WO1997039740A1

WO1997039740A1 - Patch containing 1,2-ethanediol derivatives or salts thereof

Info

Publication number: WO1997039740A1
Application number: PCT/JP1997/001363
Authority: WO
Inventors: Tetsumi Yamakawa; Keiko Takakura; Yoshiko Kubo; Yoko Shimada; Masahiro Kodani; Masaru Tai
Original assignee: Toyama Chemical Co., Ltd.
Priority date: 1996-04-22
Filing date: 1997-04-21
Publication date: 1997-10-30
Also published as: AU2576797A; ZA973394B

Abstract

A patch comprising a substrate and, formed thereon, a plaster layer containing the following components (a) to (d) exhibits higher drug absorption than that attained by oral administration, and is excellent in the persistence of blood drug level: (a) a 1,2-ethanediol derivative of general formula (1) or a salt thereof, wherein R1 is hydrogen, halogeno or alkyl, and R?2 and R3¿ are each independently alkyl; (b) urea; (c) polyethylene glycol; and (d) a film-forming nitrogenous polymer.

Description

Specification

Patches containing 1,2-ethanediol derivatives or salts thereof

The present invention provides a compound represented by the following general formula:

"Wherein, R 'represents a hydrogen atom, a halogen atom or an alkyl group;. R ² and R ³ are the same or different represent an alkyl group" 1 represented by the 2-Etanjio Lumpur derivative or a salt thereof It relates to a patch contained as an active ingredient.

Background art

Transdermal preparations are known to be easy to administer, have a clear presence or absence of administration, and allow patients and caregivers to easily control the administration.

On the other hand, 1,2-ethanediol derivatives or salts thereof described in JP-A-3-232830 and JP-A-495070 are useful compounds as cerebral function improving agents, and in particular, (R) 1-1 (benzo [ b) Thiofen-15-yl) 1-2- [2- (N, N-Jetylamino) ethoxy] ethanol hydrochloride (hereinafter referred to as T15888) is a preferred compound. The transdermal formulation is not known.

Disclosure of the invention

1,2-Ethanediol derivatives or salts thereof of general formula [1] having a cerebral function improving effect can be administered even if the patient has severe cerebral dysfunction (eg, dementia) and does not intend to take the drug. Thus, there is a need for a technique for preparing a transdermal formulation.

However, since skin has a barrier function to prevent foreign substances from entering the body from the outside world, even if a drug is administered by a transdermal formulation, a sufficient amount of the drug to exert a pharmacological effect is circulated in the body. Is not always easy to absorb. In addition, it is known that the elderly have a high barrier function in the stratum corneum (aging and skin, 48-53). Page, 1994, Kinbara Publishing), it is difficult to percutaneously absorb a sufficient amount of a drug to show medicinal effects.

In addition, the skin permeability of a drug depends on the intrinsic physicochemical properties of the drug, and is closely related to the interaction between the drug, base, and skin, and is extremely complicated. Development of skin and transmucosal absorbable preparations and new tests, experiments, and evaluation methods, pages 5 to 61, 1986, Technoy Publishing Division).

An object of the present invention is to show that it has the same or higher absorbability as an oral preparation, has physical properties suitable for use as a patch, has low skin irritation, and is stable over time. Combined, 2- [ethanediol derivative of the general formula [1] or a salt thereof, especially, 1- (benzo [b] thiophene-5-yl) _2— “2- (N, N-Jetylamino) ethoxyquin] ethanol The present inventors, which are developing transdermal preparations of the formula (1), especially patches, have conducted intensive studies to achieve the above object. As a result, the 1,2-ethanediol derivative of the general formula [1] or a salt thereof, urea, By using a combination of polyethylene glycol and a nitrogen-containing polymer coating agent, it is possible to obtain a patch with excellent percutaneous absorption, low skin irritation, and good physical properties and stability over time. Find out the present invention This has led to the formation.

The present invention is a patch wherein a plaster layer containing the following components (a) to (d) is provided on one surface of a support.

(a) General formula

Wherein, R ¹ is a hydrogen atom, a halogen atom or an alkyl group; IT and R ^: 'are the same or different and each represent an alkyl group. ”Or a 1,2-ethanediol derivative or a salt thereof

(b) Urea

(c) Polyethylene glycol

(d) Nitrogen-containing polymer coating agent Hereinafter, the present invention will be described in detail.

