JPH0733665A - Emedastine-containing tacky patch - Google Patents

Abstract

PURPOSE:To obtain a patch useful for treating and preventing various kinds of allergic diseases caused by histamine such as allergic rhinitis, allergic bronchial asthma and allergic dermatosis, having excellent percutaneous absorption of emedastine and durability. CONSTITUTION:A tacky layer comprising an acrylic tacky base, a silicone-based tacky base or a rubber-based tacky base and emedastine is laminated to one side of a substrate to provide a tacky patch.

Description

Detailed Description of the Invention

[0001]

The present invention has the following formula

[0002]

[Chemical 1] The present invention relates to an adhesive patch for the treatment and prevention of allergic diseases, which contains a compound represented by (generic name: emedastine).

[0003]

2. Description of the Related Art Emedastine is a known compound (Japanese Unexamined Patent Publication (Kokai) No. 58-79983) and is known to have a histamine release inhibitory action and an antihistamine action [Fukuda et al., Ar.
zneimittel-Forshung Drug Reseach, 34 (II), 7, 805 (19
84)], and a compound useful as a prophylactic and therapeutic drug for diseases caused by histamine, such as allergic skin diseases and allergic rhinitis.

Regarding the oral preparation containing the difumarate salt of emedastine as an active ingredient, capsules have been approved in Japan as therapeutic agents for allergic rhinitis and urticaria.

Regarding a transdermal agent containing emedastine or a pharmaceutically acceptable salt thereof, it is possible to prepare an ointment using a usual base, and the corresponding US patent (US Pat. No. 4,430,343) corresponding to the above-mentioned publication. ) And an ointment consisting of emedastine difumarate and polyethylene glycol is disclosed in the examples. In addition, JP-A-3-839
24 is an invention by two of the three inventors of the present application, that is, a transdermal composition comprising emedastine and an aliphatic monocarboxylic acid lower alkyl ester, an aliphatic dicarboxylic acid dilower alkyl ester or an oleic acid lower alkyl ester. The thing is disclosed. It is disclosed that the composition can be used to prepare a preparation for application to the skin, such as an oily ointment, gel, cream, lotion and the like. As described above, all of the known transdermal preparations of emedastine are in the form of application. However, it is difficult to apply a strictly fixed amount of an ointment, cream, lotion, or other such application form (that is, it is difficult to administer a prescribed amount of emedastine), and wipe it with clothing etc. after application. Since it is easy to leave, it is difficult to obtain a stable effect.

[0006] Generally, patches are advantageous in that they can be administered in a fixed amount and can be prevented from being wiped off by clothes or the like, but in order to put them into practical use, the transdermal absorbability and sustainability of the drug are improved. It is necessary to devise for.

[0007] Conventionally, various proposals have been made for an adhesive patch containing a drug in an adhesive layer, but there is no example in which emedastine is incorporated in an adhesive base, and when emedastine is incorporated in an adhesive base. Transdermal absorbability of emedastine,
There is no suggestion of sustainability.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide an adhesive patch containing emedastine which is excellent in transdermal absorbability and durability.

[0009]

As a result of various investigations, the present inventors have found that an adhesive layer comprising an acrylic adhesive base, a silicone adhesive base or a rubber adhesive base and emedastine is used as a support. The present inventors have completed the present invention by finding that the adhesive patch laminated on one side has excellent transdermal absorbability and sustainability of emedastine.

The patch of the present invention can be produced by a conventional method for producing an adhesive tape, for example, a solvent coating method. That is, the patch of the present invention is an adhesive base, emedastine, if necessary additives such as absorption promoters are dissolved or dispersed in a solvent, the resulting solution or dispersion is applied to the surface of the support and dried. Usually, it can be produced by forming an adhesive layer having a thickness of 10 to 200 μm on the surface of a support. Further, the above-mentioned solution or dispersion is applied onto a protective release sheet and dried to form a pressure-sensitive adhesive layer having a thickness of 10 to 200 μm on the release sheet, and then the support is brought into close contact with the pressure-sensitive adhesive layer. It can also be manufactured by.

The adhesive base is an acrylic adhesive base,
A silicone-based adhesive base or a rubber-based adhesive base is used. In particular, it is preferable to use an acrylic adhesive base or a silicone adhesive base because good transdermal absorbability and sustainability can be obtained even with a small amount of emedastine.

The compounding amount of emedastine in the adhesive layer is
It is usually 0.1 to 30% by weight based on the total dry weight of the adhesive layer. When the compounding amount of emedastine is 0.1% by weight or less, it is necessary to apply a patch having an excessively large area in order to transdermally absorb the required amount of emedastine, while 3
When 0% by weight or more is blended, the adhesiveness of the adhesive layer is reduced and it becomes difficult to apply it to the skin.

