HK1103965B - Tulobuterol adhesive patch - Google Patents

Description

Tulobuterol adhesive plaster

Technical Field

The present invention relates to a tulobuterol adhesive patch in which tulobuterol (tulobuterol) having a bronchodilating effect is used as an active ingredient, and an acrylic pressure-sensitive adhesive containing a copolymer containing acetoxyalkyl (meth) acrylate as one of constituent monomers is used in an adhesive layer.

Background

An adhesive patch containing tulobuterol as a sympathetic β 2 receptor selective agonist in an adhesive layer mainly composed of a synthetic rubber adhesive is known (for example, see patent document 1). Also known is a patch preparation containing tulobuterol in an adhesive layer mainly composed of an acrylic pressure-sensitive adhesive (see, for example, patent document 2).

In the case of a patch containing tulobuterol in a synthetic rubber-based adhesive, the crystals of tulobuterol are dispersed in the adhesive layer, and therefore, the release of tulobuterol from the adhesive layer is sustained, but there is a problem that the initial release property is poor and the release amount is insufficient. In addition, the adhesive patch using an acrylic pressure-sensitive adhesive has a problem that the patch does not have sustainability, although the initial releasability is improved.

That is, the adhesive used in the conventional tulobuterol adhesive preparation is poor in compatibility between the drug and the additive, and the drug must be mixed at a concentration higher than the saturation concentration, and the precipitation of drug crystals is observed in the adhesive layer, which is one of the reasons for insufficient releasability and skin adhesiveness.

Pressure-sensitive adhesives crosslinked with a copolymer obtained by copolymerizing acetoacetoxyalkyl (meth) acrylate and another vinyl monomer with a crosslinking agent such as a polyamine compound or an isocyanate compound are known (for example, see patent documents 3 and 4). However, no document has been found that a patch is prepared by incorporating a transdermally absorbable drug into a propylene-based pressure-sensitive adhesive layer containing a copolymer containing acetoacetoxyalkyl (meth) acrylate as one of the constituent monomers.

Patent document 1: WO97/14411

Patent document 2: japanese patent laid-open publication No. 11-228395

Patent document 3: japanese laid-open patent publication No. 6-108033

Patent document 4: japanese laid-open patent publication No. 7-238203

Disclosure of Invention

Problems to be solved by the invention

The invention provides a tulobuterol adhesive patch which is excellent in the release of tulobuterol from an adhesive layer, skin permeability, skin irritation, and safety.

Means for solving the problems

The present inventors have conducted extensive studies to solve the above problems, and as a result, have found that: the propylene-based pressure-sensitive adhesive containing a copolymer of acetoacetoxyalkyl (meth) acrylate and one or more other vinyl monomers copolymerizable with acetoacetoxyalkyl (meth) acrylate is extremely excellent in compatibility with tulobuterol and a lipophilic oily plasticizer. As a result, it was confirmed that a tulobuterol adhesive patch having excellent release properties of tulobuterol from the adhesive layer and skin permeability, low skin irritation, and excellent safety can be obtained by mixing tulobuterol and optionally a plasticizer of a lipophilic oily substance in the acrylic pressure-sensitive adhesive, and the present invention was completed.

Effects of the invention

The tulobuterol patch of the present invention obtained by mixing tulobuterol as a percutaneous absorption drug and, if necessary, a plasticizer containing a lipophilic oily substance in an acrylic pressure-sensitive adhesive containing a copolymer obtained by copolymerizing one or more monomers of acetoacetoxyalkyl (meth) acrylate and another vinyl monomer is excellent in adhesive force, and self-adhesiveness, and also excellent in the release of tulobuterol from the patch and skin permeability. Further, these effects of the tulobuterol patch of the present invention are superior to known patches in which tulobuterol is mixed in an adhesive layer containing an acrylic pressure-sensitive adhesive or a synthetic rubber-based adhesive.

In addition, when the safety of the tulobuterol patch of the present invention was evaluated by a skin irritation test using a rabbit, the skin irritation was less and the safety was superior to that of a tulobuterol patch in which tulobuterol was mixed with a synthetic rubber adhesive.

In the case of a rubber-based patch, since the self-adhesion tends to be too strong, it is necessary to add a low molecular weight polymer or the like in order to adjust the self-adhesion, but the patch of the present invention is excellent in that it is not necessary to add such a polymer. In addition, in the case of a conventionally used acrylic adhesive patch, a crosslinking agent is required in order to obtain sufficient adhesive force, but a polyamine-based compound or an isocyanate-based compound used as a crosslinking agent is toxic and may affect a drug to be mixed. In contrast, the patch of the present invention is excellent in that no crosslinking agent needs to be added.

