JP2011068610A - Patch for external use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a patch for external use excellent in solubility of a medicine and releasability of a medicine from an adhesive layer, having no reduction in the content of a medicine in the adhesive layer, also low in skin irritation, further improved with skin adhesion, and excellent in feeling of use such that peeled turning up or twisted turning up in patch or during patch is improved in the patch for external use containing a carboxylic acid medicine or an alkali salt thereof, particularly diclofenac sodium or loxoprofen sodium in the adhesive layer as an active ingredient. <P>SOLUTION: In the patch for external use containing the carboxylic acid medicine or the alkali salt thereof, particularly diclofenac sodium or loxoprofen sodium in the adhesive layer as the active ingredient, a peeled turning up or twisted turning up inhibitor is added to the adhesive layer. The peeled turning up or twisted turning up inhibitor is a solid acid, and preferably palmitic acid or stearic acid. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

The present invention relates to an external patch containing, as an active ingredient, a carboxylic acid drug or an alkali salt thereof, particularly diclofenac sodium or loxoprofen sodium hydrate (hereinafter referred to as loxoprofen sodium) in an adhesive layer. Excellent drug solubility in the adhesive layer and drug release from the adhesive layer, no decrease in drug content in the adhesive layer, low skin irritation, and improved skin adhesiveness The present invention also relates to an external patch characterized by excellent usability.

An external patch is a very excellent dosage form in that it does not cause side effects of the drug that causes problems when taken as an oral preparation, does not decrease the bioavailability, and the drug can be administered continuously. One. Therefore, for example, nonsteroidal anti-inflammatory analgesics such as indomethacin, diclofenac sodium and loxoprofen sodium as drugs, angina / heart failure treatment drugs such as nitroglycerin, climacteric disorders / osteoporosis treatment drugs such as estradiol, bronchodilation such as tulobuterol An external patch containing an active agent and the like has been developed and marketed.

Among the above, various technologies have been developed for patches containing non-steroidal anti-inflammatory analgesics such as carboxylic acid drugs or alkali salts thereof such as indomethacin, diclofenac sodium, loxoprofen sodium, etc. It is used in. For example, in order to dissolve an anti-inflammatory analgesic into a patch base, a patch containing a solubilizing agent such as an organic acid (Patent Document 1), crotamiton (Patent Document 2, Patent Document 3), or a rosin ester derivative A patch using l-menthol in combination (Patent Document 4) has been developed. In addition, a patch containing propylene carbonate (Patent Document 5) and various absorption promoters has been developed to improve the drug release from the adhesive layer when the patch is applied to the affected skin. Has been. Further, in order to suppress a decrease in the content of the drug in the adhesive patch, a fatty acid metal salt (Patent Document 6)
), Metal oxides (Patent Document 7), metal hydroxides (Patent Document 8) and the like have been developed. Furthermore, in order to solve the above problem, a patch containing a specific polymer compound such as a non-polar adhesive polymer (Patent Document 9), a polymer polyisobutylene and a low-molecular polyisobutylene (Patent Document 10). Etc. are also being developed. However, since the physicochemical properties of anti-inflammatory analgesics vary greatly depending on the compound, it is necessary to select or newly develop a technique suitable for the compound.

Among anti-inflammatory analgesics, diclofenac sodium and loxoprofen sodium have characteristics such as strong analgesic / anti-inflammatory effects and stable physical properties, and their clinical usefulness has been confirmed. Furthermore, both compounds have a chemical common property with a dissociation constant (pKa) of about 4.2. These diclofenac sodium and loxoprofen sodium are poorly soluble in commonly used bases and have problems such as crystal precipitation and reduced transdermal absorbability, making it difficult to make patches. Therefore, various preparations have been made so far.

In the case of diclofenac sodium, it is hardly soluble in an oily base, and particularly when blended with a rubber base, there are problems such as crystal precipitation of diclofenac sodium and a decrease in transdermal absorbability. Therefore, in order to improve the solubility and transdermal absorbability of diclofenac sodium in an oily base, for example, a preparation containing crotamiton as a solubilizer (see Patent Document 2), fatty acid of oleic acid, linoleic acid or linolenic acid The formulation (refer patent document 11) containing is proposed. However, the patch of Patent Document 2 does not have sufficient transdermal absorbability of diclofenac sodium, and the patch using fatty acids such as oleic acid, linoleic acid, and linolenic acid as a solubilizer is described in Patent Document 11. As described above, sodium ions produced by diclofenac-free formation are captured by these fatty acids, and skin irritation derived from the fatty acid sodium produced thereby has been a problem. In Patent Document 11, oleic acid, linoleic acid, a preparation with extremely low skin irritation without reducing release properties,
There has been proposed a preparation in which a fatty acid and isostearic acid which are liquid at room temperature having 10 to 18 carbon atoms such as linolenic acid are combined. Although the patch of Patent Document 11 obtained by combining these liquid acids and isostearic acid is excellent in releasability and skin irritation, further improvement is required in terms of reduction in adhesive strength and the like.

Loxoprofen sodium has an excellent anti-inflammatory analgesic action, and a tape preparation using a water-based patch (patient; see Patent Document 12) mixed with an aqueous patch base or a non-aqueous patch base is commercially available. (See Patent Document 13) and research and development (see Patent Document 14). However, the release of loxoprofen sodium from the aqueous patch base is relatively low,
There was a drawback of poor bioavailability. In contrast, when loxoprofen sodium is incorporated into a non-aqueous patch base such as a rubber elastomer, it is possible to obtain a patch for external use with good release of loxoprofen sodium and sufficient bioavailability. However, the solubility of loxoprofen sodium in a non-aqueous patch base is very poor, and when dissolved in a non-aqueous patch base using a general solubilizer, the content of loxoprofen sodium over time New problems, such as a decrease, were recognized. On the other hand, one of the inventors of the present invention further contains a terpene resin and / or a hydrogenated rosin ester as a base component of the pressure-sensitive adhesive layer, and further, isosorbate acid, diisopropyl myristate, and sebacine as a solubilizer for loxoprofen. An external patch using a fatty acid ester such as diisopropyl acid was developed (see Patent Document 15).

Thus, isostearic acid has an excellent effect as a solubilizing agent for nonsteroidal anti-inflammatory analgesics such as diclofenac sodium or loxoprofen sodium, but as a result of subsequent formulation studies by the present inventors, diclofenac sodium or loxoprofen. It is clear that when sodium and isostearic acid are blended in the adhesive layer, sodium isostearate is produced as a reaction product thereof, and that the adhesive containing the sodium isostearate decreases in adhesive strength over time. It became. In addition, during high sweat periods such as summer, sodium isostearate generated in the pressure-sensitive adhesive layer, combined with moisture generated by sweating, causes peeling and twisting of the patch and dripping phenomenon. It has been found that there is a problem that a problem occurs and the usability is inferior.