When the acrylic adhesive base or the silicone adhesive base is used, the transdermal absorbability of emedastine is superior to the case where the rubber adhesive base is used, and the total dry weight of the adhesive layer is The emedastine content is preferably 0.5 to 20% by weight, more preferably 2 to 10% by weight. When a rubber-based adhesive base is used, the amount of emedastine compounded with respect to the total dry weight of the adhesive layer is preferably 1 to 30% by weight, more preferably 3 to 20% by weight.

The thickness of the adhesive layer is usually 10 to 200 μm.
Is the range. If this thickness is less than 10 μm, the required amount of emedastin cannot be contained and the adhesiveness is insufficient. When the thickness exceeds 200 μm, emedastine contained in the adhesive layer near the support does not sufficiently diffuse to the surface of the adhesive layer, and the utilization rate of emedastine decreases.

As the acrylic adhesive base, alkyl acrylate (alkyl group having 1 to 18 carbon atoms, preferably 4 to 12), methacrylic acid alkyl ester (alkyl group having 1 to 18 carbon atoms, preferably 4-12)
The homopolymers or copolymers thereof are preferably used.

Specific examples of the above acrylic acid alkyl ester and methacrylic acid alkyl ester have an alkyl group of butyl, pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, isononyl, decyl, undecyl, dodecyl, tridecyl, stearyl. Acrylic acid alkyl ester or methacrylic acid alkyl ester having a linear alkyl group or branched alkyl group such as

As the acrylic adhesive base used in the present invention, the above-mentioned acrylic acid alkyl ester or /
And 60-99. Of methacrylic acid alkyl ester.
A copolymer of 5% by weight and 0.5 to 40 parts by weight of the following one or more olefinic monomers can also be preferably used.

As these monomers, acrylic acid, acrylic hydroxy lower alkyl ester (eg, hydroxyethyl acrylate, hydroxypropyl acrylate), acrylamide, acrylamide derivative (eg, dimethyl acrylamide, N-butyl). Acrylamide, N-methylol acrylamide, N-methylol propane acrylamide), acrylic acid alkylaminoalkyl ester (eg acrylic acid aminoethyl ester, acrylic acid tert-butylaminoethyl ester), acrylic acid dialkylaminoalkyl ester (eg acrylic acid Dimethylaminoethyl ester), acrylic acid alkoxyalkyl ester (eg acrylic acid methoxyethyl ester, acrylic acid ethoxyethyl ester) Tetrahydrofurfuryl acrylate esters, esters of acrylic acid with methoxy diethylene glycol, esters of acrylic acid with methoxy polyethylene glycol, esters of acrylic acid with methoxy polypropylene glycol, methacrylic acid,
Methacrylic acid hydroxy lower alkyl ester (for example, hydroxyethyl methacrylate, hydroxypropyl methacrylate), methacrylamide, methacrylamide derivative (for example, dimethylmethacrylamide, N-butylmethacrylamide, N-methylolmethacrylate) Acrylamide, N-methylolpropane methacrylamide), methacrylic acid alkylaminoalkyl ester (eg, methacrylic acid aminoethyl ester, methacrylic acid tert-butylaminoethyl ester), methacrylic acid dialkylaminoalkyl ester (eg, methacrylic acid) Acid dimethylaminoethyl ester), methacrylic acid alkoxyalkyl ester (for example, methacrylic acid methoxyethyl ester,
(Methacrylic acid ethoxyethyl ester), methacrylic acid tetrahydrofurfuryl ester, methacrylic acid and methoxydiethylene glycol ester, methacrylic acid and methoxypolyethylene glycol ester, methacrylic acid and methoxypolypropylene glycol ester, methacrylonitrile , Acrylonitrile, vinyl acetate, vinyl propionate, N-vinyl-
2-pyrrolidone, methylvinylpyrrolidone, vinylpyridine, vinylpiperidone, vinylpyrimidine, vinylpiperazine, vinylpyrazine, vinylpyrrole, vinylimidazole, vinylcaprolactam, vinyloxazole, vinylmorpholinestyrene, itaconic acid, maleic acid, maleic anhydride, styrene sulfone. Acid, allyl sulfonic acid, sulfone propyl methacrylate, sulfone propyl acrylate, methacryloyloxy naphthalene sulfonic acid, acryloyl oxynaphthalene sulfonic acid, acrylamidomethyl propane sulfonic acid and the like can be mentioned.

