JP5512910B2 - Tulobuterol-containing percutaneous absorption preparation and patch using the same - Google Patents

Description

  The present invention relates to a tulobuterol-containing transdermal absorption preparation, and more particularly to a transdermal absorption preparation containing a fine solid state of tulobuterol and a patch using the same.

で表される化合物であり、交感神経刺激作用を有するので、気管支喘息や肺気腫などの気道のつまりによる呼吸困難治療のために、気管支拡張剤として用いられてきた。このツロブテロールは、経口剤としては、その酸付加塩である塩酸ツロブテロールとして用いられるが、経皮吸収用剤としては、塩基型のツロブテロールのままで用いられてきた。
しかし、従来のツロブテロールを含有する経皮吸収製剤は、貼付剤またはテープ剤等の剤型とするために、ツロブテロールを粘着剤を中心とする膏体層に溶解させる必要があり、ツロブテロール以外にも種々の賦形剤を含んでいた（特許第２７５３８００号、特許第３２６０７６５号、特公平０７−０２５６６９号参照）。そして、その膏体製造には、賦形剤とツロブテロールを均一となるよう練合する工程が必要であり、煩雑な手間を要し、多くのコストを発生する要因となっていた。このため、可能な限りこれらの工程を省略することが必要とされていた。
また、上記の賦形剤には、かぶれの原因となるものが含まれている場合があり、これを解決するためには、賦形剤を含む粘着剤層と皮膚との接触面積を減らしたり、剥離と貼着の回数を少なくすることで対処せざるを得なかった。
更に、従来から賦形剤を用いていた理由は、貼付剤またはテープ剤としての剤型を形成させるためだけではなく、ツロブテロールを皮膚から吸収させるためには、ツロブテロールが有効成分溶解層を介して皮膚に接している必要があると考えられていたからであった。この有効成分溶解層は、有効成分を溶解もしくは分散可能である物質を含む層であり、通例は有効成分の良溶媒を含んでいるものである。
つまり、有効成分溶解層中をツロブテロールが分散もしくは溶解によって移動して初めて皮膚から吸収されると考えられていたため、賦形剤を用いて有効成分溶解層を形成させる以外に製剤化の手法は存在しないと考えられていた。
従って、ツロブテロールを皮膚から吸収させるに当たり、製造工程を簡略化してコストダウンを計ると同時に、より皮膚刺激性の低い経皮吸収製剤とすることが求められていた。Tulobuterol has the following formula (I)

And has a sympathomimetic action, and has been used as a bronchodilator for the treatment of dyspnea due to clogging of the respiratory tract such as bronchial asthma and emphysema. This tulobuterol is used as an oral preparation as its acid addition salt, tulobuterol hydrochloride, but as a transdermal absorption agent, it has been used as a base form of tulobuterol.
However, the conventional transdermal absorption preparation containing tulobuterol needs to dissolve tulobuterol in the plaster layer mainly composed of an adhesive in order to obtain a dosage form such as a patch or a tape. Various excipients were contained (see Japanese Patent No. 2753800, Japanese Patent No. 3260765, Japanese Patent Publication No. 07-025669). In addition, the production of the plaster requires a step of kneading the excipient and tulobuterol to be uniform, which necessitates troublesome work and causes many costs. For this reason, it was necessary to omit these processes as much as possible.
In addition, the above-mentioned excipients may contain those that cause rashes. To solve this, the contact area between the adhesive layer containing excipients and the skin may be reduced. , I had to deal with it by reducing the number of peeling and sticking.
Furthermore, the reason why the excipient has been used conventionally is not only to form a dosage form as a patch or a tape, but also to absorb tulobuterol from the skin, It was because it was thought that it was necessary to touch the skin. This active ingredient dissolving layer is a layer containing a substance capable of dissolving or dispersing the active ingredient, and usually contains a good solvent for the active ingredient.
In other words, since it was thought that tulobuterol moved through the active ingredient dissolved layer by dispersion or dissolution, it was thought to be absorbed from the skin, so there was a formulation method other than forming an active ingredient dissolved layer using excipients. It was thought not to.
Therefore, in order to absorb tulobuterol from the skin, it has been required to simplify the manufacturing process and reduce the cost, and at the same time, to obtain a transdermal absorption preparation with lower skin irritation.