Therefore, the drug has excellent solubility in the adhesive layer and release of the drug from the adhesive layer, has no decrease in the content of the drug in the adhesive layer, and has an improved skin adhesiveness. The provision of an excellent patch was required.

JP-A-62-126119 JP-A-4-321624 JP-A-10-120560 WO93 / 04677 JP 2002-87954 A WO96 / 08245 JP 2002-226366 A JP 2005-314328 A JP-A-10-95729 WO01 / 78690 publication Japanese Patent No. 4181232 WO98 / 08966 Publication WO2006 / 048939 WO2008 / 069283 JP 2008-214337 A

The present invention solves the above-mentioned problems, and in a patch for external use containing a carboxylic acid drug or an alkali salt thereof, particularly diclofenac sodium or loxoprofen sodium as an active ingredient in the adhesive layer, the drug for the adhesive layer Excellent solubility and release of drug from the adhesive layer, no decrease in drug content in the adhesive layer, low skin irritation, and improved skin adhesiveness. The present invention also provides a patch excellent in use feeling that peeling or twisting is prevented during the process.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have a support, a pressure-sensitive adhesive layer, and a release liner, and as an active ingredient, a carboxylic acid drug or an alkali salt thereof, particularly in the pressure-sensitive adhesive layer. It has been found that the above-mentioned problems can be solved by blending an anti-peeling or twisting-preventing agent into an external patch containing diclofenac sodium or loxoprofen sodium, thereby completing the present invention.

That is, the present invention comprises a support, a pressure-sensitive adhesive layer, and a release liner, and is peeled into the pressure-sensitive adhesive layer in an external patch containing a carboxylic acid drug or an alkali salt thereof as an active ingredient in the pressure-sensitive adhesive layer. It is an external patch containing a sag prevention agent.

The external patch of the present invention is excellent in the solubility of the carboxylic acid drug as an active ingredient or an alkali salt thereof, particularly diclofenac sodium or loxoprofen sodium in the adhesive layer and the drug release from the adhesive layer, and There is no decrease in drug content in the adhesive layer,
It is a patch with low skin irritation, and further improved skin adhesiveness, and excellent usability in that peeling or twisting is prevented at the time of application or during application.

The carboxylic acid drug or an alkali salt thereof, which is an active ingredient of the external patch of the present invention, is contained in the pressure-sensitive adhesive layer. Here, examples of the carboxylic acid drug include ketoprofen, flurbiprofen, loxoprofen, and diclofenac. Examples of the alkali salt include sodium salt, potassium salt, ammonium salt and the like. The carboxylic acid drug or alkali salt thereof contained in the external patch of the present invention is not particularly limited. Among them, diclofenac sodium or loxoprofen is strong in terms of analgesic / anti-inflammatory action and stable in physical properties. Sodium is particularly preferred.

The compounding amount of the carboxylic acid drug or the alkali salt thereof, particularly diclofenac sodium or loxoprofen sodium used in the present invention as an active ingredient is 0.
It is preferable that it is 5-10 mass%, especially 1-10 mass%. Drug content is 0.5% by mass
If the amount is less than 10% by mass, the release of the drug cannot be expected, and even if it exceeds 10% by mass, the pharmacological action cannot be improved, and the bioavailability of the drug is lowered. There is a problem
It is not preferable.

The adhesive layer of the external patch of the present invention uses a rubber-based elastomer as a base component in consideration of manufacturing cost, physical properties and quality control, that is, formulation design is easy. It is done. Examples of the rubber elastomer include styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-butadiene rubber, polyisobutylene, polybutene, butyl rubber, natural rubber, and isoprene rubber. Of these, styrene-isoprene-styrene block copolymers, polyisobutylene, polybutene, butyl rubber, and isoprene rubber are preferably used. These can be used alone or in combination of two or more. The blending amount of the rubber-based elastomer used in the present invention is preferably 10 to 50% by mass.

A carboxylic acid-based drug or an alkali salt thereof, particularly diclofenac sodium or loxoprofen sodium, which is an active ingredient of the external patch of the present invention, is dissolved in a solubilizer and mixed into the adhesive of the external patch of the present invention. These solubilizers include liquid fatty acids such as isostearic acid, isopropyl myristate, octyldodecyl myristate, cetyl myristate, isopropyl palmitate, diisopropyl adipate, diethyl sebacate, diisopropyl sebacate and the like. In addition, ethanol, isopropanol, octyldodecanol, propylene glycol, butylene glycol, polyethylene glycol, propylene glycol stearate, concentrated glycerin, and the like can be used. Among them, isostearic acid is an excellent solubilizer in that it dissolves diclofenac sodium. It is more preferable to use a fatty acid ester such as diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, or isopropyl palmitate in combination. These can be used alone or in combination of two or more.

These solubilizers may be used in an amount sufficient to dissolve the active ingredient carboxylic acid drug or an alkali salt thereof, particularly diclofenac sodium or loxoprofen sodium, and it is preferable to use an equivalent amount or more and a 5-fold amount or less with respect to the drug. When the amount is less than the equivalent amount, the drug is not dissolved. When the amount exceeds 5 times, there is no significant difference in the effect, which is not appropriate.

As mentioned above, in order to dissolve diclofenac sodium or loxoprofen sodium, it is preferable to select isostearic acid as a solubilizer. According to the study by the inventors, in the case of a patch containing diclofenac sodium, the isostearic acid to be mixed captures sodium ions from diclofenac sodium to form sodium isostearate in the adhesive layer, which is peeled off or twisted. It is necessary to add a component that prevents this peeling or twisting because it causes twisting. Even though the amount of sodium isostearate produced in this way is small, it causes twisting and twisting of the patch in combination with moisture generated by sweating during the period of heavy sweating such as in summer, resulting in problems in application. Ingredients that prevent peeling or twisting are added because the patient may experience discomfort and the feeling of use is poor.