However, among the above-mentioned olefinic monomers,
When a copolymer having a large copolymerization ratio of an acid group-containing monomer such as acrylic acid, methacrylic acid or styrene sulfonic acid is used as an adhesive base, the transdermal absorbability of emedastine tends to decrease. Therefore, it is preferable to use a copolymer having a copolymerization ratio of these acid group-containing monomers of 0.5 to 3% by weight as an adhesive base.

Accordingly, one of the more preferable copolymers is 97 to 99.5 of acrylic acid alkyl ester whose alkyl group has 4 to 12 carbon atoms and / or methacrylic acid whose alkyl group has 4 to 12 carbon atoms. A copolymer of 1% by weight and 0.5 to 3% by weight of acrylic acid or / and methacrylic acid, the other being an acrylic acid alkyl ester having an alkyl group with 4 to 12 carbon atoms and / or an alkyl group. 70 to 85% by weight of methacrylic acid alkyl ester having 4 to 12 carbon atoms, 0.5 to 3% by weight of acrylic acid and / or methacrylic acid, acrylamide, methacrylamide, hydroxyethyl acrylate
1 or 2 or more kinds of monomers selected from the group consisting of vinyl acetate, hydroxyethyl methacrylate and vinyl acetate.
It is a copolymer composed of 0 to 30% by weight.

Further, one of the most preferable copolymers from the viewpoint of tackiness and transdermal absorbability of emedastine is selected from the group consisting of 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate and butyl acrylate. One or two or more selected from 97 to 99.5% by weight and 0.5 to 3% by weight of acrylic acid are copolymers, and the other is 2-ethylhexyl acrylate or 2- A copolymer comprising 70 to 85% by weight of ethylhexyl methacrylate, 0.5 to 3% by weight of acrylic acid, 5 to 30% by weight of vinyl acetate and 3 to 4% by weight of hydroxyethyl methacrylate. .

As the silicone-based adhesive base, an adhesive containing polydimethylsiloxane as a main component is used.
For example, Dow Corning 355 medical adhesive, Bio
-PSA Q7-2920 Medical Grade Silicone Adhesive, Silastic 382 Medical
A graded elastomer (both trade names of Dow Corning) can be preferably used.

Examples of the rubber-based adhesive base include natural rubber, styrene-isoprene-styrene / block copolymer, polyisobutylene, polybutene, polyisoprene, ethylene-vinyl acetate copolymer, polyurethane, polyvinyl ether or fluororubber. Can be used.

[0024] Incidentally, for the base material which itself has low tackiness,
For imparting tackiness, rosin-based resins, polyterpene resins, coumarone-indene resins, petroleum-based resins, terpene-phenyl resins, xylene resins or alicyclic saturated hydrocarbon resins that are commonly used in adhesive tapes (for example, trade name :
It is also possible to appropriately mix Alcon and Arakawa Chemical Industries, Ltd. and use this mixture as an adhesive base.

To the adhesive layer, an aliphatic saturated monocarboxylic acid lower alkyl ester, an oleic acid lower alkyl ester, an aliphatic dicarboxylic acid dilower alkyl ester, liquid paraffin, a surfactant, or a silicone oil is adhered as an absorption promoter. It can be incorporated into layers. However, when a silicone-based adhesive base is used, the addition of an aliphatic saturated monocarboxylic acid lower alkyl ester, an oleic acid lower alkyl ester, or an aliphatic dicarboxylic acid dilower alkyl ester will have no significant effect.

The content of the absorption promoter is usually 0.1 to 30% by weight, preferably 1 to 20% by weight, based on the total amount of the adhesive layer.
Is. It is difficult to recognize the effect when the content is 0.1% by weight or less,
A blending amount of 30% by weight or more is not preferable because it reduces the tackiness of the tacky layer.

The aliphatic saturated monocarboxylic acid lower alkyl ester is preferably an aliphatic saturated monocarboxylic acid lower alkyl ester having a total carbon number of 8 to 22, and examples thereof include ethyl octanoate, ethyl decanoate, ethyl hexanoate and laurin. Ethyl acid, ethyl myristate, isopropyl myristate, butyl myristate, isopropyl palmitate, butyl stearate and the like are preferable. As the lower alkyl ester of oleic acid, methyl oleate, ethyl oleate and butyl oleate are preferable. The aliphatic dicarboxylic acid di-lower alkyl ester is preferably an aliphatic dicarboxylic acid di-lower alkyl ester having 10 to 14 carbon atoms, and examples thereof include diethyl sebacate, diisopropyl adipate, diethyl suberate and diethyl adipate. .