The nonaqueous binder obtained by copolymerizing the (meth) acrylic monomer having an acetoacetyl group and the other vinyl monomer having no acetoacetyl group used in the present invention in the nonaqueous solvent is kneaded together with tulobuterol and the plasticizer, and at this time, tulobuterol is dissolved in the remaining nonaqueous solvent and the plasticizer and completely and uniformly mixed. When the mixture is coated on a support or a release film and dried by heating, the acetoacetyl group self-crosslinks while the solvent evaporates to form a mesh structure, and the tulobuterol and the plasticizer are contained in the mesh structure in a state of being dissolved in the binder. The network structure formed by the acetoacetyl self-crosslinking may contain a large amount of oily substances. As a result, the amount of the oily substance contained in the pressure-sensitive adhesive layer can be mixed in a wide range.

By increasing or decreasing the amount of the (meth) acrylic monomer containing an acetoacetyl group in the raw material, the self-crosslinking degree of the adhesive can be changed to adjust the adhesive force and the cohesive force. Further, by adjusting the amount of the lipophilic oily substance such as a plasticizer, a percutaneous absorption enhancer, a drug dissolving agent, etc. contained in the pressure-sensitive adhesive layer, it is possible to maintain appropriate adhesive force and adhesive force.

Best Mode for Carrying Out The Invention

The adhesive patch of the present invention is an adhesive patch in which (a) a support, (b) an acrylic pressure-sensitive adhesive layer containing tulobuterol as a transdermally-absorbable drug and, if necessary, a lipophilic oily plasticizer, and (c) a release liner are sequentially laminated, wherein the acrylic pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive containing a copolymer obtained by copolymerizing acetoacetoxyalkyl (meth) acrylate and one or more other vinyl monomers.

The thickness of the support used in the patch of the present invention is usually 5 to 400 μm, preferably 5 to 250 μm, and more preferably a support having stretchability, but even a non-stretchable substance may be used as long as it has flexibility, as long as it is a material that is impermeable to a drug, and may be a support having a single-layer structure or a support having a structure in which a plurality of materials are laminated. In the case of a support having a single-layer structure, a plastic film such as polyethylene, polyester, polypropylene, polyvinyl chloride, polycarbonate, or polyurethane, or a metal film is preferably used, and the surface of the film may be further subjected to silicone treatment. The support may be colorless and transparent, or colored in white or flesh color, or the surface of the support may be coated with a pigment, or the pigment or pigment may be uniformly kneaded in the support.

When a support having a laminated structure is used, as long as at least 1 layer of a film impermeable to a drug is used, a laminated film obtained by laminating one or more materials selected from nonwoven fabrics, woven fabrics, knitted fabrics, paper, metal films and the like of polyethylene, polyester, polyurethane, polypropylene and the like on the support film having a single-layer structure can be used.

The release liner used in the patch of the present invention serves to protect the adhesive layer, and is peeled off from the patch before the patch is applied to the skin, and the patch is applied to the site of use. The thickness of the release liner is usually 15 to 200 μm, preferably 40 to 100 μm. The release liner is a material that can be easily peeled from the adhesive layer, and any material that is impermeable to the agent can be used. For example, a single layer film of a material selected from plastic films such as polyethylene, polyvinyl chloride, polyester, and polypropylene, paper, metal films, and cloth, or a laminate of a plurality of materials may be used. Films having silicone-treated surfaces of these films can also be used.

Tulobuterol, which is a percutaneous absorption drug of the present invention, is mixed in a dissolved state in an adhesive layer, and the amount of the tulobuterol mixed in the adhesive layer may be mixed in an amount that does not reach a saturation solubility with respect to the total amount of the adhesive, plasticizer, and other additives, but differs depending on the type of the adhesive and the type of the additives, and the amount of the tulobuterol mixed in the adhesive layer is preferably 1 to 10% by mass based on the total mass of the adhesive layer.

The plasticizer mixed in the adhesive layer is preferably an oleophilic oil, such as: fatty acid esters having 6 to 18 carbon atoms, dibasic acid esters having 6 to 10 carbon atoms, higher alcohols having 10 to 18 carbon atoms, castor oil, or the like.

Examples of the fatty acid ester having 6 to 18 carbon atoms include: higher fatty acid esters such as hexyl laurate, isopropyl myristate and isopropyl palmitate, and glycerin fatty acid esters such as medium-chain triglyceride.

Examples of the dibasic acid ester having 6 to 10 carbon atoms include: diisopropyl adipate, dioctyl adipate, diethyl adipate, diisopropyl sebacate, diethyl sebacate, and the like.