As a component for preventing peeling or twisting of the patch, a solid acid, particularly a carbon number of 9
Saturated fatty acids that are solid at room temperature of ~ 29 are mentioned, and specific examples include lauric acid, myristic acid, palmitic acid, stearic acid, or behenic acid. These can be used alone or in combination of two or more. The content ratio of these peeling or twisting prevention agents is 0.1 to 5 times, preferably 0.2 to 3 times, the drug content. If it is less than 0.1 mass times, the production of sodium isostearate in the pressure-sensitive adhesive layer cannot be suppressed, and if it exceeds 5 mass times, there is no significant difference in the effect of inhibiting the production of sodium isostearate. Is not appropriate.

In a diclofenac sodium-containing patch containing isostearic acid, a diclofenac sodium-containing patch excellent in adhesive strength, drug absorbability and stability can be obtained particularly when palmitic acid is added as an anti-peeling agent.

In the loxoprofen sodium-containing patch, when stearic acid is used, the adhesive strength is enhanced, and when palmitic acid is added to this, there is no problem in the stability and absorbability of the drug and the feeling of peeling is prevented. An excellent patch can be obtained.
The blending ratio of isostearic acid or stearic acid and palmitic acid is 1: 0.
1-2 is good, Preferably it is 1: 0.2-1.5, More preferably, it is 1: 0.3-1. If it is less than 1: 0.1 and more than 1: 2, there is no significant difference in the effect, which is not appropriate.

As described above, in order to improve the feeling of use of a patch containing a carboxylic acid drug or an alkali salt thereof, particularly diclofenac sodium or loxoprofen sodium, the present invention prevents peeling or twisting of the adhesive layer. In the case of a patch containing diclofenac sodium as an active ingredient, when the present invention is further mixed with an aqueous polymer compound such as starch acrylate, it is peeled off or twisted. It was found that the prevention effect is exhibited. The amount of the aqueous polymer compound such as starch acrylate added is 0.1 to 5% by mass, preferably 0, based on the total amount of the patch of the present invention.
. It is 1-3 mass%. That is, as another aspect of the present invention, in an external patch comprising an adhesive layer containing an anti-peeling agent, an external patch further comprising an aqueous polymer compound in the adhesive layer is provided. Is mentioned.

In producing the patch of the present invention, a tackifier resin may be further added to the pressure-sensitive adhesive layer.
Tackifying resins include rosin resins, hydrogenated rosin ester resins, terpene resins,
Alicyclic saturated hydrocarbon resins, petroleum resins, phenol resins, xylene resins and the like can be used. Specific examples of these include Clearon P-105, Foal 105, Archon P-
100, KE-311, KE-100, Superester S-100, Tamanol 521,
Examples thereof include YS resin 75, YS resin PX1150N, and KR-610 (all are trade names). The compounding quantity of the tackifying resin agent used for this invention is 10-40 mass%. If the blending amount is less than 10% by mass, the adhesive strength is lowered, which is not preferable. If it exceeds 40% by mass, the plaster becomes hard and problems such as a decrease in cohesive force occur, which is not preferable.

It is preferable to add an antioxidant and / or an ultraviolet absorber for stabilization during production and storage of the patch of the present invention. Antioxidants include pentaerythrityl tetrakis [3- (3,5-ditertiarybutyl-4-hydroxyphenyl)] propionate, butylhydroxyanisole, tocopherol, tocopherol acetate, dibutylhydroxytoluene, 2-mercaptobenzo Imidazole, propylene carbonate, propyl gallate, sodium pyrosulfite, sodium sulfite, sodium hydrogen sulfite, metal thiosulfate, ascorbic acid, its salt or ester with palmitic acid or stearic acid, isoascorbic acid or its salt, ethylenediamine tetra Acetic acid or a salt thereof can be used, and the amount thereof is 0.1 to 3% by mass with respect to the total amount of the patch. If the blending amount of the antioxidant is less than 0.1% by mass, it is not preferable because sufficient antioxidant power cannot be expected. In addition, when the blending amount exceeds 3% by mass, crystallization of an active ingredient carboxylic acid-based drug or an alkali salt thereof, particularly diclofenac sodium or loxoprofen sodium, is caused, resulting in a decrease in skin permeability. Absent. Examples of ultraviolet absorbers include 4-tert-butyl-4′-methoxybenzoylmethane, 2- (4-diethylamino-2-hydroxybenzoyl) benzoic acid n-hexyl ester, 4-hydroxy-3-methoxycinnamic acid, 4-hydroxy-3
-Branched alkyl ester of methoxycinnamic acid, terephthalylidene-3,3'-dicamphor-10,10'-disulfonic acid, 2- (2H-benzotriazol-2-yl)-
4-Methyl-6- [2-methyl-3- [1,3,3,3-tetramethyl-1-[(trimethylsilyl) oxydisiloxaneyl] propyl] dioxoimidazolidinepropionic acid 2
-Ethylhexyl ester, 1- (3,4-dimethoxyphenyl) -4,4-dimethyl-
Examples include 1,3-pentanedione, 2- (2-hydroxy-5-methoxyphenyl) benzotriazole, oxybenzone, 4-aminobenzoic acid ethyl ester, 4-methoxycinnamic acid 2-ethylhexyl ester, and the like.

If desired, the patch of the present invention can be blended with oils and fats such as liquid paraffin and petrolatum, and flavoring agents such as l-menthol and dl-camphor as a softening agent. As for the compounding quantity of fats and oils as a softening agent used for this invention, 10-40 mass% is preferable. As for the compounding quantity of the flavor used for this invention, 1-10 mass% is preferable. Moreover, polyethylene glycol can also be mix | blended as a drug stabilizer. As polyethylene glycol (PEG), PEG400
PEG 1500, PEG 4000, PEG 6000, PEG 20000, and the like. Usually, in order to achieve the object of the present invention, it is preferable to use a high molecular weight PEG, particularly a PEG having a molecular weight of 4000 to 20000, rather than a low molecular weight PEG. As for the compounding quantity as a stabilizer used for this invention, 0.1-10 mass% is preferable.

Further, as the support in the external patch of the present invention, a drug-impermeable, stretchable or non-stretchable support can be used. Examples of such a support include, for example, synthetic resin films or sheets of polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane, etc., or laminates, porous bodies, foams thereof. Examples include body, paper, woven fabric and woven fabric.

Furthermore, a drug-impermeable release liner can be used as the release liner in the external patch of the present invention. As such a release liner, for example, a film made of a polymer material such as polyethylene, polypropylene, or polyester, a film in which aluminum is vapor-deposited on a film, a film in which silicone oil or the like is coated on paper, etc. Although it is mentioned, a polyester film is preferable and polyethylene terephthalate film is particularly preferable from the viewpoints of lack of permeation of an acidic drug or an alkali salt thereof, processability and low cost. Further, the release liner may be a laminate film obtained by bonding a plurality of materials.

