JPH10152434A - Transdermal formulation - Google Patents

Abstract

(57) [Summary] [PROBLEMS] _{2 as an} adrenergic β ₂ -receptor stimulant
Using -tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol or a pharmaceutically acceptable salt thereof (the present compound), and having excellent transdermal absorbability of the drug; Provided is a percutaneous absorption-type preparation which can maintain its effects for a long time, has few side effects, and is useful for the prevention and treatment of urination disorders such as urgency flow, premature birth and urinary incontinence. A plaster layer containing the present compound and an adhesive is provided on one surface of a support, and the adhesive is an acrylic polymer substantially containing no carboxyl group, or The adhesive has at least one average molecular weight of 30
High molecular weight rubber component content of 0,000-2,500,000 and carbon number
A transdermal preparation comprising at least one additive selected from esters of 12-18 fatty acids, monoglycerides of fatty acids having 8-10 carbon atoms, and esters of dibasic acids having 6-10 carbon atoms.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol or a pharmaceutically acceptable salt thereof (hereinafter referred to as the compound of the present invention). Percutaneous absorption) for percutaneous administration of percutaneously administered, which, when applied to the skin surface, has excellent skin adhesion and can maintain the effective blood concentration of the compound for a long period of time. Type formulation.

[0002]

BACKGROUND OF THE INVENTION The present compound is a compound having an excellent adrenergic β ₂ -receptor stimulating action, and is used for the prevention and treatment of urinary disorders such as impending flow, premature birth and urinary incontinence. (Japanese Patent Publication No. 7-119189).

[0003] Conventionally, in the treatment of impending flow and premature birth, luteinizing hormone preparations and ritodrine, which is a β ₂ -receptor stimulant, have been used, but all of them are injectable or oral. It is believed that there is room for improvement in terms of sustained efficacy, side effects and patient compliance. In the treatment of urinary incontinence, urination disorders such as nocturnal enuresis, oxybutynin, smooth muscle relaxants such as flavoxate and anticholinergic agents have been used,
The problem of side effects specific to these drugs has not been sufficiently overcome. In addition, these patients with urinary disorders are elderly,
Because of the bias toward children, there is a need for a formulation that improves swallowing power, improves swallowability, and takes patient compliance into account. In recent years, research and development of transdermal preparations of various drugs have been actively conducted in order to maintain the effect and reduce side effects, but the percutaneous absorption of drugs is generally limited due to the barrier function of the skin. It is extremely difficult to absorb the required amount of drug from the skin with a low, practical application area.

It is an object of the present invention to provide an excellent adrenergic β
Using the present compound, which is a compound having a ₂ -receptor stimulating action, is excellent in skin permeability of the present compound, has a long lasting effect and has few side effects, prevention of impending flow, premature birth or urinary disturbance,
It is an object of the present invention to provide a transdermal preparation useful for treatment.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above object, and as a result, have found that an adhesive comprising a specific acrylic polymer or a high molecular weight rubber component and a specific additive is used. In a percutaneous absorption-type preparation in which a plaster layer comprising the present compound is provided on one side of the support, a good transdermal absorbability of the present compound is obtained, and the effect is maintained for a long time. In addition, the present inventors have found that the use of a transdermal preparation reduces side effects such as tremor and palpitations associated with a rapid increase in blood concentration, thereby completing the present invention.