Examples of the surfactant include nonionic surfactants such as polyoxyethylene sorbitan monolaurate, polyoxyethylene glyceryl monooleate, polyoxyethylene monostearate, polyoxyethylene lauryl ether and polyoxyethylene oleylamine. , Anionic surfactants such as lauroyl sarcosine, triethanolamine lauryl sulfate, sodium lauryl sulfate, sodium polyoxyethylene lauryl ether phosphate, and amphoteric surfactants such as lecithin.

Silicone oil has a viscosity of 100 to 4
00 dimethylpolysiloxane and methylphenylpolysiloxane can be preferably used.

In order to adjust the wetting properties, tackiness and low temperature properties of the adhesive layer by plasticizing it, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, as a plasticizer, may be added, if necessary. It is also possible to add glycols such as polyethylene glycol, olive oil, castor oil, squalene, oils and fats such as lanolin, mineral oil, liquid polybutene, liquid polyisoprene, liquid polyacrylate and the like. Further, a filler such as titanium oxide, zinc oxide or silicic acid anhydride may be blended in order to adjust the hardness of the adhesive layer, enhance the cohesive strength, or color the adhesive layer. Further, particularly when a rubber-based pressure-sensitive adhesive is used, a deterioration-preventing agent such as butylhydroxytoluene may be added to prevent deterioration of the pressure-sensitive adhesive layer.

For the support of the adhesive patch of the present invention, a single layer sheet made of a material that does not allow the components in the adhesive layer to pass through, a laminated film of two or more sheets, a woven fabric or a nonwoven fabric is preferably used. Examples of the material of the support include polyester such as polyethylene terephthalate, polyamide such as nylon, polyvinylidene chloride, cellulose acetate, ethyl cellulose, plasticized vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, ethylene- Ethyl acrylate copolymer, polytetrafluoroethylene, plasticized polyvinyl chloride, polyurethane, polyethylene, polypropylene and metal foil (eg aluminum foil)
Can be mentioned. A support having a low gas permeability is preferable for the transdermal absorbability of emedastine, and for example, a polyester film can be preferably used. Since the support is required to have flexibility, its thickness is usually 300 μm or less, preferably 5 to 150 μm.

The adhesive patch of the present invention is usually used in order to prevent the adhesive layer from unnecessarily adhering to instruments, containers and the like during production, transportation or storage, and to prevent the patch from deteriorating. Then, a release sheet is laminated on the surface. Then, at the time of use, this is peeled off to expose the adhesive surface, and the composition is attached to the skin for administration. As the release sheet, since it is necessary to be easily released from the adhesive layer at the time of use, polyester, polyvinyl chloride, polyvinylidene chloride, polyethylene, which has been treated with silicon on the contact surface with the adhesive layer, is usually used. A film such as terephthalate or a laminated film of high quality paper or glassine paper and polyolefin is used. The thickness of the release sheet is 1000 μm or less, preferably 30 to 200 μm.

The dose and method of administration of the patch of the present invention will vary depending on the age, body weight, symptom, etc. of the patient, but usually for adults, 0.1 to 10 mg of emedastine is contained and the surface area is 1 to 10. One patch (1 sheet) of the patch of the present invention having a size of 50 cm ² is applied to the skin once or twice a day or once every two days for use.

[0034]

The patch of the present invention has excellent transdermal absorbability of emedastine. For example, as a method for evaluating transdermal absorbability, a method in which the extracted skin is inserted between diffusion cells and the amount of the drug that permeates the skin is determined (hereinafter referred to as the diffusion cell method) is widely used. When tested by this method, it showed good skin permeability (see Test Example 1 below).

Furthermore, when the patch of the present invention was applied to rabbit skin and transdermally administered, it showed good transdermal absorbability of emedastine and was extremely persistent as compared with oral administration (see Test Example 2 below). , Was confirmed to be excellent as a preparation for transdermal administration intended for systemic action. Therefore, the patch of the present invention is useful for treating and preventing various allergic diseases caused by histamine, such as allergic rhinitis, allergic bronchial asthma, and allergic skin diseases.