Production of the external patch of the present invention is not particularly limited, and can be performed according to a known production method. Examples of preferable known production methods for the external patch of the present invention include, for example, an adhesive base component, an active ingredient carboxylic acid-based drug or an alkali salt thereof, a solubilizer and other tackifying resins used in the present invention, oxidation Organic solvents such as ethyl acetate, hexane, toluene or mixed solvents such as inhibitors / ultraviolet absorbers, softeners, flavoring agents, drugs such as PEG, additives such as stabilizers, etc. The adhesive is spread on a release liner or a support, the solvent in the solution is evaporated to form an adhesive layer, and then the support or the release liner is bonded to the external patch. Method (solvent method), adhesive base component, active ingredient carboxylic acid drug or alkali salt thereof, solubilizer and other tackifying resin used in the present invention, antioxidant / ultraviolet Absorbents, softeners, flavoring agents, drugs such as PEG, additives such as stabilizers, and other ingredients to be included in the adhesive layer are heated and melted, and this melt is spread on a release liner or support. And a method of obtaining an external patch by bonding a support or a release liner after forming an adhesive layer (hot melt method).

The patch of the present invention is preferably a non-aqueous patch, and specifically includes a tape. Its size is in the range of 50 cm ² to 200 cm ² , preferably 70c.
m ² to 140 cm ² . The thickness may be 80 μm to 150 μm. Before applying this, peel off the release sheet and divide it once a day or several times in the acute period on the affected area such as pain caused by bruises, sprains, muscle fatigue, pain associated with stiff shoulders, low back pain and joint pain. It is good to stick it.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. In the examples, “%” means “% by mass” unless otherwise specified.

Example 1
An external patch was produced by the following composition and production method.

(composition)
(1) Diclofenac sodium 1.5%
(2) Styrene-isoprene-styrene block copolymer 25%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polyisobutylene 1%
(Product name: Tetrax 3T, Nippon Petrochemical)
(4) Polybutene 3%
(Product name: HV-300F, Nippon Petrochemical)
(5) Butyl rubber 10%
(Product name: Exon Butyl 065, Exxon Chemical)
(6) 2% isostearic acid
(Product name: Isostearic acid EX, higher alcohol industry)
(7) Diisopropyl sebacate 2%
(Product name: DIS, Nikko Chemicals)
(8) Palmitic acid 1%
(Product name: Palmitic acid, Wako Pure Chemical)
(9) Hydrogenated rosin resin glycerin ester 15%
(Product name: KE-311, Arakawa Chemical Industries)
(10) Pentaerythrityl-tetrakis [3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] 0.1%
(Product name: Irganox 1010, Ciba Specialty Chemicals)
(11) Liquid paraffin 35.4%
(Product name: High Call M-352, Kaneda)
(12) l-Menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(13) Polyethylene glycol 20000 1%
(Product name: Macrogol 20000, Sanyo Kasei)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, polyisobutylene, polybutene, butyl rubber, liquid paraffin, hydrogenated rosin resin glycerin ester, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl ) Propionate] was heated and melted to a uniform state, and then diclofenac sodium, isostearic acid, palmitic acid, diisopropyl sebacate, l-menthol and polyethylene glycol 20000 were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form an adhesive layer. Thereafter, the pressure-sensitive adhesive layer was bonded to a stretchable woven fabric. then,
Cut to the desired size to obtain an external patch (Example 1).

Example 2
An external patch was produced by the following composition and production method.

(composition)
(1) Diclofenac sodium 1.5%
(2) Styrene-isoprene-styrene block copolymer 25%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polyisobutylene 1%
(Product name: Tetrax 3T, Nippon Petrochemical)
(4) Polybutene 3%
(Product name: HV-300F, Nippon Petrochemical)
(5) Butyl rubber 10%
(Product name: Exon Butyl 065, Exxon Chemical)
(6) 2% isostearic acid
(Product name: Isostearic acid EX, higher alcohol industry)
(7) Diisopropyl sebacate 2%
(Product name: DIS, Nikko Chemicals)
(8) Palmitic acid 1%
(Product name: Palmitic acid, Wako Pure Chemical)
(9) Starch acrylate 2%
(Product name: Sunwet IM-1000MPS, Sanyo Kasei)
(10) Hydrogenated rosin resin glycerin ester 15%
(Product name: KE-311, Arakawa Chemical Industries)
(11) Pentaerythrityl-tetrakis [3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] 0.1%
(Product name: Irganox 1010, Ciba Specialty Chemicals)
(12) Liquid paraffin 33.4%
(Product name: High Call M-352, Kaneda)
(13) 1-menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(14) Polyethylene glycol 20000 1%
(Product name: Macrogol 20000, Sanyo Kasei)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, polyisobutylene, polybutene, butyl rubber, liquid paraffin, hydrogenated rosin resin glycerin ester, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl ) Propionate] was heated and melted to a uniform state, and then diclofenac sodium, isostearic acid, palmitic acid, starch acrylate, diisopropyl sebacate, l-menthol and polyethylene glycol 20000 were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form an adhesive layer. Thereafter, the pressure-sensitive adhesive layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 2).

Comparative Example 1
An external patch was produced by the following composition and production method.

(composition)
(1) Diclofenac sodium 1.5%
(2) Styrene-isoprene-styrene block copolymer 25%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polyisobutylene 1%
(Product name: Tetrax 3T, Nippon Petrochemical)
(4) Polybutene 3%
(Product name: HV-300F, Nippon Petrochemical)
(5) Butyl rubber 10%
(Product name: Exon Butyl 065, Exxon Chemical)
(6) Isostearic acid 3%
(Product name: Isostearic acid EX, higher alcohol industry)
(7) Diisopropyl sebacate 2%
(Product name: DIS, Nikko Chemicals)
(8) Hydrogenated rosin resin glycerin ester 15%
(Product name: KE-311, Arakawa Chemical Industries)
(9) Pentaerythrityl-tetrakis [3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] 0.1%
(Product name: Irganox 1010, Ciba Specialty Chemicals)
(10) Liquid paraffin 35.4%
(Product name: High Call M-352, Kaneda)
(11) l-Menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(12) Polyethylene glycol 20000 1%
(Product name: Macrogol 20000, Sanyo Kasei)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, polyisobutylene, polybutene, butyl rubber, liquid paraffin, hydrogenated rosin resin glycerin ester, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl ) Propionate] is heated and melted to a uniform state, and then diclofenac sodium, isostearic acid, diisopropyl sebacate, l-menthol and polyethylene glycol 20000.
Was added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form an adhesive layer. Thereafter, the pressure-sensitive adhesive layer was bonded to a stretchable woven fabric. Then, it was cut into a desired size to obtain an external patch (Comparative Example 1).