That is, the present invention is as follows. A plaster layer containing the present compound and the pressure-sensitive adhesive is provided on one surface of the support, and the pressure-sensitive adhesive is an acrylic polymer substantially containing no carboxyl group, or the pressure-sensitive adhesive is at least One kind of average molecular weight 300,000 ~
2,500,000 high molecular weight rubber component content, at least one selected from esters of fatty acids having 12 to 18 carbon atoms, monoglycerides of fatty acids having 8 to 10 carbon atoms, and esters of dibasic acids having 6 to 10 carbon atoms A transdermal preparation, characterized by comprising an additive. The process according to the above, wherein the acrylic polymer is a copolymer comprising 2-ethylhexyl acrylate and at least one selected from hydroxyethyl acrylate, methyl methacrylate, 2-methoxyethyl acrylate, vinyl acetate, and vinylpyrrolidone. Skin absorption type preparation. The high molecular weight rubber component content has an average molecular weight of 500 to 4,
000 low molecular weight polyisobutylene or polybutene,
And / or an average molecular weight of 10,000 to 200,00
0 medium molecular weight polyisobutylene and an average molecular weight of 300,
The percutaneous absorption preparation according to the above, which is a mixture comprising 000 to 2,500,000 high molecular weight polyisobutylene. 2-tert-butylamino-1- (2-chloro-4
A pharmacologically acceptable salt of -hydroxyphenyl) ethane-1-ol is 2-tert-butylamino-1-
(2-chloro-4-hydroxyphenyl) ethane-1-
All tartrate or 2-tert-butylamino-
1- (2-chloro-4-hydroxyphenyl) ethane-
The percutaneous absorption-type preparation according to the above, which is a fatty acid salt of 1-ol having 8 to 18 carbon atoms. The percutaneous absorption-type preparation as described above, further comprising a basic pH adjuster in the plaster layer. The percutaneous absorption-type preparation according to any one of the above, which is a therapeutic agent for threatening premature birth. The transdermal preparation according to any one of-, which is a therapeutic agent for dysuria.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION An acrylic polymer, which is one of the pressure-sensitive adhesives used in the present invention, does not contain a carboxyl group and does not react with the present compound, so that it has excellent drug release and stability. , And more excellent durability. Here, the acrylic polymer substantially containing no carboxyl group refers to an acrylic polymer obtained by polymerization using a monomer having a carboxyl group modified such as acrylic acid or methacrylic acid.

The acrylic polymer includes, for example, a homopolymer of an alkyl acrylate or an alkyl methacrylate, or a copolymer thereof. Here, the alkyl in the alkyl acrylate or the alkyl methacrylate is a linear or branched alkyl having 1 to 18 carbon atoms,
Specific examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, 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 polymer used in the present invention, a copolymer of the above-mentioned alkyl acrylate and / or alkyl methacrylate with one or more of the following monomers is also preferable. Can be used for

Examples of the monomer include hydroxy lower alkyl acrylate (eg, hydroxymethyl acrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate), acrylamide, and acrylamide derivatives (eg, dimethylacrylamide, N-butylacrylamide, N-methylolacrylamide, N-methylolpropaneacrylamide), aminoalkyl acrylate (for example, aminoethyl acrylate), alkylaminoalkyl acrylate (for example, dimethylaminoethyl acrylate, acrylic acid) tert-butylaminoethyl ester), alkoxyalkyl acrylate (e.g., methoxyethyl acrylate, acryl) Ethoxyethyl ester), tetrahydrofurfuryl acrylate, ester of acrylic acid with methoxydiethylene glycol, ester of acrylic acid with methoxypolyethylene glycol, ester of acrylic acid with methoxypolypropylene glycol, hydroxy lower alkyl methacrylate (for example, Hydroxymethyl methacrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, hydroxybutyl methacrylate), methacrylamide, methacrylamide derivatives (eg, dimethyl methacrylamide, N-butyl methacrylamide, N-methylol methacrylamide, N-methylol propane) Methacrylamide), aminoalkyl methacrylate (eg, aminoethyl methacrylate) ), Alkyl methacrylate aminoalkyl esters (e.g., dimethylaminoethyl methacrylate, methacrylic acid te
rt-butylaminoethyl ester), alkoxyalkyl methacrylate (eg, methoxyethyl methacrylate, ethoxyethyl methacrylate), tetrahydrofurfuryl methacrylate, ester of methacrylic acid with methoxydiethylene glycol, methacrylic acid with methoxypolyethylene Ester with glycol, ester with methacrylic acid and methoxypolypropylene glycol, methacrylonitrile, acrylonitrile, vinyl acetate, vinyl propionate, vinylpyrrolidone, methylvinylpyrrolidone, vinylpyridine, vinylpiperidone, vinylpyrimidine, vinylpiperazine, vinylpyrazine, vinyl Pyrrole, vinylimidazole, vinylcaprolactam, vinyloxazole, vinylmorpholy , Styrene and the like.

When a copolymer comprising the above monomer and an alkyl acrylate and / or alkyl methacrylate is used as the acrylic polymer, the alkyl acrylate and / or alkyl methacrylate 30 It is desirable that the copolymer be copolymerized at a ratio of from 9 to 99.5% by weight, preferably from 50 to 90% by weight, from 0.5 to 70% by weight, preferably from 10 to 50% by weight of the monomer.

