JPH0780772B2 - Transdermal formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention contains estradiol and / or its ester as a drug and supplies the drug by transdermal absorption to stabilize the blood concentration of the drug over time. The present invention relates to a transdermal preparation capable of achieving the above.

(Prior Art) Estradiol and its ester are known as one of female hormones, and they are effective as drugs for menopausal disorders and abnormal menstruation in women. When this drug is administered orally, the liver metabolism rate is high, so that the burden on the liver is large, and the drug's bioavailability is significantly reduced by metabolism. Therefore, this drug is usually administered by injection. However, when the drug is administered by injection, the blood concentration of the drug temporarily rises, but the blood concentration is not maintained for a long time, and the drug must be frequently administered. Therefore, the use of sustained-release preparations is desired, and for example, transdermal preparations are considered to be suitable. However, it is generally difficult to administer a sufficient amount of drug through the skin because the skin has a biological defense function of preventing the entry of foreign matter into the body. Therefore, it has been attempted to increase the area of the drug-containing patch or to add a transdermal absorption enhancer, but the drug release property is still not sufficient.

In order to effectively transdermally administer estradiol or its ester, for example, JP-A-57-154122 discloses a multilayer patch. This patch comprises a support, and a drug-enhancing agent-containing layer, a diffusion film layer, and a pressure-sensitive adhesive layer, which are sequentially laminated on the support. The drug-enhancing agent-containing layer is composed of a drug-containing gel containing estradiol in a gel-like substance obtained by gelling ethanol with hydroxypropyl cellulose or the like. Both the drug and ethanol permeate the diffusion membrane layer and the pressure-sensitive adhesive layer and are absorbed through the skin. Absorption rate of ethanol through the skin is about 100-800 mcg / hr
/ cm ² , therefore, the drug dissolved in ethanol also promotes absorption through the skin. Drug release can be controlled by the amount of ethanol used. However, since such a patch has a multi-layer structure,
The manufacturing process is complicated, and when applied to the skin, it gives a feeling of strangeness due to its thickness. Since volatile ethanol is used, it has the drawback that ethanol is volatilized during storage or after application, changing the drug release capacity. Since ethanol is irritating to the skin, it is highly likely to cause skin damage such as redness. Furthermore, since a diffusion film layer (which functions as a control film) is interposed, it cannot be said that the release properties of ethanol and drugs are still sufficient. I need.

Japanese Unexamined Patent Publication (Kokai) No. 61-155321 discloses a patch in which an estradiol-containing pressure-sensitive adhesive layer is formed on a support, and the pressure-sensitive adhesive base is a rubber, a pressure-sensitive resin material, and galactomannan in water. The main component is a polymer that can swell. This patch does not become bulky like the above-mentioned patch having a multi-layer structure, and it is possible to supply the drug relatively stably in a predetermined period. However,
The overall drug release is still not sufficient.

JP-A-60-152413 discloses a percutaneous absorption preparation containing menthol as a percutaneous absorption promoter. In this publication, when a preparation containing 17β-estradiol-3-sodium as a drug in a lipophilic base,
It is described that high drug permeability was achieved in skin tests with nude mice. However, since this preparation uses menthol, the menthol is volatilized as in the case of ethanol, and the drug releasing ability is changed. Furthermore, menthol has a transdermal absorption enhancing effect only when the drug is water-soluble. Therefore, estradiol cannot obtain its effect unless it is in the salt form as described above.

Japanese Patent Application Laid-Open No. 61-17513 discloses a predetermined ratio (1: 1 to 1: 5 W /
W) a mixture of propylene glycol and glycerin;
And if necessary, dissolve the drug at a rate of 0.5 mg / ml,
And a percutaneous absorption preparation containing a pharmacologically acceptable solvent is disclosed. This formulation allows the drug to be administered relatively effectively under mild conditions on the skin. However, since a solvent is used, it volatilizes,
The drug release is altered. Moreover, the overall release of the drug is not yet sufficient, and a patch with a relatively large area is required to obtain a satisfactory drug effect.

