preparation was obtained in the same manner as in Example 1, except that the polyester nonwoven fabric was not laminated between the pressure-sensitive adhesive layer and the drug storage layer forming film.

Comparative Example 2 (Monolysis Type Preparation) The adhesive solution A was prepared by adding (-)-the present compound base and isopropyl myristate to the adhesive solid content in an amount of 1 respectively.
It was added and mixed so as to be 0% and 40%, and applied and dried on a release liner so that the thickness after drying became 40 μm. The nonwoven fabric side of a support (a laminated film of a nonwoven fabric made of polyester having a basis weight of 8 g / m ² and a polyester film having a thickness of 6 μm) was adhered thereto to obtain a percutaneously absorbable preparation.

Experimental Example 1 In the transdermal preparations of Examples 1 to 7 and Comparative Examples 1 and 2, the amount of the drug permeated through the skin was measured using the abdominal skin of a excised and dehaired rat. (Measurement method) Rat skin was attached to a glass permeation cell so that the part corresponding to the front side of the skin was in contact with the transdermal preparation, and the part corresponding to the back side of the skin was in contact with physiological saline. The permeated drug was quantified by high performance liquid chromatography. This result is shown in FIG. 3 as a change with time of the accumulated drug permeation amount.

The preparation of Comparative Example 1 was significantly more deformed than the one of the present invention, such as wrinkles and ripples. In addition, when peeled from the skin, the peeling occurred between the drug storage layer forming film and the adhesive layer, and the adhesive layer remained on the skin surface.

The transdermal preparation of the present invention exhibited better skin permeability than that of Comparative Example 2.

[0072]

According to the transdermal preparation of the present invention, since the fabric layer is provided between the drug storage layer forming film and the pressure-sensitive adhesive layer, the drug storage layer forming film and the pressure-sensitive adhesive layer are strongly adhered. In addition, adhesive residue is suppressed when the drug storage layer forming film and the pressure-sensitive adhesive layer are peeled off and peeled off from the skin after use. Also, due to the presence of the fabric layer,
Even when the drug storage layer forming film shows swelling properties with respect to the dissolving agent, deformation of the preparation itself is suppressed. In addition, the preparation of the present invention is a transdermal preparation with excellent transdermal absorbability of the drug.

[Brief description of the drawings]

FIG. 1 is a cross-sectional view schematically showing a transdermal preparation of the present invention.

FIG. 2 is a cross-sectional view schematically showing a transdermal preparation of the present invention.

FIG. 3 is a graph showing the amount of drug permeated through the skin in the transdermal preparations of Examples and Comparative Examples as a change with time of the accumulated drug permeation amount.

[Explanation of symbols]

 REFERENCE SIGNS LIST 1 transdermal absorption preparation 2 support 3 drug storage layer 4 drug storage layer forming film 5 fabric 6 adhesive layer 7 release liner

Continued on the front page (72) Inventor Mitsuhiko Hori 1-1-2 Shimohozumi, Ibaraki-shi, Osaka Nitto Denko Corporation (72) Inventor Yoshihisa Nakano 1-1-2 Shimohozumi, Ibaraki-shi, Osaka Nitto Denko stock In-company (72) Inventor Osamu Nagata 37-1, Inoguchi 37, Katsuyama-shi, Fukui Prefecture Hokuriku Pharmaceutical Co., Ltd. (72) Inventor Kazuya Matsuo 1-1-1, Inoguchi 37, Katsuyama-shi, Fukui Pharmaceutical F term (reference) 4C076 AA74 AA77 AA81 BB31 CC17 DD37E DD43Z DD45N DD46N DD47N EE03A EE24A FF03 FF04 4C206 AA01 AA02 FA11 KA01 MA03 MA05 MA52 MA83 NA11 NA12 ZA81

Claims (6)

[Claims] 1. The method according to claim 1, wherein the film is formed on the drug storage layer forming film itself,
Alternatively, 2-tert-butylamino-1- (2-chloro-4) may be added to the drug storage layer formed by the drug storage layer forming film and the impermeable support laminated on the drug storage layer forming film.
-Hydroxyphenyl) ethane-1-ol or a pharmacologically acceptable salt thereof is encapsulated, and a percutaneous absorption in which a fabric layer and an adhesive layer are sequentially laminated on the other surface of the drug storage layer forming film Type formulation. 2. The percutaneous absorption preparation according to claim 1, wherein a solubilizer and / or a percutaneous absorption enhancer is further enclosed in the drug storage layer. 3. The transdermally absorbable preparation according to claim 2, wherein the solubilizer is an alcohol having 1 to 4 carbon atoms. 4. The transdermal absorption enhancer is at least one of esters of fatty acids having 12 to 18 carbon atoms, diesters of dicarboxylic acids having 6 to 10 carbon atoms and glycerin esters of fatty acids having 8 to 10 carbon atoms. 2. The transdermally absorbable preparation according to 2. 5. The percutaneously absorbable preparation according to claim 1, wherein the drug storage layer forming film is an ethylene-vinyl acetate copolymer having a vinyl acetate content of 5 to 40% by weight. 6. The transdermal preparation according to claim 1, wherein the drug storage layer and / or the pressure-sensitive adhesive layer contains a basic pH adjuster.