Particularly preferred acrylic polymers include 2-ethylhexyl acrylate, hydroxyethyl acrylate, methyl methacrylate and 2-acrylic acid.
Examples of the copolymer include at least one selected from methoxyethyl, vinyl acetate, and vinylpyrrolidone. More specifically, 2-ethylhexyl acrylate 7
0 to 95% by weight and hydroxyethyl acrylate 5 to 30
Weight percent of a copolymer or 2-ethylhexyl acrylate 60-90 weight% and methyl methacrylate 10-40
A copolymer consisting of 30 to 70% by weight of 2-ethylhexyl acrylate, 10 to 50% by weight of 2-methoxyethyl acrylate, and 10 to 50% by weight of vinyl acetate; Ethylhexyl 50
Or a copolymer consisting of 10 to 50% by weight of vinylpyrrolidone and 30 to 30% by weight of 2-ethylhexyl acrylate.
80% by weight, 10 to 40% by weight of methyl methacrylate and 3 to 30% by weight of 2-methoxyethyl acrylate.

The high-molecular weight rubber component-containing material, which is another adhesive used in the present invention, has an average molecular weight of 300,00.
It is not particularly limited as long as it contains a high molecular weight rubber component of 0 to 2,500,000 and does not adversely affect the release and stability of the compound. The high molecular weight rubber component,
It is an essential component for imparting a cohesive force suitable for skin adhesion to the pressure-sensitive adhesive, and is preferably contained in the high-molecular-weight rubber component-containing material in an amount of 10% by weight or more, more preferably 20% by weight or more. When this component is not contained, the possibility that glue protrudes from the periphery of the preparation at the time of application or remains on the skin surface at the time of peeling off increases.

In order to impart appropriate tackiness to the high molecular weight rubber component-containing material, for example, rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin, terpene-phenyl resin, xylene resin, alicyclic resin A tackifier such as an aromatic saturated hydrocarbon resin may be blended.

As the high-molecular-weight rubber component contained in the high-molecular-weight rubber component used in the pressure-sensitive adhesive of the present invention, specifically, polyisobutylene, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymer (SIS) Styrene-butadiene-styrene block copolymer (SBS) and the like, and these can be used as one kind or as a mixture of two or more kinds.

Among them, it is preferable to use polyisobutylene as an adhesive component from the viewpoints of interaction with a drug, release property, etc. In this case, an essential component having an average molecular weight of 300,000 to 2,500,000 is used. Contains high molecular weight polyisobutylene, and further has an average molecular weight of 10,000
~ 200,000 medium molecular weight polyisobutylene and / or
Or, it preferably contains low molecular weight polyisobutylene or polybutene having an average molecular weight of 500 to 4,000. Here, 10 to 80% by weight of high molecular weight polyisobutylene,
Preferably 20 to 70% by weight, medium molecular weight polyisobutylene in the range of 0 to 90% by weight, preferably 10 to 80% by weight, low molecular weight polyisobutylene or polybutene in the range of 0 to 80% by weight, preferably 10 to 60% by weight. It is desirable to mix.

In the present invention, the average molecular weight is a viscosity average molecular weight calculated from Flory's viscosity formula.

In the present invention, when a high-molecular-weight rubber component-containing material is used as the pressure-sensitive adhesive, it is necessary to promote the diffusion of the present compound in the plaster layer, obtain a good release property, and provide an appropriate amount to the skin. In order to obtain adhesive strength, it has excellent compatibility with adhesives, dissolves this compound sufficiently, does not cause separation of the adhesive components and additives over time (blooming), and has good adhesive properties and release properties. Additives that do not adversely affect, that is, at least one additive selected from esters of fatty acids having 12 to 18 carbon atoms, monoglycerides of fatty acids having 8 to 10 carbon atoms and esters of dibasic acids having 6 to 10 carbon atoms. There is a need.