As a result of intensive investigations in view of the above circumstances, the present inventors have found that there is no need to use excipients that have been thought to be necessary for dissolving tulobuterol, that is, between tulobuterol and the skin. The present invention has been completed by finding that tulobuterol can be absorbed through the skin without the presence of an active ingredient-dissolving layer.
That is, the present invention provides a percutaneous absorption preparation in which tulobuterol is supported in a fine solid state in the voids or micropores formed by a fibrous or porous structure and / or on the surface of the structure.
The present invention also provides the above transdermally absorbable preparation further containing a basic substance.
Furthermore, the present invention provides a patch comprising the base material layer, the adhesive layer and the percutaneously absorbable preparation layer having a smaller area than the adhesive layer laminated in this order.

FIG. 1 is a drawing schematically showing an example of the structure of a patch using the transdermally absorbable preparation of the present invention. In addition, the code | symbol in FIG. 1 is as follows.
DESCRIPTION OF SYMBOLS 1 ... Base material layer 2 ... Adhesive layer 3 ... Drug-impermeable layer 4 ... Transdermal absorption preparation layer 5 ... Protective film FIG. It is a figure which shows a density | concentration.

The fibrous structure used in the tulobuterol-containing percutaneous absorption preparation of the present invention is not particularly limited, but has a woven fabric, a nonwoven fabric, a knitted fabric, a form in which fibers are simply shaped into a layer, or a paper form. Can be used. A preferred form is a woven fabric, a non-woven fabric or paper, and a particularly preferred form is a non-woven fabric.
There is no limitation in particular as a raw material which comprises this fibrous structure, A various well-known raw material can be used. Specifically, materials made of cellulose such as paper or derivatives thereof; fiber materials derived from plants such as cotton and hemp; fiber materials derived from animals such as silk and wool; inorganic materials such as glass fibers and metal fibers; Examples thereof include organic materials such as polyester, polyethylene, and polyamide.
Among these fiber materials, preferred are cellulose or its derivatives, cotton, polyester, polyethylene, and polyamide, and particularly preferred is polyester.
On the other hand, the porous structure used in the transdermally absorbable preparation of the present invention is not particularly limited, but a porous structure that is not isolated but continuous is preferable. That is, there are two types of foamable resins, an open-cell type and a non-open-cell type, and both can be used in the present invention, but it is desirable to use an open-cell type with good air permeability in terms of skin irritation. .
There is no limitation in particular as a raw material of this porous structure, A various well-known raw material can be used. Specific examples include polyurethane, polystyrene, polyethylene, silicone resin, polyvinyl chloride, polypropylene, polyester, polyamide, foamable metal, charcoal, cork, leather, natural rubber, and preferably polyurethane, polystyrene, and polyethylene. Can be mentioned. Particularly preferred is polyurethane, and in combination with the above form, an open-cell polyurethane foamable resin is particularly preferred.
In the present invention, tulobuterol needs to be supported in voids or micropores formed by a fibrous or porous structure (hereinafter referred to as “structure”) and / or in the surface of the structure. This support may be simply held by frictional force or may be held by intermolecular force. Moreover, you may adhere directly to the raw material surface of a structure, and you may adhere via the adhesion component.
Examples of methods for supporting tulobuterol include, for example, a method of dissolving tulobuterol in an appropriate solvent, and then applying this solution to the structure and drying, a method of attaching a refined tulobuterol crystal powder to the structure, etc. Is mentioned. At that time, if the adhesion is insufficient, adhesive components such as polyacrylic acid, polyvinyl alcohol, carboxyvinyl polymer, gelatin, gum arabic, methacrylic acid-methyl methacrylate copolymer (trade name: Eudragit LS), methacrylic A solution containing acid-ethyl acrylate copolymer (trade name: Eudragit L30D) is soaked into the structure, then dried, and the surface of the structure is covered with an adhesive component, and then tulobuterol is supported. You may squeeze it.