(Problems to be Solved by the Invention) The present invention is to solve the above-mentioned conventional problems, and an object of the present invention is to contain estradiol and / or its ester, and to enhance the skin permeability of the drug, It is to provide a transdermal preparation capable of supplying a sufficient amount of a drug even in a small amount or a small area. Another object of the present invention is to provide a percutaneous absorption preparation which has the above-mentioned excellent properties, does not damage the skin, and has a simple structure, which is easy to manufacture.

(Means for Solving the Problem) The percutaneous absorption preparation of the present invention is a percutaneous absorption preparation containing a drug and an absorption enhancer of the drug in a base, wherein the drug is estradiol and / or its ester. And
The absorption enhancer is lactic acid, which achieves the above object.

The medicinal component of the transdermal patch of the present invention is estradiol and / or its ester, and examples of the ester include benzoic acid ester, valeric acid ester, cypionic acid ester, propionic acid ester and the like.
This drug is contained in the formulation in an amount of 8 to 50% by weight, preferably 10 to 14%.
It is contained in a weight percentage. This ratio indicates the content with respect to the whole preparation in the case of ointment and cream preparations, and shows the content with respect to the drug-containing layer (adhesive layer) in the case of patches such as tape preparations and poultices. The same applies to the content of the transdermal absorption enhancer described below. If the amount of the drug is too small, the drug effect is insufficient, and if it is excessive, the drug is crystallized in the base and is not sufficiently released.

The percutaneous absorption enhancer contained in the percutaneous absorption preparation of the present invention is lactic acid, and the ratio of lactic acid in the preparation is 0.1 to 30% by weight, preferably 1 to 25% by weight, more preferably 3 to 7% by weight. Contained in. If the amount is too small, the effect of promoting percutaneous absorption of the drug cannot be obtained. If the amount is excessive, the compatibility with the base decreases, and in the case of a tape preparation containing a drug in the adhesive layer, the adhesive physical properties decrease.

The preparation may further contain a higher fatty acid ester as another transdermal absorption enhancer. This higher fatty acid ester includes a higher fatty acid having 10 to 18 carbon atoms and a higher carbon number of 1
Fatty acid esters obtained from ~ 20 alcohols are used. Examples of fatty acids having 10 to 18 carbon atoms capable of forming such higher fatty acid ester include myristic acid, palmitic acid, lauric acid, stearic acid, palmitoleic acid,
Examples include oleic acid, vaccenic acid, linoleic acid, and linolenic acid. Examples of the alcohol having 1 to 20 carbon atoms include methanol, ethanol, propanol, isopropanol, butanol, hexanol, pentanol, heptanol, octanol, decanol and cetanol. As the higher fatty acid ester, isopropyl myristate, isopropyl palmitate and the like are suitable.
The higher fatty acid ester has a function of enhancing the transdermal absorption promoting effect of lactic acid. If the formulation is a tape formulation,
Improves the adhesive physical properties of the adhesive base and the adhesiveness of the preparation. The higher fatty acid ester is contained in the preparation in an amount of 30% by weight or less, preferably 1 to 25% by weight, more preferably 2 to 10% by weight. If the higher fatty acid ester is in excess, estradiol will precipitate in the base. As a result, for example,
Adhesiveness is reduced in tape formulations.

The transdermal absorption enhancer is contained in an amount of 1 to 100 parts by weight, preferably 5 to 20 parts by weight, based on 100 parts by weight of the adhesive base.

The percutaneous absorption preparation of the present invention containing the above-mentioned estradiol and / or its ester and the above-mentioned absorption enhancer includes a tape preparation, a patch preparation, a poultice preparation, an ointment preparation, a cream preparation, a liniment preparation and the like.

Of the above-mentioned preparations, the tape preparation and the patch preparation have an adhesive layer containing a drug and an absorption enhancer formed on one side of a support. The base (adhesive) of the tape preparation or patch is sufficient as long as it has an adhesive force capable of fixing the preparation on the skin surface at room temperature for a long time, and is not particularly limited. For example, an acrylic adhesive, a rubber adhesive, a silicone resin adhesive or the like may be used, and an acrylic adhesive is usually used.

In the case of acrylic adhesives, because of their adhesive properties,
(Co) polymer of (meth) acrylic acid alkyl ester obtained from aliphatic alcohol having 4 to 18 carbon atoms and (meth) acrylic acid and / or the above (meth) acrylic acid alkyl ester and other functional monomer The copolymer of is preferably used.