[0019] esters of fatty acids, specifically, lauric acid (C ₁₂₎ hexyl, myristic acid (C ₁₄₎ isopropyl palmitate (C ₁₆₎ C ₁₂ ~ isopropyl, etc.
Esters of C ₁₈ fatty acids with C ₁ -C ₁₀ alkyls. Specific examples of monoglycerides of fatty acids include caprylic acid (C ₈ ) monoglyceride and capric acid (C ₁₀ )
Monoglycerides such as the C ₈ -C ₁₀ fatty acids such as monoglycerides and the like. Specific examples of dibasic acid esters include di (C ₁ -C ₁₀ ) alkyl of C ₆ -C ₁₀ dibasic acids such as (C ₆ ) diisopropyl adipate, dioctyl adipate, and (C ₁₀ ) diethyl sebacate. And the like. The C ₁ -C ₁₀ alkyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, isononyl, decyl, and the like. Among them, isopropyl myristate as a fatty acid ester, caprylic acid monoglyceride as a fatty acid monoglyceride, and dioctyl adipate as a dibasic acid ester are preferable, and isopropyl myristate is more preferably used.

The additive is present in the paste layer in an amount of 5 to 50% by weight, preferably 10 to 40% by weight, more preferably 20 to 40% by weight.
It is desirable to be blended in the range of weight%. If the amount of the additive is less than 5% by weight, sufficient percutaneous absorption of the present compound tends not to be obtained. If the amount exceeds 50% by weight, the cohesive force of the plaster layer decreases, and Occasionally, glue residue on the skin surface tends to occur.

In the present invention, the present compound contained in the plaster layer has an asymmetric carbon in the molecule, and has a (-) form and a (+) form.
There are two kinds of optical isomers, and in the present invention, the (−)-form and the (±) -form having pharmacological activity are preferably used. The compound can be produced by a method known per se.

The compound of the present invention in the form of a pharmacologically acceptable salt includes an acid addition salt and an alkali addition salt which can be produced by a conventional method. Examples of the acid addition salt include, for example, an inorganic acid salt with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, Organic acid salts with methanesulfonic acid, p-toluenesulfonic acid, 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. Further, as another organic acid salt, a specific fatty acid salt having enhanced lipophilicity of the present compound can be used. As such fatty acids, those having 8 to 18 carbon atoms are preferred in terms of having lipophilicity suitable for transdermal absorption and having a molecular size suitable for transdermal absorption, and specifically, , 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 is usually 1 to 30% by weight, preferably 3 to 20% by weight, more preferably 5 to 10% by weight in the plaster layer. If the amount is less than 1% by weight, it will be difficult to obtain the blood concentration of the present compound required for treatment, and if it exceeds 30% by weight, the adhesiveness will be reduced and it will be difficult to apply it to the skin. Tend.

The thickness of the plaster layer having the above constitution is preferably 20 to 100 μm, preferably 20 to 100 μm, in order to withstand long-time application to the skin and to prevent adhesive residue on the skin surface when peeled off. 50 μm is more preferred.

If necessary, the plaster layer may contain citric acid,
For pH adjusters such as lactic acid, gluconic acid, triethanolamine, triisopropanolamine, ethylenediamine, triethylamine, ammonia, sodium hydroxide and potassium hydroxide, solubilizers, antioxidants such as ascorbic acid, tocopherol, dibutylhydroxytoluene Representative stabilizers, glycerin, propylene glycol, plasticizers such as polyethylene glycol, titanium oxide,
Various known additives such as fillers such as zinc oxide and hydrous silicon dioxide may be blended. Further, by blending a basic pH adjuster such as triethanolamine, triisopropanolamine, sodium hydroxide, etc., the present compound which is in the form of a salt is liberated in the plaster layer to form the compound in the form of a base. Lipophilicity is increased, and good transdermal absorbability can be obtained. The basic pH adjuster to be added is preferably added in an amount (equivalent) necessary to neutralize the acid added to the present compound in the form of a base. If the amount is less than the equivalent amount, good transdermal absorbability may not be obtained.If the amount is more than the equivalent amount, the plaster layer becomes basic and When applying the absorption-type preparation to the skin, skin irritation may occur.

The support used in the percutaneous absorption preparation of the present invention is not particularly limited as long as it can form and support a plaster layer containing the present compound on one surface thereof. Compounds and additives that are lost from the back surface through the support and do not cause a decrease in content or efficacy,
That is, those components are made of a material that is impermeable, and those that have the flexibility to follow the movement of the skin surface to such an extent that no significant unpleasant sensation is caused when applied to the skin surface are particularly preferable.