Examples of the halogen atom of R ¹ in the general formula [1] include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of the alkyl group for R ′, R ² and R ³ include methyl, ethyl, propynole, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, Examples include straight-chain or branched C ,, _2- alkyl groups such as decyl and pendecyl.

As a 1,2-ethanediol derivative of the general formula [1] or a salt thereof, R ¹ is a hydrogen atom or a fluorine atom, and R 3 is a straight-chain C ₄ compound such as methyl, ethyl or propyl. A compound or a salt thereof that is an alkyl group is preferable, and a compound or a salt thereof in which R ¹ is a hydrogen atom or a fluorine atom, and IT and R ³ are an ethyl group is preferable. Specifically, 11- (benzo [b] thiophen-5-yl) -12- [2- (N, N-getylamino) ethoxy] ethanol and 2- [2- (N, N-getylamino) ethoxy 1-1- (6-Fluorobenzo [b] thiophen-5-yl) Ethanol or a salt thereof and an optically active substance are preferred compounds.

The 1,2-ethanediol derivative of the general formula [1] or a salt thereof is disclosed in JP-A-3-23230, JP-A-4-95070, JP-A-6-9615 and W096 / 12717 (PCT / JP95 / 2162). Can be produced by the method described in (1).

The amount of the 1,2-ethanediol derivative of the general formula [1] or a salt thereof used in the patch of the present invention is preferably 0.1 to 20% by weight, more preferably 0.5 to 12% by weight. %.

The polyethylene glycol used in the patch of the present invention has the following formula

H0CH ₂ (CH ₂ 0CH ₂ ) n Compounds represented by CH ₂ 0H (n = 2 to 13), specifically, for example, triethylene glycol, tetraethylene glycol, polyethylene glycol 300, polyethylene Glycol 400, polyethylene glycol 600 and the like. Particularly preferred are triethylene glycol and tetraethylene glycol.

The amount of polyethylene glycol used in the patch of the present invention is preferably It is 1 to 30% by weight, more preferably 2.5 to 20% by weight.

The amount of urea used in the patch of the present invention is preferably 0.5 to 10% by weight, and more preferably 2 to 8% by weight.

The nitrogen-containing polymer coating agent used in the patch of the present invention contains a (meth) acrylate ester having no nitrogen in the ester residue and a (meth) acrylate ester having a nitrogen in the ester residue. It is a copolymer.

The ester residue of a (meth) acrylate ester that does not contain nitrogen in the ester residue is a straight-chain or branched C, ₁ that may be substituted with one or two hydroxyl groups. _And alkyl groups, and preferred groups include methyl group, ethyl group, 2-hydroxyethyl group, butyl group, hexyl group, octyl group, 2-ethylhexyl group, decyl group, and lauryl group. Particularly, a methyl group, an ethyl group and a butyl group are preferred.

As the ester residue containing nitrogen ester residue (meth) acrylic acid ester, d - _H alkylamino ethyl group or C, - «alkyl ammonium Nio Echiru group and the like, C i ₈ alkylamino ethyl And-,, alkyl groups of the C, H alkylammonioethyl group include methyl, ethyl, propyl, butyl, hexyl, octyl, and 2-ethylhexyl groups. A methyl group is preferred. More specifically, examples include dimethylaminoethyl, dimethylammonioethyl and trimethylammonioethyl groups.

Specific examples of the nitrogen-containing polymer coating agent include methyl methacrylate “butyl methacrylate” 2-dimethylaminoethyl copolymer (trade name: Odragit E) 00: Laem Pharma Co., Ltd. And methacrylic acid trimethylammonium metholcobolima-1 (trade name: Eudragit RS30D: Laem manufactured by Pharma).

The compounding amount of the nitrogen-containing polymer coating agent used in the patch of the present invention is preferably 0.5 to 20% by weight, more preferably 2 to 17% by weight, and particularly preferably 2 to 10% by weight. is there.

The patch of the present invention may contain C _(i ^ alcohol and / or C Ester of fatty acid and alcohol is blended.

Cr, 'Alcohols include hexyl alcohol, heptyl alcohol, octyl alcohol, nonyl alcohol, decyl alcohol, pendecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, cetyl alcohol, oleyl alcohol, 9-Decene-1-ol, linoleyl alcohol, linolenyl alcohol,], 2-dodecanediol and 1,2,6-hexantriol are preferred, but oleyl alcohol is particularly preferred.