Test example 1
Skin Adhesion Test Examples 1 and 2 and Comparative Example 1 were each cut into 15 mm × 70 mm and used as samples. Each sample was affixed to the subject's back skin by a circuit method. After a predetermined time has elapsed, the sample is peeled off at a rate of 300 mm / min from the bottom in a 90 ° direction with respect to the sticking surface using a Tensilon universal testing machine, and the integrated average load at the time of peeling is obtained, and the adhesive strength (N / 15 mm) It was. The test was carried out for 6 subjects, and the average value and standard deviation of the adhesive strength were determined. The peeling time was measured immediately after sticking and after 8 hours.

As a result, skin adhesion (average value ± standard deviation value) after 0 hours and 8 hours after application of Example 1 (containing palmitic acid) and Example 2 (containing palmitic acid and starch acrylate); unit:
N / 15 mm) are 0.81 ± 0.12, 0.64 ± 0.19, and 0.80 ± 0.
It was 08, 0.76 ± 0.17, and there was not much difference in the adhesiveness to the skin after 0 hours of application and 8 hours of application, whereas in Comparative Example 1, 0.51 ± 0.07 to 0.27. It was ± 0.16, and the adhesive strength after 8 hours of application was reduced by about half of 0 hours after application. From these results, it is shown that by adding an anti-peeling agent (palmitic acid), a decrease in the adhesive force during sticking is suppressed and an anti-peeling effect is produced. In addition, the skin adhesive strength from 0 hours to 8 hours after application of Example 2 (palmitic acid, starch acrylate) was suppressed from decreasing over time as compared to Example 1 (palmitic acid). The effect of the compound (starch acrylate) is shown.

Example 3
An external patch was produced by the following composition and production method.

(composition)
(1) Diclofenac sodium 1.5%
(2) Styrene-isoprene-styrene block copolymer 23%
(Product name: Kraton D1161P, JSR Kraton elastomer)
(3) Polybutene 4%
(Product name: HV-300F, Nippon Petrochemical)
(4) Butyl rubber 10%
(Product name: Exon Butyl 065, Exxon Chemical)
(5) Isostearic acid 5%
(Product name: Isostearic acid EX, higher alcohol industry)
(6) Diisopropyl sebacate 2%
(Product name: DIS, Nikko Chemicals)
(7) Palmitic acid 2%
(Product name: Palmitic acid, Wako Pure Chemical)
(8) Starch acrylate 3%
(Product name: Sunwet IM-1000MPS, Sanyo Kasei)
(9) Alicyclic saturated hydrocarbon resin 12.7%
(Product name: Alcon P-100, Arakawa Chemical Industries)
(10) Pentaerythrityl-tetrakis [3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] 0.1%
(Product name: Irganox 1010, Ciba Specialty Chemicals)
(11) Liquid paraffin 33.4%
(Product name: High Call M-352, Kaneda)
(12) l-Menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(13) Polyethylene glycol 20000 0.3%
(Product name: Macrogol 20000, Sanyo Kasei)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, polybutene, butyl rubber, liquid paraffin, alicyclic saturated hydrocarbon resin, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate After heating and melting to a uniform state, diclofenac sodium, isostearic acid, palmitic acid, starch acrylate, diisopropyl sebacate, l-menthol and polyethylene glycol 2000
0 was added to obtain a uniform melt. Next, this melt is used using a doctor knife coating machine.
A pressure-sensitive adhesive layer was formed by spreading on a polyethylene terephthalate film so as to have a thickness of 100 μm. Thereafter, the pressure-sensitive adhesive layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 3).

Example 4
An external patch was produced by the following composition and production method.

(composition)
(1) Diclofenac sodium 1.5%
(2) Styrene-isoprene-styrene block copolymer 28.1%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polybutene 5%
(Product name: HV-300F, Nippon Petrochemical)
(4) Butyl rubber 10%
(Product name: Exon Butyl 065, Exxon Chemical)
(5) Isostearic acid 3.5%
(Product name: Isostearic acid EX, higher alcohol industry)
(6) Diisopropyl sebacate 2%
(Product name: DIS, Nikko Chemicals)
(7) Palmitic acid 2%
(Product name: Palmitic acid, Wako Pure Chemical)
(8) 1% starch acrylate
(Product name: Sunwet IM-1000MPS, Sanyo Kasei)
(9) Hydrogenated rosin resin glycerin ester 13.7%
(Product name: KE-311, Arakawa Chemical Industries)
(10) Pentaerythrityl-tetrakis [3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] 0.1%
(Product name: Irganox 1010, Ciba Specialty Chemicals)
(11) Liquid paraffin 28.8%
(Product name: High Call M-352, Kaneda)
(12) l-Menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(13) Polyethylene glycol 20000 1.3%
(Product name: Macrogol 20000, Sanyo Kasei)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, polybutene, butyl rubber, liquid paraffin, hydrogenated rosin resin glycerin ester, pentaerythrityl-tetrakis [3
-(3,5-di-t-butyl-4-hydroxyphenyl) propionate] is heated and melted to a uniform state, and then diclofenac sodium, isostearic acid, palmitic acid,
Starch acrylate, diisopropyl sebacate, l-menthol and polyethylene glycol 20000 were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form an adhesive layer. Thereafter, the pressure-sensitive adhesive layer was bonded to a stretchable woven fabric. Then, it was cut into a desired size to obtain an external patch (Example 4).

Example 5
An external patch was produced by the following composition and production method.