Specifically, polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, polyvinyl acetate, ethylene-vinyl acetate copolymer, polyurethane, polyvinyl chloride, plasticized polyvinyl chloride, plasticized vinyl acetate- Polyamide such as vinyl chloride copolymer, polyvinylidene chloride, nylon, cellulose acetate, ethyl cellulose, ethylene-ethyl acrylate copolymer, plastic film such as polytetrafluoroethylene, ionomer resin, and metal foil such as aluminum foil and tin foil , A non-woven fabric, a single-layer film made of cloth, paper, or the like, or a laminated film thereof. The thickness of such a support is usually 5 to 500.
μm, preferably in the range of 5-200 μm.

These supports may be subjected to a corona discharge treatment, a plasma treatment, an oxidation treatment or the like on the surface on which the paste layer is laminated, in order to improve the adhesion to the paste layer and the anchoring property. preferable.

The method for producing the transdermal preparation of the present invention is not particularly limited. For example, the present compound and a pressure-sensitive adhesive are dissolved or dispersed in a solvent, and the obtained solution or dispersion is applied to one surface of a support. And a method of drying to form a plaster layer on the surface of the support. Alternatively, the above-mentioned solution or dispersion is coated on a release liner for protection, dried to form a paste layer on the release liner, and then the support is adhered to the paste layer. can do.

The transdermal preparation of the present invention is intended to prevent the plaster layer from being unnecessarily adhered to instruments, containers and the like during production, transportation or storage, and to prevent deterioration of the preparation. It is desirable to cover and protect the exposed surface of the plaster layer with a release liner until immediately before application to the skin surface.
Then, it is peeled off at the time of use to expose the surface of the plaster layer, and is applied to the skin for administration. As a release liner,
It is not particularly limited as long as it can be easily peeled from the plaster layer at the time of use, for example, a silicone resin, a polyester, a poly, which has been subjected to a peeling treatment by applying a silicone resin, a fluororesin or the like to a surface in contact with the plaster layer. Films such as vinyl chloride, polyvinylidene chloride, and polyethylene terephthalate, paper such as high-quality paper and glassine paper, and laminated films of high-quality paper or glassine paper and polyolefin are used. The thickness of the release liner is usually 10 to 20.
0 μm, preferably 50 to 100 μm.

For the prevention and treatment of urgency, premature birth and urinary disorders
The dosage of the transdermal preparation of the present invention in
It depends 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.

[0032]

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.

Production Example 2-tert which is a component contained in the transdermal preparation of the present invention.
The fatty acid salt of -butylamino-1- (2-chloro-4-hydroxyphenyl) ethane-1-ol can be produced by a conventional method, and has the following properties. (1) (-)-2-tert-butylamino-1- (2-
Chloro-4-hydroxyphenyl) ethane-1-ol oleate Properties: colorless prism crystals (AcOEt) Melting point: 83 to 85 ° C Light intensity: [α] ²⁰ _D −37.4 ° (c = 1.0, MeO
H)

(2) (-)-2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethane-1-ol caprylate Properties: colorless needles (AcOEt) Melting point: 128 １３０130 ° C. Light intensity: [α] ²⁰ _D -50.1 ° (c = 1.0, MeO
H)

(3) 2-tert-butylamino-1-
(2-chloro-4-hydroxyphenyl) ethane-1-
All undecylenate Properties: colorless prism crystals (MeOH) Melting point: 173-176 ° C

(4) 2-tert-butylamino-1-
(2-chloro-4-hydroxyphenyl) ethane-1-
All myristate Properties: colorless prism crystals (MeOH) Melting point: 149-151 ° C

Example 1 45 parts of 2-ethylhexyl acrylate, 2-ethyl acrylate
25 parts of methoxyethyl and 30 parts of vinyl acetate were polymerized in ethyl acetate under an inert gas atmosphere to prepare an acrylic pressure-sensitive adhesive solution containing no carboxyl group. To this solution was added (-)-2-tert-butylamino-1-
(2-chloro-4-hydroxyphenyl) ethane-1-
The oar was added and mixed so that the blending amount in the plaster layer became 10%, and the mixture was sufficiently stirred, and then applied on a release liner so as to have a thickness of 40 μm after drying, and dried. A body layer was formed. Next, the plaster layer was adhered to a support (a polyester film having a thickness of 12 μm) to obtain a transdermal preparation of the present invention.

Example 2 Instead of (-)-2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol (10% in the plaster layer), (±) -2-t
The process of the present invention was carried out in the same manner as in Example 1 except that tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethane-1-ol (30% in the paste layer) was used. A skin absorption type preparation was obtained.