The present invention will be described below with reference to test examples. Test Example 1 Skin permeation test (diffusion cell method) 1) Specimen and dose Patches of Examples 1 to 3 and 5 to 8: area 8 cm ² , respectively
Containing 6 mg of emedastine per sheet Patch of Example 4: Area 8 cm ² , containing 1.2 mg of emedastine per sheet

2) Test method The abdominal skin of male Wistar rats (body weight 200 to 300 g) was shaved [sheared with Speedy Electric Hair Clipper NP-8 (manufactured by Shimizu Denki Kogyo), and then National Super Leather ES855 (Matsushita). [Shaking with Denko]], and one day later, the rat was anesthetized with ether, and the shaved abdominal skin was peeled off. This is a vertical diffusion cell (Kercso
Tested by mounting on an engineering company, effective area 8 cm ² . The receptor fluid isotonic phosphate buffer 45
ml (pH 7.4) was used. The sample was affixed and administered to the donor side. The cell temperature was maintained at 37 ° C, and 0.1 ml of the receptor solution was sampled after every fixed time (0.5, 1, 2, 3, 4, 5, 6 hours), and the emedastine concentration was adjusted to the high speed under the following conditions. It was quantified by liquid chromatography. Next, the amount of emedastine that penetrated the skin was determined from this emedastine concentration and the amount of receptor fluid. The test was performed three times for each sample, and the average value of the results was obtained. High performance liquid chromatography conditions-Column: Inertsil ODS 5-150 [1
50 mm x 4.6 mm, manufactured by Gasclo Industry Co., Ltd.]-Eluent: 3.9 g of sodium dihydrogen phosphate dihydrate and 2.5 g of sodium lauryl sulfate were added to purified water 1000
A mixed solution of 1 volume of solution dissolved in ml and adjusted to pH 2.4 with phosphoric acid and 1 volume of acetonitrile-Column temperature: 40 ° C-Flow rate: 1.0 ml / min-Detection method: Absorbance measurement at UV280 nm

3) Test Results Table 1 shows the amount of emedastine that penetrated the skin at 0.5, 1, 2, 3, 4, 5 and 6 hours after administration (average value of 3 cases per group, unit: μg). .

[0039]

[Table 1]  PatchTime (hours) after administration 0.5 1 2 3 4 5 6 Example 1 patch 24 45 219 463 734 998 1279 Example 2 patch 20 127 523 982 1423 1854 2154 Example 3 patch 34 182 657 1221 1731 2161 2558 Example 4 patch 6 19 71 129 185 236 283 Example 5 patch 35 214 669 1048 1361 1613 1757 Example 6 patch 13 50 154 234 304 304 339 407 Example 7 patch 5 36 140 265 382 491 582 Patch of Example 8 6 38 132 234 338 431 530 From the above results, the patch of the present invention shows that transdermal absorption of emedastine
It is clear that the yield is excellent.

Test Example 2 Transdermal Absorption Test (Comparison with Transdermal Administration to Rabbits and Oral Administration) When the patch of the present invention is transdermally administered to rabbits and the absorption and sustainability of emedastine are orally administered Compared with. In addition, emedastine difumarate was used for oral administration. 1) Sample a) Patch of Example 2: Emedastine content 0.75 mg
/ Cm ² . The dose of emedastine is 11.3 mg / kg
To determine the rabbit weight, calculate the patch area according to the rabbit weight, cut the patch into squares corresponding to the area, and stick to the rabbit. b) Patch of Example 6: emedastine content 0.75 mg
/ Cm ² . The dose of emedastine is 11.3 mg / kg
To determine the rabbit weight, calculate the patch area according to the rabbit weight, cut the patch into squares corresponding to the area, and stick to the rabbit. c) Emedastine difumarate: 11.3 mg / kg of emedastine was orally administered (comparative test).

2) Test method Transdermal administration test method : The backs of Japanese white male rabbits (1 group, 3 cases, weight: 2.6 to 2.9 kg) were clipped on a back clipper [Speedic Electric Hair Clipper NP-8 (Shimizu Electric). (Manufactured by Kogyo Co., Ltd.)] was used for shearing. Immediately after applying a depilatory cream (Epirat, manufactured by Kanebo Co., Ltd.), the remaining hair was removed and the stain was removed with ethanol for disinfection. A sample is applied (dosage: 11.3 mg / kg as emedastine, the application area is 39 to 44 cm ² depending on the weight of the rabbit), and an adhesive elastic bandage is applied over it to prevent the rabbit from stripping the sample. (Elastopo No. 100, manufactured by Nichiban Co., Ltd.)
Covered with.