C ii _{2 2} fatty acids and C, - the ester of an alcohol, Echiru capric acid, Mi Risuchin isopropyl, Panoremichin acid isopropyl adipate diisopropyl, Jechiru sebacate, diisopropyl sebacate, Orein acid Echiru, O maleic acid Oreiru And ethyl linoleate. Particularly preferred is ethyl sebacate.

The compounding amount of the ester of C alcohol and Z or C fatty acid and alcohol of C used in the patch of the present invention is preferably 0.1 to 20% by weight, more preferably 3 to 10% by weight. It is.

The patch of the present invention may further contain, if necessary, a plasticizer, a skin irritation reducing agent, a pH adjuster, and the like. Glycerin and the like are used as a plasticizer and a skin irritation reducing agent, and hydrochloric acid, sodium hydroxide, diisopropanolamine, and genamine are used as pH adjusters.

Examples of the base used in the patch of the present invention include an acrylic pressure-sensitive adhesive composed of a monomer having no carboxyl group.

Acrylic adhesives include homopolymers or copolymers of (meth) acrylates and copolymers of (meth) acrylates with one or more other polymerizable monomers, (Meth) acrylate esters containing nitrogen as a residue are excluded.

Examples of the polymerizable monomer include vinyl acetate. Examples of the acrylic pressure-sensitive adhesive include methyl acrylate′-acrylic acid-2-ethylhexyl copolymer resin emulsion (trade name: Nikkisol TS— 62: Nippon Carbide Co., Ltd.), Ethyl acrylate 'methyl methacrylate copolymer emulsion (trade name: Oydragit) NE 30 D: Laem-Falma) or a mixture thereof. The support of the patch of the present invention is not particularly limited as long as it is drug-impermeable and can form and support a plaster layer. Examples thereof include polyethylene, polypropylene, polyester, polyvinyl acetate, and ethylene / polyethylene. Vinyl acetate copolymer, polyvinyl chloride, polyurethane, nylon, aluminum and the like can be used. These materials are used as a single layer film or a laminated film. The thickness of the support is preferably from 5 to 500 fim, more preferably from 5 to 200 rn. The patch of the present invention has a release paper on the sticking surface to protect the plaster layer surface until use. The release paper is not particularly limited, but polyethylene terephthalate or paper subjected to a release treatment with silicone resin or the like is used.

The patch of the present invention can be produced by a method usually used in this field. Examples of the production method include (1) pulverizing a nitrogen-containing polymer coating agent, and then emulsifying a base emulsion. (2) a method of mixing an aqueous dispersion of the nitrogen-containing polymer coating agent and an emulsion of the base, (3) a method of dissolving the nitrogen-containing polymer coating agent with an acid, and then emulsifying the base. There is a method of adding a liquid.

In the case of the method (1), after the ground nitrogen-containing polymer coating agent is dispersed in polyethylene glycol, an aqueous solution of the drug and urea is added, and the mixture is stirred uniformly. Then, add the base emulsion and stir, and adjust the pH as necessary.

In the case of the method (2), an aqueous dispersion of the nitrogen-containing polymer film agent is mixed with an aqueous solution of polyethylene glycol, a drug and urea, and then, if necessary, an emulsion of the base, whose pH has been adjusted in advance, is prepared. Add and stir.

In the case of the method (3), a nitrogen-containing polymer coating agent and an acid are heated in an aqueous solution to form a uniform solution. An aqueous solution of the drug and urea is added to the obtained solution to make it uniform, and then polyethylene glycol is further added to make a uniform solution. Thereafter, if necessary, an emulsion of the base whose pH has been adjusted in advance is added and stirred.

Examples of the acid used in the method (3) include acetic acid, caprylic acid, capric acid, lauric acid, oleic acid, succinic acid, adipic acid, suberic acid, sebacic acid, lactic acid, gluconic acid, Organic acids, such as mono-, di-, and tricarboxylic acids, such as malic acid, tartaric acid, and citric acid; one of inorganic acids, such as hydrochloric acid, sulfuric acid, and phosphoric acid Species or a combination of two or more species may be mentioned, but acetic acid, lauric acid, adipic acid, lactic acid and hydrochloric acid are preferred.