Examples of the (meth) acrylic acid ester include butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, octyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, and (meth).
Isooctyl acrylate, decyl (meth) acrylate,
Examples include isodecyl (meth) acrylate, lauryl (meth) acrylate, and stearyl (meth) acrylate.

Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, a monomer having an amino group, and the like. Examples of monomers having a hydroxyl group include hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate. Examples of the monomer having a carboxyl group include α-β unsaturated carboxylic acids such as acrylic acid and methacrylic acid; maleic acid monoalkyl esters such as butyl maleate; maleic acid; fumaric acid; crotonic acid. Maleic anhydride also gives the same (co) polymerization components as maleic acid. Examples of the amide group-containing monomer include alkyl (meth) acrylamides such as acrylamide, dimethyl acrylamide, and diethyl acrylamide; alkyl ether methylol (meth) acrylamides such as butoxymethyl acrylamide and ethoxymethyl acrylamide; diacetone acrylamide; and vinylpyrrolidone. Examples of the monomer having an amino group include dimethylamino acrylate.

Among acrylic adhesives, a copolymer containing 45 to 80 mol% of 2-ethylhexyl acrylate (EHA) and 20 to 55 mol% of N-vinyl-2-pyrrolidone (VP), especially EHA55
Copolymers containing ~ 70 mol% and VP30-45 mol% are preferred. Such a copolymer containing EHA and VP further contains an acrylic ester other than EHA as a copolymerization component.
It may be contained in a proportion of not more than mol%, preferably not more than 15 mol%. Acrylic acid esters other than EHA used here include propyl (meth) acrylate, butyl (meth) acrylate, hexyl (meth) acrylate, 2-
Ethyl butyl (meth) acrylate, heptyl (meth)
Acrylate, octyl (meth) acrylate, nonyl (meth) acrylate, decyl (meth) acrylate,
Examples include lauryl (meth) acrylate.

In order to increase the cohesiveness of the acrylic copolymer, the polyfunctional monomer is added to 0.001% of all the monomers forming the copolymer.
It is preferably contained in a proportion of 5 to 0.5% by weight. Polyfunctional monomers include di (meth) acrylate, tri (meth) acrylate, and tetra (meth) acrylate, including hexamethylene glycol dimethacrylate, trimethylolpropane trimethacrylate, and the like.

As the support for the tape preparation, patch, and poultice, which will be described later, a support usually used for patches is used. Materials for such a support include cellulose acetate, ethyl cellulose, polyethylene terephthalate (PET), plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, Examples include polyethylene, polyvinylidene chloride, and aluminum. These are, for example,
It is used as a single-layer sheet (film) or a laminate of two or more sheets. Materials other than aluminum may be used as woven or non-woven fabrics.

A drug-containing (adhesive) layer containing a drug and an absorption promoter is formed on the surface of the support to obtain a tape preparation or a patch. To form the pressure-sensitive adhesive layer, various coating methods such as a solvent coating method, a hot melt coating method, and an electron beam curing emulsion coating method can be used. Among them, the solvent coating method is preferably used. To form the pressure-sensitive adhesive layer by the solvent coating method, for example, the pressure-sensitive adhesive is diluted with a suitable solvent, and a drug, an absorption promoter, and if necessary, a compounding agent are added and uniformly mixed to obtain the adhesive layer. The resulting solution is applied to the surface of the support and dried. Instead of directly applying the solution to the surface of the support, the solution may be applied onto a release paper coated with a silicone resin or the like, dried and then brought into close contact with the support. Such release paper is used to protect the surface of the adhesive layer of the patch until use. The thickness of the adhesive layer also varies depending on the dosage form and purpose of use, but it is usually 30 to 2
It is 00 μm. If it is less than 30 μm, the required amount of drug cannot be contained and the adhesiveness is insufficient. When it exceeds 200 μm, the drug contained in the pressure-sensitive adhesive layer near the support does not sufficiently diffuse, and the drug release property decreases.