Thereafter, blood was collected from the right ear vein over time,
Heparin was added and centrifuged to obtain plasma. Emedastine in plasma was determined by the method of Hamada et al. (Chem.Pharm.Bull.34, 1168).
Page, 1986) and quantified by gas chromatography. The conditions of gas chromatography are as follows. Gas chromatography conditions ・ Capillary column: DB-1 (100% dimethyl
Polysiloxane, 15 m x 0.53 mm, film thickness 0.
15 μm, manufactured by J & W) ・ Column temperature: 185 ° C. ・ Injection temperature: 280 ° C. ・ Carrier gas: Helium 42 ml / min ・ Detection method: Nitrogen-phosphorus detector oral administration test method : Japanese traditional white male rabbit (1 group) Three cases, body weight 2.8-3.1 kg, were fixed to an Oshida rabbit fixator, and an aqueous solution of emedastine difumarate (concentration 10 m
g / ml) was administered at a rate of 11.3 mg / kg body weight in terms of emedastine into the stomach of a rabbit using a cannula. Thereafter, blood was collected from the right ear vein over time, heparin was added, and centrifugation was performed to obtain plasma. Emedastine in plasma was analyzed by the method of Hamada et al. (Chem. Pharm. Bull. 34, 1168, 1986.
(See year) and quantified by gas chromatography.

3) Test Results The time course of the plasma concentration of emedastine (average value of 3 cases per group) is shown in FIG. In FIG. 1, curve a shows the time course of plasma concentration of emedastine when the patch of Example 2 was transdermally administered, curve b shows that when the patch of Example 6 was administered, and curve c. Emedastine-2
It shows that when fumarate is orally administered. In addition, the area under the plasma concentration-time curve (AUC _0-25h ) was calculated, and was _{6678 ng} when the patch of Example 2 was administered.
-H / ml, 115 when the patch of Example 6 is administered
The dose was 6 ng · h / ml and 115 ng · h / ml when emedastine difumarate was orally administered.

As described above, the patch of the present invention exhibits extremely excellent transdermal absorbability and durability of emedastine.

[0045]

EXAMPLES The present invention will be described below with reference to examples. Incidentally, in the formulation of Example means the mg of each composition contained ² per patch area 1cm the amount mg / cm ^2, and the compounding%, is contained in the adhesive layer of the adhesive patch The weight percent of each composition is meant.

Example 1 a) Formulation: Composition Compound amount mg / cm ² (compound%) Active ingredient: Emedastine 0.75 (10) Base: Acrylic adhesive base 6.75 (90) Support: Polyester Film (manufactured by 3M, trade name Scotch pack) b) Manufacturing method: acrylic adhesive base solution (70 parts by weight of 2-ethylhexyl acrylate, 26 parts by weight of vinyl acetate, 3.5 parts by weight of hydroxyethyl methacrylate and acrylic acid) 0.5 parts by weight was dissolved in a mixed solvent of 50 parts by weight of toluene and 50 parts by weight of ethyl acetate, and copolymerized in the presence of 0.5 parts by weight of benzoyl peroxide at 80 ° C. for 9 hours. 100 g of copolymer having an average molecular weight of about 400,000 and a copolymer content of 41%) prepared by diluting
Then, 4.6 g of emedastine was mixed and stirred to prepare a mixed solution (adhesive layer solution) of the acrylic adhesive base and emedastine, and the mixture was allowed to stand for 20 minutes to remove bubbles. A part of the adhesive layer solution was taken and poured on a surface of a release sheet (made by Honshu Paper Co., Ltd., cut with a polyethylene-coated glassine separator) having an area of 350 cm ² placed on a glass plate, and an applicator (Baker Applicator No. 0052,
Uesima) to a uniform thickness. 80 ° C
For 15 minutes in a warm air drier, a support (polyester film, thickness 2.75 μm) is adhered using a roller, the thickness of the adhesive layer is about 0.07 mm, 0.75 mg per 1 cm ^2. A patch containing emedastine was obtained. In the test of Test Example 1, a circle having a radius of about 1.6 cm (area 8 cm ² ) was cut and used.

Examples 2 to 4 a) Formulation: compounding amount mg / cm ² (compounding%) composition Example 2 Example 3 Example 4 Active ingredient: emedastine 0.75 (10) 0.75 (10) 0.15 (2) Base: Acrylic adhesive base 6.00 (80) 5.25 (70) 6.75 (90) Additive: Diethyl sebacate 0.75 (10) 1.50 (20) 0.60 (8) Support: Polyester film (manufactured by 3M, product Name Scotch pack) b) Manufacturing method: Instead of dissolving emedastine in an acrylic adhesive base solution to prepare an adhesive layer solution, an amount of emedastine and sebacic acid corresponding to the above formulation is added to the acrylic adhesive base solution. Example 2 and Example 3 were carried out in the same manner as in Example 1 except that diethyl and an adhesive layer solution were prepared.
In both of Example 4 and Example 4, the thickness of the adhesive layer was about 0.
A 08 mm patch was obtained. The emedastine content per 1 cm ² of each of the patches of Examples 2 and 3 was 0.75 m.
g, the emedastine content per 1 cm ² of the patch of Example 4 was 0.15 mg.