The amount of acid used is 0.8-2.0 times equivalent to the nitrogen-containing polymer film agent.

If necessary, the plaster solution obtained by the respective methods, C '"Arco Ichiru and / or C _{2 ¾} 2 fatty acids and the C 2 ₂ alcohols emulsified in water using a pre-surfactant Add the ester and stir evenly.

Examples of the surfactant include polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene ethylene ether, polyoxyethylene stearyl ether, polyoxyethylene behenyl ether, polyoxyethylene castor oil, and polyoxyethylene cured. Castor oil, polyoxyethylene nonyl phenyl ether, polyoxyethylene octyl phenyl ether, polyoxyethylene sorbit beeswax, polyoxyethylene phytosterol, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene monooleate Sorbitan, polyoxyethylene lanolin, polyethylene glycol monolaurate, polyethylene glycol monostearate, monooleic acid Although ethylene glycolate one Le and the like, monolaurate polyethylene glycol, polyoxyethylene O lipped Ruch We sulfonyl ether are preferably used. The amount of surfactant is C _{6 2 2} alcohols and Z or C ^ _{2 2} fatty acid and c,. 01 to 1 × 0. respect _{2 2} esters with alcohols (weight ratio).

The plaster solution obtained by mixing the respective prescription components according to the above method is applied onto a support, dried and then affixed with release paper, or the plaster solution is applied on release paper and dried, and the resulting plaster layer is obtained. A patch can be produced by bringing the adhesive into close contact with the support.

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1

250 mg of triethylene glycol, using a pneumatic grinder L, pulverized to a particle size of 20 / in or less, methyl methacrylate, butyl methacrylate, dimethyl methacrylate 2-dimethylaminoethyl copolymer (trade name: Eudragit) E100: Lame After dispersing 75mg of (Alma), (R) -1-(Benzo [b] thiophen-5-yl) -2-L2- (N, N-Jetylamino) ethoxy] ethanol hydrochloride (hereinafter referred to as 3OmL of an aqueous solution containing 100 mg and 125 mg of urea was added, and the mixture was stirred uniformly. Then, methyl acrylate 'acrylic acid-2-ethylhexyl copolymer resin emulsion [trade name: Nikkiso TS-620, solid content 57-6]% (W / W): Nippon Power —Bide Co.] 3. 20 g was added and stirred at room temperature for 1 hour to obtain a plaster solution. The obtained plaster solution was uniformly coated on a polyester support so as to have a T-588 content of 2 mg / 10 cm ² / plast 50 mg, dried at 40 ° C. for 15 hours, and then separated with a silicone resin. A treated release paper made of polyethylene terephthalate was adhered to obtain a patch. Example 2

Aqueous solution containing fatty acids of Eudragit E100 [trade name: Plastoid E35M, solid content 27-33% (W / W): manufactured by Laem Pharmaceutical Co.] 500mg, T-588mg and 500mg 3 ml of an aqueous solution containing 125 mg of urea was added and stirred uniformly. Further, 250 mg of triethylen glycol was added to make a uniform solution, and then 2.07 g of TS-620 was added and stirred to obtain a plaster solution. Thereafter, a patch was obtained in the same manner as in Example 1.

Example 3

After dispersing Eudragit E 100 75m ground to a particle size of 20m or less using a pneumatic grinder in 250mg of triethylene glycol, 3ml of an aqueous solution containing T-588 lOOmg and 125mg of urea was added and homogenized. Stirred. After that, add Nisol Zol TS-620 0.275 and stir at room temperature for 30 minutes, then emulsify 250 mg of oleyl alcohol in 1% (W / V) aqueous solution of polyoxyethylene (15) octylphenyl ether in advance. 2.5 ml of the solution was added, and the mixture was stirred at room temperature for 30 minutes to obtain a plaster solution. Thereafter, a patch was obtained in the same manner as in Example 1.

Example 4

A solution of 250 mg of oleyl alcohol in a 1% (W / V) aqueous solution of polyquinethylene (15) octyl phenyl ether. Instead of adding 2.5 ml, instead of adding 250 ml of getyl sebacate to polyethylene glycol monolaurate, (10 EO) 1 (/ V) Pasted in the same manner as in Example 3 except that 2.5 ml of a solution emulsified in an aqueous solution was added. A patch was obtained.