Example 3 The acrylic pressure-sensitive adhesive solution obtained in Example 1 was added with (-)-
2-tert-butylamino-1- (2-chloro-4-
(Hydroxyphenyl) ethane-1-ol tartrate and triethanolamine as a basic pH regulator;
After adding and mixing so that the mixing amount in the plaster layer becomes 10%, and stirring the mixture sufficiently, a transdermal preparation of the present invention was obtained in the same manner as in Example 1.

Example 4 90 parts of 2-ethylhexyl acrylate and 10 parts of hydroxyethyl acrylate were polymerized in ethyl acetate under an inert gas atmosphere to prepare a carboxyl-free acrylic pressure-sensitive adhesive solution. (-)-2
-Tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol was added and mixed so that the blending amount in the plaster layer became 10%, and the mixture was sufficiently stirred. Then, the composition was coated on a release liner so that the thickness after drying was 40 μm, and dried to form a plaster layer. Next, the plaster layer was adhered to a support (a polyester film having a thickness of 12 μm) to obtain a transdermal preparation of the present invention.

Example 5 75 parts of 2-ethylhexyl acrylate and 25 parts of vinylpyrrolidone were polymerized in ethyl acetate under an inert gas atmosphere to prepare an acrylic pressure-sensitive adhesive solution containing no carboxyl group. To this solution was added (-)-2-tert.
-Butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol was added and mixed so that the blending amount in the plaster layer became 10%, and the mixture was sufficiently stirred.
It was applied on a release liner so that the thickness after drying was 40 μm, and dried to form a plaster layer. Next, the plaster layer was adhered to a support (a polyester film having a thickness of 12 μm) to obtain a transdermal preparation of the present invention.

Example 6 70 parts of 2-ethylhexyl acrylate and 30 parts of methyl methacrylate were polymerized in ethyl acetate under an inert gas atmosphere to prepare an acrylic pressure-sensitive adhesive solution containing no carboxyl group. To this solution was added (-)-2-ter
After adding and mixing t-butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol so that the compounding amount in the plaster layer becomes 10%, and stirring sufficiently, It was applied on a release liner so that the thickness after drying was 40 μm, and dried to form a plaster layer. Next, the plaster layer was adhered to a support (a polyester film having a thickness of 12 μm) to obtain a transdermal preparation of the present invention.

Comparative Example 1 In place of the acrylic pressure-sensitive adhesive solution of Example 1, 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid were used.
A transdermal preparation was obtained in the same manner as in Example 1, except that an acrylic pressure-sensitive adhesive solution containing a carboxyl group, which was obtained by polymerization in ethyl acetate under an inert gas atmosphere, was used.

Example 7 High molecular weight polyisobutylene (viscosity average molecular weight 2,100,000
, VISTANEX MML-140, manufactured by Exxon Chemical Co., Ltd., 50 parts, medium molecular weight polyisobutylene (viscosity average molecular weight 60,000, HIMO
30 parts of L6H, manufactured by Nippon Petrochemical Co., Ltd. and 20 parts of alicyclic petroleum resin (softening point: 100 ° C., Alcon P-100, manufactured by Arakawa Chemical Co., Ltd.) are dissolved in hexane to give a solution containing a high-molecular-weight rubber component. Was prepared. To this solution was added (-)-2-ter
t-Butylamino-1- (2-chloro-4-hydroxyphenyl) ethane-1-ol and isopropyl myristate (fatty acid ester) as an additive were added in an amount of 10% and 40%, respectively, in the plaster layer. , And the mixture was sufficiently stirred, and then applied on a release liner so as to have a thickness of 40 μm after drying, and dried to form a plaster layer. Next, a plaster layer was adhered to the nonwoven fabric side of the support (a laminated film of a polyester nonwoven fabric having a basis weight of 8 g / m ² and a polyester film having a thickness of 6 μm) to obtain a percutaneous absorption-type preparation of the present invention.

Example 8 The high molecular weight rubber component-containing solution obtained in Example 7 was added to
(-)-2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethane-1-ol tartrate, isopropyl myristate (fatty acid ester) as an additive, and triethanolamine as a pH adjuster Is 10% and 40% respectively in the plaster layer
Then, the mixture was added and mixed so that the concentration became 10%, and the mixture was sufficiently stirred. Then, a transdermal preparation of the present invention was obtained in the same manner as in Example 7.