In the test of Test Example 1, each patch was used after being cut into a circle having a radius of about 1.6 cm (area: 8 cm ² ). In addition, in the test of Test Example 2, in order to adjust the dose of emedastine to 11.3 mg / kg of rabbit body weight, the patch area was calculated according to the body weight of the rabbit, and the patch of Example 2 corresponding to the area was calculated. The agent was cut into squares for use.

Example 5 a) Formulation: Composition Blend amount mg / cm ² (blending%) Active ingredient: Emedastine 0.75 (10) Base: Silicone-based adhesive base 4.05 (54) Additive: Silicone Oil 2.70 (36) Support: Polyester film (manufactured by 3M, trade name Scotch pack) b) Manufacturing method: Silicone-based adhesive base solution (Dow Corning 355 medical adhesive solution, manufactured by Dow Corning) 100 g And silicone oil (Dow Corning 3
12.31 g (60 medicinal fluid) was mixed, and the solvent was distilled off while heating and stirring at 50 ° C. in a water bath to concentrate to about 77 g (containing 40 w / v% as a silicone component).
To 50 g of this, 2.22 g of emedastine was mixed and stirred to prepare an adhesive layer solution, which was left standing for 20 minutes to remove air bubbles.
An area of 35 parts of the adhesive layer solution placed on a glass plate
A release sheet of 0 cm ² (made by Honshu Paper Co., Ltd., cut with a polyethylene-coated glassine separator) was poured on the surface, and an applicator (Baker Applicator N
o. 0052, manufactured by Uesima Co., Ltd.) to a uniform thickness. This is dried in a warm air dryer at 50 ° C. for 10 minutes, and a support (polyester film, thickness 2.75 μm) is adhered to this using a roller, and the thickness of the adhesive layer is about 0.08 mm, 1 cm. 0.75m of emedastine per ²
A patch containing g was obtained. In the test of Test Example 1, a circular shape (area: 8 cm ² ) having a radius of about 1.6 cm was cut and used.

Example 6 a) Formulation: Composition Compounding amount mg / cm ² (compounding%) Active ingredient: Emedastine 0.75 (10) Base: Rubber-based adhesive base 6.75 (90) Support: Polyester Film (manufactured by 3M, trade name Scotch pack) b) Manufacturing method: 20 g of polyisobutylene (trade name, VISTANEX MML-80, Exxon Chemical) having an average molecular weight of 990,000, polyisobutylene having an average molecular weight of 40,000 (trade name, HIMOL 4H, Japan) Petrochemical Co., Ltd.) 25 g, polyisobutylene 15 g having an average molecular weight of 1260 (trade name, HV-300, Nippon Petrochemical Co., Ltd.) and alicyclic saturated hydrocarbon resin 40 g (trade name, Alcon P-100, Arakawa Industry Co., Ltd.) ) Is dissolved in 150 g of n-hexane, and the solid content is 40 w / w%. It was prepared. To 100 g of this, 4.4 g of emedastine was mixed and stirred to prepare a pressure-sensitive adhesive layer solution, which was allowed to stand for 20 minutes to remove air bubbles. Take a part of the adhesive layer solution and pour it onto the surface of a release sheet 350 cm ² (made by Honshu Paper Co., Ltd., cut with a polyethylene-coated glassine separator) placed on a glass plate, and apply an applicator (Baker Applicator No. 0052, Uesima). (Made by the company). This is dried in a warm air dryer at 80 ° C. for 15 minutes, and a support (polyester film, thickness 2.75 μm) is adhered to it using a roller,
A patch containing 0.75 mg of emedastine per cm ^{2 of the} adhesive layer having a thickness of about 0.08 mm was obtained.

In the test of Test Example 1, the radius was about 1.6c.
It was cut into a circle of m (area: 8 cm ² ) and used. Also,
In the test of Test Example 2, the dose of emedastine was 11.3.
In order to obtain mg / kg of rabbit body weight, the application area was calculated according to the body weight of the rabbit, and this was cut into squares corresponding to the area and used.