The poultice also has a drug-containing layer containing a drug and an absorption enhancer formed on one surface of the support. It is usually less adhesive than tape preparations and patches, so it is fixed to the skin surface with a bandage. As the main component of the base of poultice,
For example, natural polymers such as sodium alginate, gelatin, corn starch and tragacanth gum; cellulosic polymers such as methyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose; starch polymers such as dextrin and carboxymethyl starch; polyvinyl alcohol, sodium polyacrylate, methoxyethylene- Synthetic polymers such as maleic anhydride copolymer, polyvinyl ether, and polyvinylpyrrolidone are used.

The above polymer, drug and absorption enhancer are mixed uniformly,
A desired poultice is obtained by forming a drug-containing layer on the surface of the support. Purified water; moisturizing agents such as polyhydric alcohols (eg, glycerin, propylene glycol); kaolin, bentonite, zinc white,
Inorganic fillers such as titanium dioxide; viscosity modifiers; crosslinkers;
An antiaging agent or the like may be contained.

Beeswax, oil and fat, lanolin, white petrolatum, paraffin, plastis base, higher fatty acid, higher alcohol, emulsifier, macrogol, carboxyvinyl polymer, etc. are used as the main components of the bases of ointments and cream preparations. A drug and an absorption promoter are mixed with these compounds to obtain an ointment or a cream preparation. When mixing, if necessary, fat-soluble solubilizers such as crotamiton, liquid paraffin, isopropyl myristate, and diethyl sebacate; purified water; water-soluble solubilizers such as ethanol and polyhydric alcohols (eg, glycerin); stabilizers, pH A regulator or the like is added.

(Action) The absorption enhancer contained in the preparation of the present invention changes the physical properties of the base or the skin in the base or in the skin, and as a result, the partition coefficient of the drug between the base layer and the skin changes. Or, it is thought that the diffusion rate of the drug in the base material, stratum corneum, epidermis and dermis changes. Therefore, by containing the absorption enhancer, a preparation capable of maintaining a high blood concentration in a small area for a long time can be obtained. For example, in a tape preparation, a sufficient drug effect can be obtained even with a small area. The absorption enhancer used in the present invention is not irritating to the skin and is highly safe.

Therefore, erythema is avoided even in a person who is sensitive to skin irritation. The preparation of the present invention, for example, in the case of a tape preparation, the preparation to be applied has a small area, so that the sticking operation is easy and there is little discomfort during sticking. Since the adhesive layer has a single simple structure, it is easy to manufacture and can be prepared in a thin shape. Since such a tape preparation does not contain a volatile component unlike the adhesive patch containing ethanol disclosed in the section of the prior art, the composition does not change during storage and a predetermined quality is maintained.

(Example) Hereinafter, the present invention will be described with reference to Examples.

Example 1 2-ethylhexyl acrylate (EHA) 302.0 g (65 mol%), vinylpyrrolidone (VP) 98.0 g (35 mol%) and hexamethylene glycol dimethacrylate 40.0 mg
(0.02% by weight based on all monomers) was charged into a separable flask, and 70.6 g of ethyl acetate was added to adjust the monomer concentration to 85% by weight. This solution was heated at 60 ℃ in a nitrogen atmosphere, lauroyl peroxide (polymerization initiator) and ethyl acetate were added little by little, and the polymerization reaction was carried out for 32 hours. An ethyl solution was obtained.
A solution of 17-β-estradiol and lactic acid in tetrahydrofuran was added to the obtained polymer so that the solid content (weight sum of polymer, estradiol and lactic acid) concentration was 22% by weight, and the solid content of estradiol and lactic acid was They were added so that their concentrations became 10.5% by weight and 2% by weight, respectively, and they were mixed uniformly by a dissolver. Similarly, solutions were prepared so that the concentrations of the lactic acid were 5% by weight and 7% by weight, respectively. Each of these solutions was applied to a 38 μm-thick polyethylene terephthalate (PET) -siliconized release paper so that the thickness after drying was 40 μm, and then dried. It has a thickness of 38
A μm PET support was attached to obtain a patch. Table 1 shows the compositions of the patches prepared in this Example and Examples 2-3 described later and Comparative Examples 1-4.

Example 2 EHA215.2 g (45 mol%), VP129.7 g (45 mol%), decyl methacrylate 55.1 g (10 mol%), and trimethylolpropane triacrylate 40.0 mg (in all monomers)
The same procedure as in Example 1 was carried out except that a polymer was obtained in the same manner as in Example 1 using 0.01% by weight).