Example 9 Instead of the high molecular weight rubber component-containing solution of Example 7, a high molecular weight polyisobutylene (viscosity average molecular weight 990,000, VI
STANEX MML-80, manufactured by Exxon Chemical Co., 37.5 parts, medium molecular weight polyisobutylene (viscosity average molecular weight 40,000, HIMOL)
4H, Nippon Petrochemical Co., Ltd.) 12.5 parts and low molecular weight polybutene (viscosity average molecular weight 1,260, HV-300, Nippon Petrochemical Co., Ltd.) solution obtained by dissolving 50 parts in hexane And using an equal mixture of isopropyl myristate (fatty acid ester) and monoglyceride caprylic acid (fatty acid monoglyceride) (30% in the plaster layer) instead of the additive of Example 7. A transdermal preparation of the present invention was obtained in the same manner as in Example 7.

Example 10 A styrene-butadiene-styrene block copolymer (SB) was used in place of the high molecular weight rubber component-containing solution of Example 7.
S) (styrene / butadiene = 30/70 (weight ratio);
Viscosity average molecular weight 300,000, 80 parts of Cariflex TR-1101, manufactured by Shell Chemical Co., Ltd.) and alicyclic petroleum resin (softening point 105
C., Escolets 5300, manufactured by Exxon Chemical Co., Ltd.) A solution of a high-molecular-weight rubber component obtained by dissolving 20 parts in toluene was used. Instead of the additive of Example 7, dioctyl adipate (dibasic acid ester, Amount 4 in plaster layer
0%) to obtain a transdermal preparation of the present invention in the same manner as in Example 7.

Example 11 The acrylic pressure-sensitive adhesive solution obtained in Example 1 was added with (-)-
2-tert-butylamino-1- (2-chloro-4-
(Hydroxyphenyl) ethane-1-ol oleate is added so that the blending amount in the plaster layer becomes 10%,
After mixing and stirring sufficiently, a percutaneous absorption-type preparation of the present invention was obtained in the same manner as in Example 1.

Example 12 The high molecular weight rubber component-containing solution obtained in Example 7 was added to
(-)-2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethane-1-ol caprylate was added so that the blending amount in the plaster layer would be 10%. After mixing and stirring sufficiently, a percutaneous absorption-type preparation of the present invention was obtained in the same manner as in Example 7.

Example 13 The high molecular weight rubber component-containing solution obtained in Example 7 was
(-)-2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethane-1-ol tartrate, isopropyl myristate (fatty acid ester) as an additive, and water as a basic pH adjuster Sodium oxide (added as an ethanol solution) was added so as to be 10%, 40%, and 2%, respectively, in the plaster layer, mixed and sufficiently stirred. The transdermal preparation of the present invention was obtained.

Comparative Example 2 A transdermal preparation was obtained in the same manner as in Example 7, except that no additive (isopropyl myristate) was added.

Comparative Example 3 Medium molecular weight polyisobutylene (viscosity average molecular weight 60,000, HI
A high molecular weight rubber component obtained by dissolving 80 parts of MOL 6H, manufactured by Nippon Petrochemical Co., Ltd. and 20 parts of alicyclic petroleum resin (softening point: 100 ° C., Alcon P-100, manufactured by Arakawa Chemical Co.) in hexane. A transdermal preparation was obtained in the same manner as in Example 7, except that a solution not containing was used.

Experimental Example 1 Transdermal preparations obtained in Examples 1 to 13 and Comparative Examples 1 and 2 [Tables 1 and 2 show the composition of the plaster layer. In the table, (-)-the present compound is (-)-2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol or its pharmacologically acceptable. (±) -The present compound is (−)-2-te
rt-butylamino-1- (2-chloro-4-hydroxyphenyl) ethan-1-ol or a pharmacologically acceptable salt thereof] is punched into a 6 mmφ and in the center of a molted snake skin having a diameter of 16 mm. Equipment for sticking and permeation test (Automatic Flow Thru Diffusion Cell Apparatus,
Vangard International Inc.) and the amount of the compound permeated into water on the receptor side was measured by liquid chromatography. The results are shown in FIG. 1 and FIG. 2 as a change with time of the accumulated permeation amount of the present compound.