(composition)
(1) Diclofenac sodium 1.5%
(2) Styrene-isoprene-styrene block copolymer 30%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polyisobutylene 2%
(Product name: Tetrax 3T, Nippon Petrochemical)
(4) Butyl rubber 8%
(Product name: Exon Butyl 065, Exxon Chemical)
(5) 3.3% isostearic acid
(Product name: Isostearic acid EX, higher alcohol industry)
(6) Diisopropyl sebacate 2%
(Product name: DIS, Nikko Chemicals)
(7) Palmitic acid 1%
(Product name: Palmitic acid, Wako Pure Chemical)
(8) 0.1% starch acrylate
(Product name: Sunwet IM-1000MPS, Sanyo Kasei)
(9) Hydrogenated rosin resin glycerin ester 14%
(Product name: KE-311, Arakawa Chemical Industries)
(10) Pentaerythrityl-tetrakis [3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] 0.1%
(Product name: Irganox 1010, Ciba Specialty Chemicals)
(11) Liquid paraffin 34.3%
(Product name: High Call M-352, Kaneda)
(12) l-Menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(13) Polyethylene glycol 20000 0.7%
(Product name: Macrogol 20000, Sanyo Kasei)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, polyisobutylene, butyl rubber, liquid paraffin, hydrogenated rosin resin glycerin ester, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate ] Was melted by heating to obtain a uniform state, and then diclofenac sodium, isostearic acid, palmitic acid, starch acrylate, diisopropyl sebacate, l-menthol and polyethylene glycol 20000 were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form an adhesive layer. Thereafter, the pressure-sensitive adhesive layer was bonded to a stretchable woven fabric. Then, it was cut into a desired size to obtain an external patch (Example 5).

Example 6
An external patch was produced by the following composition and production method.

(composition)
(1) Diclofenac sodium 1.5%
(2) Styrene-isoprene-styrene block copolymer 29.5%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polyisobutylene 2%
(Product name: Tetrax 3T, Nippon Petrochemical)
(4) Butyl rubber 8%
(Product name: Exon Butyl 065, Exxon Chemical)
(5) 3.8% isostearic acid
(Product name: Isostearic acid EX, higher alcohol industry)
(6) Diisopropyl sebacate 2%
(Product name: DIS, Nikko Chemicals)
(7) Palmitic acid 1.3%
(Product name: Palmitic acid, Wako Pure Chemical)
(8) Starch acrylate 0.6%
(Product name: Sunwet IM-1000MPS, Sanyo Kasei)
(9) Hydrogenated rosin resin glycerin ester 14.5%
(Product name: KE-311, Arakawa Chemical Industries)
(10) Pentaerythrityl-tetrakis [3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] 0.1%
(Product name: Irganox 1010, Ciba Specialty Chemicals)
(11) Liquid paraffin 33%
(Product name: High Call M-352, Kaneda)
(12) l-Menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(13) Polyethylene glycol 20000 0.7%
(Product name: Macrogol 20000, Sanyo Kasei)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, polyisobutylene, butyl rubber, liquid paraffin, hydrogenated rosin resin glycerin ester, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate ] Was melted by heating to obtain a uniform state, and then diclofenac sodium, isostearic acid, palmitic acid, starch acrylate, diisopropyl sebacate, l-menthol and polyethylene glycol 20000 were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form an adhesive layer. Thereafter, the pressure-sensitive adhesive layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 6).

Example 7
An external patch was produced by the following composition and production method.

(composition)
(1) Loxoprofen sodium hydration 5%
(2) Styrene-isoprene-styrene block copolymer 12.5%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Butyl rubber 10%
(Product name: Exon Butyl 065, Exxon Chemical)
(4) Palmitic acid 3%
(Product name: LUNAC P-95, Kao)
(5) Stearic acid 9%
(Product name: Purified stearic acid, Kao)
(6) Isopropyl palmitate 3%
(Product name: IPP-EX, Nikko Chemicals)
(7) Alicyclic saturated hydrocarbon resin 30%
(Product name: Alcon P-100, Arakawa Chemical Industries)
(8) Dibutylhydroxytoluene 1%
(Product name: Yoshinox BHT, API-CARP)
(9) Liquid paraffin 18.5%
(Product name: High Call M-352, Kaneda)
(10) l-Menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(11) Polyethylene glycol 6000 5%
(Product name: Macrogol 6000, Sanyo Chemical Industries)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, liquid paraffin, alicyclic saturated hydrocarbon resin, butyl rubber and polyethylene glycol 6000 are heated and melted, and l-menthol is added to obtain a uniform state. Then, loxoprofen sodium, stearic acid, Palmitic acid, isopropyl palmitate and dibutylhydroxytoluene were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 7).

Example 8
An external patch was produced by the following composition and production method.

(composition)
(1) Loxoprofen sodium hydrate 5%
(2) Styrene-isoprene-styrene block copolymer 14%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polyisobutylene 5%
(Product name: Tetrax 3T, Nippon Petrochemical)
(4) Polybutene 10%
(Product name: HV-300F, Nippon Petrochemical)
(5) Isopropyl myristate 5%
(Product name: IPP-EX, Nikko Chemicals)
(6) Palmitic acid 1.5%
(Product name: LUNAC P-95, Kao)
(7) Stearic acid 5%
(Product name: Purified stearic acid, Kao)
(8) Terpene resin 29%
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(9) Dibutylhydroxytoluene 3%
(Product name: Yoshinox BHT, API-CARP)
(10) Liquid paraffin 17.5%
(Product name: High Call M-352, Kaneda)
(11) 1-menthol 1%
(Product name: Natural thin cargo brain, Nagaoka business)
(12) Polyethylene glycol 20000 4%
(Product name: Macrogol 20000, Sanyo Chemical Industries)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, liquid paraffin, terpene resin, polyisobutylene, polybutene and polyethylene glycol 20000 are heated and melted,
After adding menthol to a uniform state, loxoprofen sodium, stearic acid,
Palmitic acid, isopropyl myristate and dibutylhydroxytoluene were added to obtain a uniform melt. Next, this melt was added to a thickness of 100 μm using a doctor knife coating machine.
m was spread on a polyethylene terephthalate film to form a plaster layer. Thereafter, the plaster layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 8).

Comparative Example 2
An external patch was produced by the following composition and production method.

(composition)
(1) Loxoprofen sodium hydrate 5%
(2) Styrene-isoprene-styrene block copolymer 17%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polybutene 3%
(Product name: HV-300F, Nippon Petrochemical)
(4) Butyl rubber 6%
(Product name: Exon Butyl 065, Exxon Chemical)
(6) Isostearic acid 5%
(Product name: Isostearic acid EX, higher alcohol industry)
(7) Isopropyl myristate 5%
(Product name: IPP-EX, Nikko Chemicals)
(8) Hydrogenated rosin resin glycerin ester 32%
(Product name: KE-311, Arakawa Chemical Industries)
(9) Dibutylhydroxytoluene 3%
(Product name: Yoshinox BHT, API-CARP)
(10) Liquid paraffin 16%
(Product name: High Call M-352, Kaneda)
(11) l-Menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(12) Polyethylene glycol 20000 5%
(Product name: Macrogol 20000, Sanyo Chemical Industries)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, liquid paraffin, hydrogenated rosin resin glycerin ester, butyl rubber, polybutene and polyethylene glycol 20000
Was heated and melted, and l-menthol was added to obtain a uniform state, and then loxoprofen sodium, isostearic acid, isopropyl myristate and dibutylhydroxytoluene were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable woven fabric. Then, it was cut into a desired size to obtain an external patch (Comparative Example 2).