Example 3 For the polymer-containing solution obtained in Example 1, 17β-
Estradiol, lactic acid, and isopropyl myristate were added so that the solid content (corresponding to the total of the above components and the polymer) in the solution was 25% by weight. However,
Of the total solids, 17β-estradiol was 10.5% by weight,
Lactic acid is 5.0% by weight, and isopropyl myristate is
The addition was made so that it was contained in a proportion of 2.0% by weight.
The mixed solution was uniformly mixed with a dissolver, and a patch was obtained in the same manner as in Example 1. Separately, patches were prepared such that the content of isopropyl myristate was 5% by weight and 7% by weight instead of the above 2.0% by weight.

Comparative Example 1 For the polymer-containing solution obtained in Example 1, 17β-
Estradiol was added so that the amount of solid content in the solution (corresponding to the sum of the 17β-estradiol and the polymer) was 25% by weight, and the concentration of estradiol in the solid content was 10.5% by weight. In addition, it was mixed uniformly with a dissolver. Similarly, solutions were prepared so that the concentrations of 17β-estradiol were 12% by weight and 15% by weight. Using these, a patch was prepared according to Example 1 (however, without adding a transdermal absorption enhancer).

Comparative Example 2 For the polymer-containing solution obtained in Example 1, 17β-
Estradiol and isopropyl myristate,
The solid content (corresponding to the total of the above components and the polymer) in the solution was added so as to be 25% by weight. However, 17β-estradiol was added at 10.5 wt% and isopropyl myristate was added at 3.0 wt% of the total solid content. The mixed solution was uniformly mixed with a dissolver, and a patch was obtained in the same manner as in Example 1. Separately, patches were prepared such that isopropyl myristate was 5% by weight, 7% by weight, and 10% by weight, respectively.

Comparative Example 3 The same as Comparative Example 2 except that myristic acid was used instead of isopropyl myristate.

Comparative Example 4 The same as Comparative Example 2 except that glycyrrhetinic acid was used instead of isopropyl myristate.

Experimental Example 1 Of the patches of Examples 1 to 3 and Comparative Examples 2 to 4, 17β
-A patch containing 10.5% by weight of estradiol and 5% by weight of a percutaneous absorption enhancer (lactic acid, isopropyl myristate, myristic acid or glycyrrhetinic acid) (however, in Example 3, lactic acid and isopropyl myristate). Of 5% by weight), and from Comparative Example 1, those containing 10.5% by weight of 17β-estradiol were used. The amount of 17β-estradiol in these patches is 4 mg / 10 cm ² , respectively. Separately, as a commercially available estradiol patch, Estraderm 0.05 (manufactured by CIBA; having the same structure as the patch disclosed in JP-A-57-154122) was used as the patch of Comparative Example 5.

The aluminum patches of the patches obtained in Examples and Comparative Examples of the present invention and Estraderm were opened and stored in air for 30 days. After storage, no precipitation of 17β-estradiol crystals was observed in any of the patches.

A drug permeability test through the skin was performed using these patches. A diffusion cell 10 shown in FIG. 1 was prepared. This diffusion cell 10 has a cylindrical bottomed receptor tank 1 and a cylindrical bottomed donor tank 2 having an opening 21 at the bottom. The donor tank 2 is stacked above the receptor tank 1 airtightly and concentrically via a pair of O-rings 31 and 32. The receptor tank 1 has a sampling port 11 protruding laterally on its side. The skin 4 used for the test is sandwiched between the O-rings 31 and 32, and the opening 21 of the donor tank 2 is entirely covered with the skin 4.

A hairless mouse (male, 6 weeks old) was killed by cervical dislocation, the skin was peeled off, and its subcutaneous fat composition was removed to obtain a skin piece of about 5 cm x 5 cm. Apply the above patch (10 cm ² ) to it,
It was set between both O-rings 31 and 32 of the diffusion cell 10. The receptor tank 1 is filled with the following receptor liquid, and the stirring bar is used.
The receptor fluid was stirred by 12.