[0054]

[Table 1]

[0055]

[Table 2]

The skin permeability of the preparation using the acrylic pressure-sensitive adhesive containing a carboxyl group (Comparative Example 1) and the preparation using the rubber component as the pressure-sensitive adhesive and containing no additive (Comparative Example 2) were extremely low. Was. In contrast, the formulation of the present invention showed good skin permeability.

EXPERIMENTAL EXAMPLE 2 The transdermal preparations obtained in Examples 7 to 10, 12 to 13 and Comparative Examples 2 to 3 were cut into a width of 20 mm and a length of 50 mm. After pasting for 1 hour
Peeling was performed at a rate of 100 mm / min in the direction of 80 degrees, and the skin adhesion was measured. Further, the adhesive residue on the skin surface after peeling was evaluated visually. Table 3 shows the results.

[0058]

[Table 3]

In the preparation containing no additive (Comparative Example 2), the skin adhesive strength was low, and in the preparation using a pressure-sensitive adhesive containing no high molecular rubber component (Comparative Example 3), cohesive failure of the pressure-sensitive adhesive was observed. Glue remained on the skin surface due to On the other hand, all of the preparations of the present invention had good or practically no problem of skin adhesion and adhesive residue on the skin surface.

[0060]

According to the present invention, the present compound contained in the plaster layer is continuously released to the skin surface and migrates into the blood,
Its effective blood concentration lasts for a long time. Therefore, the preparation of the present invention is useful as a percutaneous absorption-type preparation for the prevention and treatment of urinary disorders such as impending flow, premature birth or urinary incontinence.

[Brief description of the drawings]

FIG. 1 is a graph showing the change over time in the accumulated permeation amount of the present compound.

FIG. 2 is a graph showing the change over time of the accumulated permeation amount of the present compound.

Continued on the front page (72) Inventor Takeaki Nakagawa 1-1-2 Shimohozumi, Ibaraki-shi, Osaka Nitto Denko Corporation (72) Inventor Mitsuhiko Hori 1-2-1, Shimohozumi, Ibaraki-shi, Osaka Nitto Denko stock Within the company (72) Inventor Saburo Otsuka 1-1-2 Shimohozumi, Ibaraki-shi, Osaka Nitto Denko Corporation

Claims (7)

[Claims] (1) 2-tert-butylamino-1- (2
-Chloro-4-hydroxyphenyl) ethan-1-ol or a pharmacologically acceptable salt thereof, and a plaster layer containing an adhesive are provided on one surface of the support,
The pressure-sensitive adhesive is an acrylic polymer substantially containing no carboxyl group, or the pressure-sensitive adhesive contains at least one kind of a high-molecular-weight rubber component having an average molecular weight of 300,000 to 2,500,000; A transdermal preparation comprising at least one additive selected from esters of fatty acids having 12 to 18 carbon atoms, monoglycerides of fatty acids having 8 to 10 carbon atoms, and esters of dibasic acids having 6 to 10 carbon atoms. 2. A copolymer in which the acrylic polymer comprises 2-ethylhexyl acrylate and at least one selected from hydroxyethyl acrylate, methyl methacrylate, 2-methoxyethyl acrylate, vinyl acetate, and vinylpyrrolidone. The transdermal preparation according to claim 1, which is: 3. The high-molecular-weight rubber component-containing material has a low molecular weight polyisobutylene or polybutene having an average molecular weight of 500 to 4,000, and / or an average molecular weight of 10,000 to 4,000.
The transdermal preparation according to claim 1, which is a mixture of 200,000 medium molecular weight polyisobutylene and high molecular weight polyisobutylene having an average molecular weight of 300,000 to 2,500,000. 4. A method for preparing 2-tert-butylamino-1- (2
A pharmacologically acceptable salt of -chloro-4-hydroxyphenyl) ethan-1-ol is 2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl)
The tartrate salt of ethane-1-ol or the fatty acid salt of 8 to 18 carbon atoms of 2-tert-butylamino-1- (2-chloro-4-hydroxyphenyl) ethane-1-ol. Skin absorption type preparation. 5. The transdermal preparation according to claim 1, further comprising a basic pH adjuster in the plaster layer. 6. The therapeutic agent for imminent flow / premature delivery
A transdermal preparation according to any one of the above. 7. The transdermally absorbable preparation according to claim 1, which is a therapeutic agent for dysuria.