The solvent used for dissolving tulobuterol is not particularly limited as long as it can dissolve tulobuterol in an amount necessary for formulation, but methanol, ethanol, n-pentane, n-hexane, diethyl ether, acetic acid. Examples include ethyl, n-propanol, isopropanol, acetone, cyclopentane, cyclohexane, benzene, toluene, petroleum ether and the like. Of these, methanol, ethanol, isopropanol, acetone, and ethyl acetate are preferable from the viewpoint of worker safety and cost, and it is particularly desirable to use methanol, ethanol, and isopropanol.
Furthermore, the percutaneous absorption preparation of the present invention may contain a basic substance in order to increase the transdermal absorption rate of tulobuterol. As such a basic substance, any inorganic or organic substance that does not irritate the skin can be used without any particular limitation. Specific examples include disodium hydrogen phosphate, sodium acetate, and sodium bicarbonate. It is exemplified as a particularly preferable one.
The solvent for dissolving the basic substance is not particularly limited, but water, methanol, ethanol, n-pentane, n-hexane, diethyl ether, ethyl acetate, n-propanol, isopropanol, acetone, cyclopentane, cyclohexane. , Benzene, toluene, petroleum ether, etc. can be used by selecting those that can dissolve the basic substance. Among these, water is preferable from the viewpoint of cost and safety.
In addition, when tulobuterol and a basic substance are simultaneously supported on the structure, a common one of the above-described solvents may be used, or a solvent in which both solvents are mixed at an appropriate ratio may be used.
By the above method, the average particle size of tulobuterol supported on the structure is usually 50 μm or less, preferably 10 μm or less. When the average particle size of tulobuterol is larger than this, the holding force on the carrier is insufficient, and tulobuterol may spill out of the structure, reducing the effect. Tulobuterol may be attached to the structure material as an amorphous material even if it is a crystal.
In the transdermally absorbable preparation of the present invention, the degree of persistence can be controlled. In this case, a method of adjusting the concentration of tulobuterol supported on the structure, a method of selecting a material of the structure, a method of selecting a fiber diameter or a hole diameter of the structure material, and the like can be given.
The percutaneously absorbable preparation of the present invention thus obtained is not particularly limited as long as the structure on which tubuterol is supported can be brought into contact with the skin, and can be used as a dosage form such as a patch or a tape. However, the percutaneously absorbable preparation of the present invention may be simply fixed so as to contact the skin with an adhesive tape or the like.
Hereinafter, a patch is taken as an example of a dosage form using the transdermally absorbable preparation of the present invention, and the configuration aspect thereof will be described with reference to the drawings.
FIG. 1 schematically shows the structure of the patch of the present invention, wherein 1 is a base material layer, 2 is an adhesive layer, 3 is a drug-impermeable layer, 4 is a percutaneous absorption preparation layer, and 5 is a protective film. Indicates.
In the patch of the aspect shown in FIG. 1, the base material layer 1, the adhesion layer 2, the drug impermeable layer 3, and the transdermal absorption preparation layer 4 are laminated in this order. Among these, the drug-impermeable layer 3 and the percutaneously absorbable preparation layer 4 each have an area smaller than the pressure-sensitive adhesive layer 2, and the pressure-sensitive adhesive layer 2 is adhered to the skin or the like so as to wrap around these layers. The protective film 5 is sealed so as to cover the pressure-sensitive adhesive layer 2 and the transdermal absorption preparation layer 4.
Of the above, the base material layer 1 is not particularly limited as long as it is a sheet-like material that can hold the pressure-sensitive adhesive layer 2 and the transdermal absorption preparation layer 4, and is used as a base material layer of a general pressure-sensitive adhesive tape. Anything can be used. For example, a nonwoven fabric, a knit, polyester, etc. can be used advantageously.
The adhesive layer 2 is a layer for fixing the transdermal absorption preparation layer 4 to the skin with its adhesive strength, and any kind of adhesive may be used as long as it has appropriate adhesiveness to the skin. Preferable examples include pressure-sensitive adhesives such as acrylic pressure-sensitive adhesives, rubber-based pressure-sensitive adhesives, and silicon-based pressure-sensitive adhesives.
Among preferred adhesives, acrylic adhesives include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, vinyl acetate, methoxyethyl (meth) acrylate, or (Meth) acrylic acid (co) polymers or block copolymers thereof.
Rubber-based adhesives include natural rubber, synthetic isoprene rubber, polyisobutylene rubber (PIB), polyvinyl ether, polyethylene, polyisoprene, polybutadiene, styrene-butadiene-styrene block copolymer (SBS), and styrene-isoprene copolymer. Examples thereof include a polymer and a styrene-isoprene-styrene block copolymer (SIS). In particular, a styrene-isoprene-styrene block copolymer is preferable.