Receptor solution preparation method: NaH ₂ PO ₄ 5 × 10 ^-4 M, NaH in distilled water
₂ PO ₄ 2 × 10 ^-4 M, NaCl1.5 × 10 ^-1 M and gentamicin 1
An aqueous solution of NaOH is added to a buffer solution containing 0 ppm to adjust the pH to 7.2, and 20% by weight of polyethylene glycol 400 is added to this to prepare a receptor solution.

The entire diffusion cell 10 was placed in a constant temperature bath maintained at 37 ° C. 1,3,6,18 and 24 hours after the start of the test, 1 ml of the receptor fluid was collected from the sampling port 11, respectively,
1 ml of fresh receptor fluid was added. The drug concentration of the collected receptor solution was measured and the drug permeability was calculated. The number of experimental samples was 3, and the average value was calculated. The results are shown in FIG.

From FIG. 2, it can be seen that the patch of the present invention is superior in the permeability of 17β-estradiol through the skin as compared with the patch of each comparative example. In particular, the patch of Example 3 further containing a higher fatty acid ester as an absorption enhancer shows excellent drug release over a long period of time. Furthermore, it is clear that the patch of the present invention can maintain excellent performance without being stored under special conditions such as sealing the patch.

Experimental Example 2 The same patch (10 cm ² ) as that used in Experimental Example 1 was applied to the upper arm of each of three test subjects (healthy person, male).
After 2 hours, this was peeled and collected. The patch was extracted with methanol and the concentration of 17β-estradiol was measured by HPLC. Regarding the patch of Comparative Example 5, after peeling, it was cut into small pieces and extracted with methanol.
Calculate the drug remaining in the patch after peeling from the drug concentration,
The difference from the drug initially contained in the patch was defined as the amount transferred to the skin. Table 2 shows the amount of skin transfer when using each patch.
Shown in.

It can be seen from Table 2 that the patch of the present invention has an extremely large amount of drug transfer to the skin when the patch has the same area and the same dose as each patch of the comparative example.

(Effect of the Invention) According to the present invention, as described above, a drug which contains estradiol and / or its ester has a high skin permeability and a sufficient amount of the drug can be supplied even in a small area. A skin absorption formulation is provided. Further, the drug has an excellent effect that it is released in a predetermined amount over a long period of time. The adhesive base used in the tape preparation has no skin irritation and avoids skin damage such as redness.
The preparation of the present invention can be widely used as a sustained release preparation of estradiol.

[Brief description of drawings]

FIG. 1 is a perspective view showing a diffusion cell for testing the skin permeability of the drug contained in the patch, and FIG. 2 is a graph showing the skin permeability of estradiol contained in the present invention and other patches. Is.

Claims (7)

[Claims] 1. A percutaneous absorption preparation containing a drug and an absorption enhancer of the drug in a base, wherein the drug is estradiol and / or its ester, and the percutaneous absorption enhancer is lactic acid. Is a transdermal preparation. 2. The transdermal preparation according to claim 1, wherein the lactic acid is contained in a proportion of 0.1 to 30% by weight. 3. A carbon number as another transdermal absorption enhancer.
The percutaneous absorption preparation according to claim 1, which contains a higher fatty acid ester obtained from a higher fatty acid having 10 to 18 and an alcohol having 1 to 20 carbon atoms. 4. The percutaneous absorption preparation according to claim 3, wherein the total amount of the percutaneous absorption enhancer is 1 to 100 parts by weight based on 100 parts by weight of the base. 5. The percutaneous absorption preparation according to claim 1, which is a tape preparation in which an adhesive layer containing the drug and the absorption promoter is provided on one surface of a support. 6. The percutaneous absorption preparation according to claim 5, wherein the adhesive base of the adhesive layer is an acrylic adhesive. 7. The acrylic pressure-sensitive adhesive has a (co) polymer of a (meth) acrylic acid alkyl ester having an alkyl group having 4 to 18 carbon atoms and / or an alkyl group having 4 to 18 carbon atoms (meta). ) A copolymer of an alkyl acrylate and another functional monomer, wherein the (meth) acrylic acid alkyl ester (co) polymer is 50% in the adhesive.
The percutaneous absorption preparation according to claim 6, which is contained in a proportion of not less than wt%.