Example 5

25 ml of water was added to 0.47 g of lactic acid [content 90% (W / W)] (0.44 equivalent relative to Eudraggid E100), and the mixture was uniformly dissolved and heated to 60 ° C. Furthermore, add 103 g of Eudragit E and 1.25 g of capric acid (0.67 equivalents to Eudragit E 100) ground to a particle size of 500 / m or less, and dissolve uniformly at 60 ° C. After stirring vigorously until the total amount reached 30 g with water, a clear solution of Eudragit E100 was obtained. To 75 Om of this solution, 3 ml of an aqueous solution containing 588 mg T-OOmg and 125 mg of urea was added and stirred uniformly. Further, 250 mg of triethylene glycol was added to make a uniform solution, and then 3.13 g of Nitrosol TS-620 was added and stirred to obtain a plaster solution. Thereafter, a patch was obtained in the same manner as in Example 1.

Example 6

In Example 1, instead of Eudragit E100, an aqueous dispersion of ethyl acrylate, methyl methacrylate, and methacrylate-modified trimethylammonium mucotyl copolymer (trade name: Eudragit RS30D, solid Min. 30! ¾ (W / W): Patch by the same operation as in Example 1 except that 0.83 g of Rame Pharma Co., Ltd. was used, and 2.91 g of TS-6620 was added. I got

Example 7

Instead of adding T-588, 2-OO2- (N- (N, N-Jetylamino) ethoxy) 1-1- (6-fluorobenzo [b] thiophen-1-yl) ethanol hydrochloride was added in lOOmg. A patch was obtained in the same manner as in Example 2 except that the operation was performed.

Example 8

1.5 ml of water was added to 250 mg of Plastoid E35M to make it homogeneous. Further, 250 mg of T-588, 62.5 mg of urea and 125 mg of triethylene glycol were added to make a uniform solution, and 1.21 g of TS-620 was added and stirred to obtain a plaster solution. Thereafter, a patch was obtained in the same manner as in Example 1.

Example 9

To 500 mg of Plastoid E35M, 3 ml of an aqueous solution containing T-588 lOOmg was added and stirred uniformly. Add 250 mg of triethylene glycol and 62.5 mg of urea. After the solution was made uniform, 3.18 g of TS-6620 (distilled sol) was added and stirred to obtain a plaster solution. Thereafter, a patch was obtained in the same manner as in Example 1.

Example 10

To 500 mg of Plastoid E3, 3 mL of an aqueous solution containing T-588 lOOmg and 125 mg of urea was added and stirred uniformly. Further, 250 mg of triethylene glycol and 125 mg of urea were added to make a uniform solution, and 2.87 g of TS-620 was added and stirred to obtain a plaster solution. Thereafter, a patch was obtained in the same manner as in Example 1. Example 1 1

A patch was obtained in the same manner as in Example 2, except that 25 mg of triethylene glycol and 3.44 g of Nitrosol TS-620 were added.

Example 1 2

A patch was obtained in the same manner as in Example 2, except that 500 mg of triethylene glycol and 2.66 g of Nitrosol TS-620 were added.

Example 13

A patch was obtained in the same manner as in Example 2, except that 2.5 pounds of plus toe E 3 1 1 ^ was added and 2.09 g of two-stroke solvent TS-620 was added.

Example 14

A patch was obtained in the same manner as in Example 1 except that 12.5 mg of Eudragit E100 and 3.30 g of Nikkisol TS-620 were added.

Example 15

A patch was obtained in the same manner as in Example 2 except that the amount of T-588 contained in the added aqueous solution was 2.5 mg, and that 3.23 of TS-620 was added.

Reference example 1

To 3 ml of an aqueous solution containing T-588 lOOmg, 3.93 g of Nissosol TS-620 was added and uniformly stirred to obtain a plaster solution. Thereafter, a patch was obtained in the same manner as in Example 1.

Next, the effects of the patch of the present invention will be described.