Test example 2
Skin Adhesion Test Examples 7 and 8 and Comparative Example 2 were each cut into 20 mm × 70 mm to prepare samples. Each sample was affixed to the subject's back skin by a circuit method. After a predetermined time has elapsed, the sample is peeled off at a rate of 1000 mm / min from the bottom in the direction of 90 ° with the Tensilon universal testing machine, the integrated average load at the time of peeling is obtained, and the adhesive strength (N / 20 mm) It was. Conducted on 8 subjects,
The average value and standard deviation of the adhesive strength were determined. The peeling time was measured immediately after sticking and after 8 hours.

Skin adhesion (average value ± standard deviation value; unit: N / 20 mm) after 0 hours and 8 hours after application of Example 7 and Example 8 (both containing stearic acid and palmitic acid) was 0 respectively.
. 99 ± 0.25, 0.95 ± 0.74, 1.20 ± 0.25, 1.25 ± 0.72, and there is not much difference in adhesion to the skin after 0 hours and 8 hours after application In contrast, Comparative Example 2
Of 0.97 ± 0.21 to 0.10 ± 0.08, and the adhesive strength after 8 hours of application was considerably reduced with respect to 0 hours of application. From these results, it is shown that the effect of preventing the peeling-off is produced by using the anti-peeling agent (stearic acid, palmitic acid) in combination.

Example 9
An external patch was produced by the following composition and production method.

(1) Loxoprofen sodium hydrate 3%
(2) Styrene-isoprene-styrene block copolymer 10%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Butyl rubber 10%
(Product name: Exon Butyl 065, Exxon Chemical)
(4) Isopropyl palmitate 4.5%
(Product name: IPP-EX, Nikko Chemicals)
(5) Palmitic acid 3%
(Product name: LUNAC P-95, Kao)
(6) Stearic acid 9%
(Product name: Purified stearic acid, Kao)
(7) Alicyclic saturated hydrocarbon resin 30.5%
(Product name: Alcon P-100, Arakawa Chemical Industries)
(8) Terpene resin 4%
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(9) Dibutylhydroxytoluene 1%
(Product name: Yoshinox BHT, API-CARP)
(10) Liquid paraffin 20%
(Product name: High Call M-352, Kaneda)
(11) l-Menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(12) Polyethylene glycol 6000 2%
(Product name: Macrogol 6000, Sanyo Chemical Industries)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, liquid paraffin, terpene resin, alicyclic saturated hydrocarbon resin, butyl rubber and polyethylene glycol 6000 are heated and melted,
After adding l-menthol and making it uniform, loxoprofen sodium, stearic acid, palmitic acid, isopropyl palmitate and dibutylhydroxytoluene are added,
A uniform melt was obtained. Next, this melt is made to have a thickness of 10 using a doctor knife coating machine.
A plaster layer was formed by spreading on a polyethylene terephthalate film so as to have a thickness of 0 μm.
Thereafter, the plaster layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 9).

Example 10
An external patch was produced by the following composition and production method.

(1) Loxoprofen sodium hydrate 10%
(2) Styrene-isoprene-styrene block copolymer 12%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polyisobutylene 5%
(Product name: Tetrax 3T, Nippon Petrochemical)
(4) Polybutene 9.5%
(Product name: HV-300F, Nippon Petrochemical)
(5) Isopropyl myristate 5%
(Product name: IPM-EX, Nikko Chemicals)
(6) Palmitic acid 1.5%
(Product name: LUNAC P-95, Kao)
(7) Stearic acid 5%
(Product name: Purified stearic acid, Kao)
(8) Terpene resin 22%
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(9) Dibutylhydroxytoluene 3%
(Product name: Yoshinox BHT, API-CARP)
(10) Liquid paraffin 18%
(Product name: High Call M-352, Kaneda)
(11) Polyethylene glycol 20000 9%
(Product name: Macrogol 20000, Sanyo Chemical Industries)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, liquid paraffin, terpene resin, polyisobutylene, polybutene and polyethylene glycol 20000 are heated and melted, and loxoprofen sodium, stearic acid, palmitic acid, isopropyl myristate and dibutylhydroxytoluene are added, and uniform A melt was obtained. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 10).

Example 11
An external patch was produced by the following composition and production method.

(1) Loxoprofen sodium hydrate 5%
(2) Styrene-isoprene-styrene block copolymer 14%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polybutene 3%
(Product name: HV-300F, Nippon Petrochemical (4)) Butyl rubber 5%
(Product name: Exon Butyl 065, Exxon Chemical)
(5) Diisopropyl adipate 10%
(Product name: DID, Nikko Chemicals)
(6) Palmitic acid 3%
(Product name: LUNAC P-95, Kao)
(7) Stearic acid 9%
(Product name: Purified stearic acid, Kao)
(8) Hydrogenated rosin resin glycerin ester 25%
(Product name: KE-311, Arakawa Chemical Industries)
(9) Dibutylhydroxytoluene 3%
(Product name: Yoshinox BHT, API-CARP)
(10) Liquid paraffin 16%
(Product name: High Call M-352, Kaneda)
(11) l-Menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(12) Polyethylene glycol 20000 4%
(Product name: Macrogol 20000, Sanyo Chemical Industries)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, liquid paraffin, hydrogenated rosin resin glycerin ester, alicyclic saturated hydrocarbon resin, butyl rubber, polybutene and polyethylene glycol 20000 are heated and melted, and l-menthol is added to obtain a uniform state. After
Loxoprofen sodium, stearic acid, palmitic acid, diisopropyl adipate and dibutylhydroxytoluene were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 11).

Example 12
An external patch was produced by the following composition and production method.