Furthermore, examples of the silicone-based pressure-sensitive adhesive include those containing polyorganosiloxane such as polydimethylsiloxane as a main component.
In addition to the above-mentioned pressure-sensitive adhesive, a known tackifier or softener can be blended in the pressure-sensitive adhesive layer. For example, as a tackifier, a rosin-based rosin or a rosin derivative hydrogenated, disproportionated, polymerized or esterified; a terpene resin such as α-pinene or β-pinene; a terpene-phenol resin; Aliphatic, aromatic, alicyclic, or copolymer petroleum resins; alkyl-phenyl resins; xylene resins and the like are used. In addition, as the softening agent, higher fatty acid esters such as polybutene, liquid paraffin, liquid isoprene rubber, polyisobutylene, or isopropyl myristate; silicon oil; almond oil, olive oil, camellia oil, permanent oil, peanut oil, etc. Vegetable oil is used, particularly liquid paraffin.
In addition, the drug-impermeable layer 3 is formed of the adhesive layer 2 and the percutaneously absorbable preparation layer 4 in order to prevent tubuterol from moving to the adhesive layer 2 and reducing the concentration of tulobuterol in the transdermal absorbable agent layer 4. Arranged between.
As the drug-impermeable layer 3, a known material that does not transmit tulobuterol and has a certain flexibility can be used. Specifically, various plastic films, aluminum foils, and silicon resin films can be exemplified.
The area of the drug-impermeable layer 3 needs to be smaller than that of the adhesive layer 2 because the adhesive layer 2 needs to be attached to the skin. Further, from the function of preventing contact between the transdermal absorption preparation layer 4 and the adhesive layer 2, the size is such that the periphery of the transdermal absorption agent layer 4 protrudes outside within a range of approximately 5 mm or less. It is preferable. From the viewpoint of manufacturability, it is particularly preferable that the size is the same as that of the transdermally absorbable preparation layer.
The drug-impermeable layer 3 can be omitted when the transfer of tulobuterol to the adhesive layer 2 is not so important or when an aqueous adhesive having low affinity with tulobuterol is used as the adhesive layer. It is.
As described above, the percutaneously absorbable preparation layer 4 is a layer in which tubuterol is held, and is composed of the above-described embodiments and materials.
The thickness of the percutaneously absorbable preparation layer 4 is not particularly limited, but if it is too thin, the volume of the space for holding the drug is insufficient, so that a sufficient amount of drug cannot be held. It is inferior to the feeling of use. Therefore, in a state where the structure is not compressed, it is usually desirable that the thickness is about 0.05 mm to 10 mm, preferably 0.1 mm to 5 mm, particularly preferably about 0.2 mm to 2 mm.
In addition, since a product in which a drug-impermeable layer and a drug-holding layer are integrated in advance is commercially available (LMW-9004 / # 6A manufactured by Japan Vilene Co., Ltd.), a percutaneous absorption preparation is prepared using this, It can also be used as a patch.
The protective film 5 protects the preparation until use, and is peeled off during use. As this protective film 5, various known materials can be used. Specific examples include films such as polyethylene, polypropylene, polyester, polyvinyl acetate, polyvinyl chloride, polyurethane, and paper subjected to silicon coating treatment.
Although the mechanism of absorption of tulobuterol in the present invention is not clear, in the part where tulobuterol directly touches the skin, migration to the skin, absorption occurs, and in the form of supplementing tulobuterol near the skin where the concentration is insufficient, It is presumed that tulobuterol present in the part not directly in contact with the skin moves at the molecular level near the skin.
In the preparation, the percutaneous absorption rate of tulobuterol is increased by allowing a basic substance to coexist with tulobuterol. Although the mechanism of this action is unknown, it is presumed that by adding a basic substance, the pH of the skin surface can be kept more basic, and the transdermal absorption capacity of tulobuterol can be increased. The
Conventionally, in wound treatment patches such as bandages, it is known to hold a drug such as a bactericidal agent on a nonwoven fabric, gauze, etc. and use it for local treatment (for example, Japanese Patent Laid-Open No. 54-122717). reference). However, in the case where the target drug is absorbed through non-injured skin, acts non-locally, and the drug is absorbed over time, there is no known drug drug retained in this way. .