• Percutaneous absorption test in rat

On the day before drug administration, the back of a rat (Wistar, male, weighing 200-250 g) was flashed. The hair was removed with a can and hair removal cream (trade name: Debel Hair Removal Cream: Seishido), and the patch obtained in Examples 1-3 and Reference Example 1 (T-588 content 2mg / 10cm) Plaster (50 mg) was administered to the back. As a control, 1 ml of an aqueous solution containing T-5882 mg was orally administered. Blood is collected from the jugular vein over time, serum is separated, and a strong cation exchange resin (TSK GEL SP Toyopearl: Tosoh) and a weak cation exchange resin (TSK GEL CM—Toyopearl: Tosoh) are used. Then, T-588 was extracted from the serum, and the blood concentration was measured by high performance liquid chromatography. Table 1 shows the area under the one-hour blood concentration curve (AUC0-4) for each sample.

【table 1】

AUC0-4 Oral ratio

(ng X hr / ml) Example 1 708.9 1.54

Example 2 558.2 1.21

Example 3 737.1 1.60

Reference Example 1 305.4 0.66

Oral administration 461.5 1.00 Industrial availability

The patch containing the 1,2-ethanediol derivative represented by the general formula [1] of the present invention or a salt thereof has an absorbability more than that of oral administration, and is excellent in persistence in blood concentration. Furthermore, good percutaneous absorption can be expected even for skin that has a prominent drying tendency and that has a high stratum corneum barrier function as seen in the elderly, who is the subject of administration of this drug. Moreover, the physical properties of the plaster layer such as adhesive strength, adhesive strength, cohesive strength and anchoring strength are good, and no skin irritation is observed. It also has excellent stability over time of the drug in the plaster layer.

Claims

l τ Claims

1. A patch in which a plaster layer containing the following components (a) to (d) is provided on one surface of a support.

(a) General formula [1]

Wherein R ¹ is a hydrogen atom, a halogen atom or an alkyl group; R ² and R ^: 'are the same or different and represent an alkyl group; represented by 1], a 2-ethanediol derivative or a salt thereof

(b) Urea

(c) polyethylene glycol

(d) Nitrogen-containing polymer coating agent

2. The patch according to claim ¹ , wherein in the general formula [1], R ¹ is a hydrogen atom or a fluorine atom; and R ² and R ³ are the same or different and are C, and alkyl groups.

3. The patch according to claim 2, wherein in the general formula [1], R ² and R ^: ′ are ethyl groups.

4. The patch according to claim 1, wherein the polyethylene glycol is a compound represented by the formula: HOCH ₂ (CH ₂ 0CH ₂ ) „CH ₂ 0H (n is an integer of 2 to 13).

5. The nitrogen-containing polymer coating agent is a copolymer containing a (meth) acrylate ester containing no nitrogen in the ester residue and a (meth) acrylate ester containing nitrogen in the ester residue. The patch according to any one of 1 to 4.

6. A straight or branched carbon number in which the ester residue of a (meth) acrylate ester containing no nitrogen is optionally substituted by one or two hydroxy groups. 6. An ester group of a (meth) acrylate ester having 1 to 12 alkyl groups and containing a nitrogen in the ester residue, is an alkylaminoethyl group or an alkylammonioethyl group. The patch as described in the above.

7. The patch according to claim 6, wherein the ester residue of the (meth) acrylate ester containing no nitrogen in the ester residue is a methyl group, an ethyl group or a butyl group.

8. The patch according to claim 6, wherein the ester residue of the (meth) acrylate ester containing nitrogen in the ester residue is a dimethylaminoethyl group, a dimethylammonioethyl group or a trimethylammonioethyl group.

9. The patch according to claim 8, wherein each of the components (a) to (d) has the following composition.

(a) the compound of the general formula [1] or a salt thereof is contained in an amount of 0.1 to 20% by weight;

(b) the amount of urea is 0.5 to 10% by weight;

(c) the content of polyethylene glycol is 1 to 30% by weight;

(d) The compounding amount of the nitrogen-containing polymer film agent is 0.5 to 20% by weight.

1 0. In addition to the components (a) to (d)

(10) The patch according to any one of (1) to (9), further comprising (e) an ester of an alcohol having 6 to 22 carbon atoms and / or a fatty acid having 2 to 22 carbon atoms and an alcohol having 1 to 22 carbon atoms.

11. The patch according to claim 10, wherein the component (e) is oleyl alcohol, getyl sebacate or a mixture thereof.

12. The patch according to claim 10 or 11, comprising component (e) in a proportion of 0.1 to 20% by weight.