(1) Loxoprofen sodium hydrate 3%
(2) Styrene-isoprene-styrene block copolymer 15%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polybutene 5%
(Product name: HV-300F, Nippon Petrochemical)
(4) Isostearic acid 3%
(Product name: Isostearic acid EX, higher alcohol industry)
(5) Isopropyl myristate 5%
(Product name: IPM-EX, Nikko Chemicals)
(6) Palmitic acid 3%
(Product name: LUNAC P-95, Kao)
(7) Stearic acid 5%
(Product name: Purified stearic acid, Kao)
(8) Terpene resin 35%
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(9) Dibutylhydroxytoluene 3%
(Product name: Yoshinox BHT, API-CARP)
(10) Liquid paraffin 18%
(Product name: High Call M-352, Kaneda)
(11) Polyethylene glycol 20000 5%
(Product name: Macrogol 20000, Sanyo Chemical Industries)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, liquid paraffin, terpene resin, polybutene and polyethylene glycol 20000 are heated and melted, and loxoprofen sodium, isostearic acid, stearic acid, palmitic acid, isopropyl myristate and dibutylhydroxytoluene are added, and uniform A melt was obtained. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 12).

Example 13
An external patch was produced by the following composition and production method.

(1) Loxoprofen sodium hydrate 5%
(2) Styrene-isoprene-styrene block copolymer 14%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Butyl rubber 10%
(Product name: Exon Butyl 065, Exxon Chemical)
(4) Isopropyl palmitate 5%
(Product name: IPP-EX, Nikko Chemicals)
(5) Palmitic acid 6%
(Product name: LUNAC P-95, Kao)
(6) Stearic acid 3%
(Product name: Purified stearic acid, Kao)
(7) Hydrogenated rosin resin glycerin ester 32%
(Product name: KE-311, Arakawa Chemical Industries)
(8) Dibutylhydroxytoluene 3%
(Product name: Yoshinox BHT, API-CARP)
(9) Liquid paraffin 16%
(Product name: High Call M-352, Kaneda)
(10) l-Menthol 3%
(Product name: Natural thin cargo brain, Nagaoka business)
(11) Polyethylene glycol 6000 3%
(Product name: Macrogol 6000, Sanyo Chemical Industries)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, liquid paraffin, hydrogenated rosin resin glycerin ester, butyl rubber and polyethylene glycol 6000 were heated and melted,
After adding l-menthol and making it uniform, loxoprofen sodium, stearic acid, palmitic acid, isopropyl palmitate and dibutylhydroxytoluene are added,
A uniform melt was obtained. Next, this melt is made to have a thickness of 10 using a doctor knife coating machine.
A plaster layer was formed by spreading on a polyethylene terephthalate film so as to have a thickness of 0 μm.
Thereafter, the plaster layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 13).

Example 14
An external patch was produced by the following composition and production method.

(1) Loxoprofen sodium hydrate 5%
(2) Styrene-isoprene-styrene block copolymer 14%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polybutene 5%
(Product name: HV-300F, Nippon Petrochemical)
(4) Isopropyl myristate 5%
(Product name: IPM-EX, Nikko Chemicals)
(5) Diisopropyl adipate 3%
(Product name: DID, Nikko Chemicals)
(6) Palmitic acid 4%
(Product name: LUNAC P-95, Kao)
(7) Stearic acid 5%
(Product name: Purified stearic acid, Kao)
(8) Hydrogenated rosin resin glycerin ester 35%
(Product name: KE-311, Arakawa Chemical Industries)
(9) Dibutylhydroxytoluene 3%
(Product name: Yoshinox BHT, API-CARP)
(10) Liquid paraffin 16%
(Product name: High Call M-352, Kaneda)
(11) Polyethylene glycol 20000 5%
(Product name: Macrogol 20000, Sanyo Chemical Industries)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, liquid paraffin, hydrogenated rosin resin glycerin ester, polybutene and polyethylene glycol 20000 are heated and melted, loxoprofen sodium, stearic acid, palmitic acid, isopropyl myristate, diisopropyl adipate and dibutylhydroxytoluene Was added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 14).

Example 15
An external patch was produced by the following composition and production method.

(1) Loxoprofen sodium hydrate 5%
(2) Styrene-isoprene-styrene block copolymer 15%
(Product name: Kraton D-KX401cs, JSR Kraton Elastomer)
(3) Polyisobutylene 5%
(Product name: Tetrax 3T, Nippon Petrochemical)
(4) Isopropyl myristate 5%
(Product name: IPM-EX, Nikko Chemicals)
(5) Diisopropyl sebacate 1%
(Product name: DIS, Nikko Chemicals)
(6) Palmitic acid 4%
(Product name: LUNAC P-95, Kao)
(7) Stearic acid 5%
(Product name: Purified stearic acid, Kao)
(8) Hydrogenated rosin resin glycerin ester 35%
(Product name: KE-311, Arakawa Chemical Industries)
(9) Dibutylhydroxytoluene 3%
(Product name: Yoshinox BHT, API-CARP)
(10) Liquid paraffin 16%
(Product name: High Call M-352, Kaneda)
(11) 1-menthol 1%
(Product name: Natural thin cargo brain, Nagaoka business)
(12) Polyethylene glycol 20000 5%
(Product name: Macrogol 20000, Sanyo Chemical Industries)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, liquid paraffin, hydrogenated rosin resin glycerin ester, alicyclic saturated hydrocarbon resin, polyisobutylene and polyethylene glycol 20000 are heated and melted, and l-menthol is added to obtain a uniform state. Thereafter, loxoprofen sodium, stearic acid, palmitic acid, isopropyl myristate, diisopropyl sebacate and dibutylhydroxytoluene were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable woven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (Example 15).

As described above, an anti-slipping or twisting-preventing agent is added to the adhesive layer in an external patch containing a carboxylic acid drug or an alkali salt thereof, particularly diclofenac sodium or loxoprofen sodium, as an active ingredient. By doing so, it is excellent in drug solubility and drug release from the adhesive layer, there is no decrease in drug content in the adhesive layer, skin irritation is low, and skin adhesiveness is improved. The present invention also provides a patch excellent in usability in that peeling or twisting is prevented at the time of application or during application.

Claims (7)

An external patch in which an adhesive layer containing an active ingredient is formed on a support, and the adhesive layer contains an anti-peeling agent in the adhesive layer. The external patch according to claim 1, wherein the anti-peeling agent is a solid acid. The external patch according to claim 2, wherein the solid acid is a saturated fatty acid having a carbon number of 9 to 29 and solid at normal temperature. The patch for external use according to claim 3, wherein the saturated fatty acid having 9 to 29 carbon atoms and solid at normal temperature is lauric acid, myristic acid, palmitic acid, stearic acid or behenic acid. The external patch according to any one of claims 1 to 4, wherein the adhesive layer further contains an aqueous polymer compound. The external patch according to claim 5, wherein the aqueous polymer compound is starch acrylate. The external patch according to any one of claims 1 to 6, wherein the active ingredient is diclofenac sodium or loxoprofen sodium.