  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Nonwoven fabric with drug-impermeable layer prepared by dissolving 100 mg of tulobuterol in 10 mL of methanol and cutting 0.2 mL of this solution into a size of 3.2 cm × 3.2 cm (LMW-9004 / # 6A, manufactured by Japan Vilene Co., Ltd., 50 g / m ²⁾ ) And then air-dried.
On the other hand, after cutting a commercially available adhesive tape (trade name: registered trademark BookTape Scotch No. 845 3M) into 5 cm × 5 cm, the non-woven fabric with the drug-impermeable layer is adhered and disposed on the drug-impermeable layer surface. Furthermore, it was covered with a protective film from above to obtain a patch of the present invention.

7 mL of a solution obtained by dissolving 143 mg of tubuterol in methanol to 10 mL and 3 mL of a solution prepared by dissolving 42.6 mg of disodium hydrogen phosphate in water to 10 mL were mixed, and 0.2 mL of this solution was 3.2 cm × 3.2 cm. After dropping uniformly onto a non-woven fabric with a drug-impermeable layer (LMW-9004 / # 6A weight per unit area: 50 g / m ² manufactured by Japan Vilene Co., Ltd.) cut to the above dimensions, it was air-dried. Thereafter, the patch of the present invention was prepared in the same manner as in Example 1.

7 mL of a solution prepared by dissolving 143 mg of tulobuterol in methanol to 10 mL and 3 mL of a solution prepared by dissolving 42.6 mg of sodium acetate in water to 10 mL were mixed, and 0.2 mL of this solution was adjusted to a size of 3.2 cm × 3.2 cm. After dropping uniformly onto the cut non-woven fabric with drug-impermeable layer (LMW-9004 / # 6A basis weight 50 g / m ² manufactured by Japan Vilene), it was air-dried. Thereafter, the patch of the present invention was prepared in the same manner as in Example 1.

7 mL of a solution in which 143 mg of tulobuterol was dissolved in methanol and 7 mL of a solution in which 42.6 mg of sodium bicarbonate was dissolved in water to make 10 mL were mixed, and 0.2 mL of this solution was measured at a size of 3.2 cm × 3.2 cm. The resulting mixture was uniformly dropped onto a non-woven fabric with a drug-impermeable layer (LMW-9004 / # 6A weight per unit area: 50 g / m ² manufactured by Japan Vilene Co., Ltd.) and then air-dried. Thereafter, the patch of the present invention was prepared in the same manner as in Example 1.

表１及び図２より、実施例１〜４の血漿中のツロブテロール濃度は、比較のそれと同等、もしくはそれ以上の値であり、本発明の経皮吸収製剤は十分な実用性を有していることが判った。また、塩基性物質を配合した実施例２〜４は、塩基性物質を配合していない実施例１と比較して４〜６ｈｒの時間帯において、血漿中のツロブテロール濃度が高い値を示しており、塩基性物質を配合することにより吸収率を高めることが可能であった。
＜皮膚一次刺激性試験＞
日本白色種ウサギの雄を、非絶食下、体重２．０ｋｇ前後で実験に使用した。試験日前日に、ウサギの背中の毛をバリカンで剃った。試験日当日、更にウサギの背中の毛をバリカンで完全に剃った後、実施例２及び比較の経皮吸収製剤（貼付剤）をウサギの背中に各３枚貼付し、上から粘着包帯を巻きテープを押えた。貼付後２４時間後にテープをはがし、皮膚反応の評価をＤｒａｉｚｅの基準に従って行った（ｎ＝４）。結果を表２に示す。

表２より、比較の製剤を貼付した箇所には多くの炎症が認められたが、実施例２を貼付した箇所には全く炎症は認められなかった。以上より、本発明の経皮吸収製剤は、賦形剤を用いた比較例に比べて皮膚刺激性が低いことが判った。
また、実施例５については、吸収量が少ないものの、一定の吸収が認められた。単位面積あたりのツロブテロール濃度の調整により十分な量の薬剤を吸収させられること、および皮膚刺激性は実施例２と同様優れていることが推測でき、総合的に比較例より優れている。100 mg of tulobuterol was dissolved in methanol to 10 mL, and 0.2 mL of this solution was uniformly added dropwise to a polyurethane porous resin (UC0050 manufactured by Kuraray Co., Ltd.) cut to a size of 3.2 cm × 3.2 cm, and then air-dried. . The polyurethane porous resin retaining the tulobuterol was placed on a drug-impermeable layer (MR-25, manufactured by Mitsubishi Chemical Polyester Co., Ltd.) of a polyethylene terephthalate film treated with silicone. Furthermore, they are adhered and arranged on a commercially available adhesive tape (trade name: registered trademark, TapeTape Scotch No. 845 3M), which is cut into a size of 5 cm × 5 cm. Then, it was covered with a protective film to obtain a patch of the present invention.
Test Example The patches obtained in Examples 1 to 5 were subjected to a plasma concentration measurement test and a skin primary irritation test by the following methods. For comparison, a commercially available percutaneous absorption type tubuterol preparation (trade name: registered trademark Hokunarin (r) tape 2 mg) in which tulobuterol is dissolved in an excipient was used.
<Plasma concentration measurement test>
Seven-week-old male hairless rats were bred for one week and used for experiments at a weight of about 260 g under non-fasting conditions. After shaving the rat's hair completely, wipe the abdomen and back with 70% ethanol, dry the body, and then paste 3 sheets of Examples 1 to 5 and comparative percutaneous absorption preparations (patch) on the abdomen, An adhesive bandage was wound from above and the tape was pressed. 8 hours after application, fasting and fasting were performed, and blood was collected from the jugular vein at a predetermined time, and plasma was separated. The plasma level of tulobuterol was measured by HPLC after adjusting the plasma to 9.5 with borate buffer, extracting with ethyl acetate / acetone (3/1), concentrating, and then HPLC (n = 4-6). The results are shown in Table 1 and FIG.