Example 7 a) Formulation: Composition Compounding amount mg / cm ² (compounding%) Active ingredient: Emedastine 0.75 (10) Base: Rubber-based adhesive base 6.00 (80) Additive: Sebacin Diethyl acid 0.75 (10) Support: Polyester film (manufactured by 3M, trade name Scotchpack) b) Manufacturing method: Instead of dissolving emedastine in a rubber-based adhesive base solution, an amount corresponding to the above formulation is used. In the same manner as in Example 6 except that emedastine and diethyl sebacate were dissolved to prepare a pressure-sensitive adhesive layer solution, the thickness of the pressure-sensitive adhesive layer was about 0.08 mm, and 0.75 m of emedastine was added per 1 cm ^2.
An adhesive patch containing g was obtained.

Example 8 a) Formulation: Composition Compound amount mg / cm ² (compound%) Active ingredient: Emedastine 0.75 (10) Base: Acrylic adhesive base 6.75 (90) Support: Polyester Film (manufactured by 3M, trade name Scotch Pack) b) Manufacturing method: Acrylic adhesive base solution (32 parts by weight of 2-ethylhexyl acrylate, butyl acrylate)
65 parts by weight and 3 parts by weight of acrylic acid are dissolved in a mixed solvent of 50 parts by weight of toluene and 50 parts by weight of ethyl acetate and copolymerized at 80 ° C. for 9 hours in the presence of 0.5 part by weight of benzoyl peroxide. Prepared by diluting with 60 parts by weight of toluene (viscosity 6000 cp, copolymer content 38%) 100 g of emedastine was mixed and stirred to prepare a mixed solution of acrylic adhesive base and emedastine (adhesive layer solution) Then, it was allowed to stand for 20 minutes to remove air bubbles. Thereafter, in the same manner as in Example 1, a patch having an adhesive layer thickness of about 0.07 mm and 0.75 mg of emedastine per 1 cm ² was obtained. In the test of Test Example 1, a circle with a radius of about 1.6 cm (area 8 cm
^It was cut into ² ) and used.

[Brief description of drawings]

FIG. 1 is a graph showing the time course of plasma concentration of emedastine when the patch of the present invention was transdermally administered to rabbits and emedastine difumarate was orally administered. In the figure, the curve a shows the time course of the plasma concentration of emedastine when the patch of Example 2 was administered, and the curve b is Example 6
Of the patch and curve c shows that of emedastine difumarate administered orally.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 9/70 354 47/32 E 47/34 E

Claims (8)

[Claims] 1. An adhesive patch in which an adhesive layer comprising an acrylic adhesive base, a silicone adhesive base or a rubber adhesive base and emedastine is laminated on one side of a support. 2. The compounding amount of emedastine in an adhesive layer comprising an acrylic adhesive base and emedastine is 0.5 to 2
The adhesive patch according to claim 1, which is 0% by weight. 3. The compounding amount of emedastine in an adhesive layer comprising a silicone-based adhesive base and emedastine is 0.5 to.
The adhesive patch according to claim 1, which is 20% by weight. 4. The compounding amount of emedastine in an adhesive layer comprising a rubber-based adhesive base and emedastine is 1 to 30% by weight.
The adhesive patch according to claim 1, which is 5. The acrylic adhesive base is (a) 97 of an alkyl acrylate having an alkyl group having 4 to 12 carbon atoms or / and an methacrylic acid alkyl ester having an alkyl group having 4 to 12 carbon atoms. .About.99.5% by weight and (b) acrylic acid or / and methacrylic acid of 0.
The adhesive patch according to claim 1 or 2, which is a copolymer composed of 5 to 3% by weight. 6. The acrylic adhesive base is one or two or more 97 selected from the group consisting of (a) 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, and butyl acrylate. ~ 99.5 wt% and (b)
The adhesive patch according to claim 1, which is a copolymer composed of 0.5 to 3% by weight of acrylic acid. 7. The acrylic adhesive base is (a) 70 of an alkyl acrylate having an alkyl group having 4 to 12 carbon atoms and / or an methacrylic acid alkyl ester having an alkyl group having 4 to 12 carbon atoms. ~ 85 wt% and (b)
0.5 to 3 of acrylic acid and / or methacrylic acid
10% by weight and 10 to 30% by weight of one or more monomers selected from the group consisting of (c) acrylamide, methacrylamide, hydroxyethyl acrylate, hydroxyethyl methacrylate and vinyl acetate. The adhesive patch according to claim 1 or 2, which is a copolymer consisting of 8. The acrylic adhesive base is (a) 70 to 85% by weight of 2-ethylhexyl acrylate or 2-ethylhexyl methacrylate, and (b) 0.5 to 3% by weight of acrylic acid. %, (C) 5 to 30% by weight of vinyl acetate and 3 to 4% by weight of (di) hydroxyethyl methacrylate, 3. The adhesive patch according to claim 1, which is a copolymer.