From Table 1 and FIG. 2, the concentration of tulobuterol in plasma of Examples 1 to 4 is equal to or higher than that of the comparison, and the transdermally absorbable preparation of the present invention has sufficient practicality. I found out. Moreover, Examples 2-4 which mix | blended the basic substance have shown the high value of the tulobuterol density | concentration in plasma in the time slot | zone of 4-6 hr compared with Example 1 which is not mix | blended the basic substance. It was possible to increase the absorption rate by adding a basic substance.
<Skin primary irritation test>
Japanese white rabbit males were used for experiments under non-fasting conditions and weighing around 2.0 kg. The day before the test day, the rabbit's back hair was shaved with a clipper. On the day of the test, the hair on the back of the rabbit was further shaved with a hair clipper, and then each of the two transdermal absorption preparations (patch) of Example 2 and the comparison was applied to the back of the rabbit, and an adhesive bandage was wound from above. Pressed the tape. 24 hours after application, the tape was peeled off, and skin reaction was evaluated according to the criteria of Draize (n = 4). The results are shown in Table 2.

As shown in Table 2, many inflammations were observed at the site where the comparative preparation was applied, but no inflammation was observed at the site where Example 2 was applied. From the above, it was found that the percutaneous absorption preparation of the present invention has low skin irritation compared to the comparative example using the excipient.
Moreover, about Example 5, although the absorption amount was small, fixed absorption was recognized. It can be presumed that a sufficient amount of drug can be absorbed by adjusting the concentration of tulobuterol per unit area, and that the skin irritation is excellent as in Example 2, and is comprehensively superior to the comparative example.

  According to the present invention, it is possible to provide a transdermal absorption preparation with a completely new absorption mechanism by attaching tulobuterol to the space (voids or micropores) or the surface of the fibrous or porous structure. is there. Thereby, the tulobuterol transdermal absorption preparation which does not contain an excipient | filler can be provided, a manufacturing process can be simplified and cost reduction can be measured, and skin irritation can be made low simultaneously.

Claims (9)

It is characterized in that tulobuterol is supported in a fine solid state directly inside the voids or micropores formed by a fibrous or porous structure and / or on the surface of the structure, or after the structure surface is covered with an adhesive component. A transdermally absorbable preparation.   The percutaneous absorption preparation according to claim 1, wherein the fibrous structure is a woven fabric, a nonwoven fabric or paper. The percutaneous absorption preparation according to claim 1 or 2 , wherein the material of the fibrous structure is cellulose or a derivative thereof, cotton, polyester, polyethylene, or polyamide.   The percutaneous absorption preparation according to claim 1, wherein the material of the porous structure is polyurethane, polystyrene or polyethylene. The percutaneous absorption preparation according to any one of claims 1 to 4 , further comprising a basic substance. The transdermally absorbable preparation according to claim 5 , wherein the basic substance is disodium hydrogen phosphate, sodium acetate or sodium hydrogen carbonate. A patch in which the base layer, the adhesive layer, and the tulobuterol-containing percutaneous absorption preparation layer according to any one of claims 1 to 6 having a smaller area than the adhesive layer are laminated in this order. The patch according to claim 7, further comprising a drug-impermeable layer between the adhesive layer and the tulobuterol-containing transdermal preparation layer. The patch according to claim 7 or 8, further comprising a protective film for protecting the adhesive layer and the tulobuterol-containing percutaneous absorption preparation layer so as to cover both layers.

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