Examples of the higher alcohol having 10 to 18 carbon atoms include: hexyldecanol, myristyl alcohol, lauryl alcohol, oleyl alcohol, octyldodecanol, and the like.

The plasticizer is one or more lipophilic oils selected from the above mentioned ones, and may be used alone or in combination, wherein isopropyl myristate is most preferably used. These plasticizers are very preferable because they have a plasticizing effect of the binder, function as a tulobuterol dissolving agent, and have an effect of promoting percutaneous absorption of tulobuterol. These plasticizers are liquid at room temperature (1 to 30 ℃). The amount of the plasticizer to be mixed is not more than about 40% by mass of the total mass of the pressure-sensitive adhesive layer, and more preferably not more than about 35% by mass of the total mass of the pressure-sensitive adhesive layer, and if it exceeds 45% by mass, it is difficult to hold the oily substance in the pressure-sensitive adhesive layer, and the oily substance tends to separate from the pressure-sensitive adhesive layer, which is not preferable.

As the pressure-sensitive adhesive used in the adhesive layer of the adhesive patch of the present invention, an acrylic pressure-sensitive adhesive containing a copolymer obtained by copolymerizing acetoacetoxyalkyl (meth) acrylate and one or more vinyl monomers copolymerizable with acetoacetoxyalkyl (meth) acrylate can be preferably used.

The acetoacetoxyalkyl (meth) acrylate is an alkylene glycol in which one hydroxyl group is acylated with acetoacetyl and the other hydroxyl group is acylated with acrylic acid or methacrylic acid, and for example, an acetoacetoxyalkyl (meth) acrylate selected from 2-acetoacetoxyethyl methacrylate and 2-acetoacetoxyethyl acrylate is used, but 2-acetoacetoxyethyl methacrylate is most preferable. The content of the acetoacetoxyalkyl (meth) acrylate is preferably from about 5 to about 50% by mass, more preferably from about 10 to about 45% by mass, based on 100% by mass of the total copolymer.

The vinyl monomer copolymerizable with the acetoacetoxyalkyl (meth) acrylate may be any compound having a double bond copolymerizable with the acetoacetoxyalkyl (meth) acrylate in the molecule, and for example, one or two kinds of vinyl monomers selected from the group consisting of alkyl (meth) acrylates having an alkyl group of 1 to 12 carbon atoms, functional monomers having a functional group such as a hydroxyl group, an amide group, an alkoxyalkyl group in the molecule, and ethylene glycol (meth) acrylates such as polyalkylene glycol di (meth) acrylates may be used.

Specific examples of the alkyl (meth) acrylate having an alkyl group with 1 to 12 carbon atoms include: methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, butyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, octyl (meth) acrylate, dodecyl (meth) acrylate, and the like. Specific examples of the functional monomers having a functional group in the molecule are: 2-methoxyethyl (meth) acrylate, diacetone acrylamide, 2-hydroxyethyl (meth) acrylate, and the like. Specific examples of (meth) acrylic acid glycol esters are: diethylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, tetraethylene glycol di (meth) acrylate, and the like.

The copolymerization of acetoacetoxyalkyl (meth) acrylate with other vinyl monomer can be carried out in the same manner as in the production method of an acrylic pressure-sensitive adhesive using a polymerization initiator such as a peroxide compound or an azo compound. The acrylic pressure-sensitive adhesive used in the present invention may be any of a non-aqueous adhesive in which the copolymer is dissolved in an organic solvent, and an aqueous emulsion-type adhesive in which the copolymer is dispersed in an aqueous solvent together with a surfactant having little skin irritation.

The surfactant having little skin irritation, which is mixed in the aqueous emulsion type adhesive, may be, for example, one or more surfactants selected from at least one anionic surfactant such as sodium lauryl sulfate and sodium dodecylbenzenesulfonate, a nonionic surfactant such as a polyoxyethylene lauryl ether and a polyoxyethylene oleyl ether, a cationic surfactant, or a peptide surfactant such as a surfactant (サ - フアクチン), alone or in combination.

The solvent used in the nonaqueous adhesive usable in the pressure-sensitive adhesive may be any organic solvent that volatilizes in the heat drying step in the production of the adhesive patch. Examples of such organic solvents are: hydrocarbons such as toluene, xylene, benzene, cyclohexane and n-hexane, and ethyl acetateLower fatty acid esters such as propyl acetate, butyl acetate and ethyl propionate, ketones such as acetone, methyl ethyl ketone and cyclohexanone, isopropyl ether, dibutyl ether, tetrahydrofuran and dibutyl etherEthers such as alkanes. In the aqueous emulsion type adhesive, any solvent can be used as long as it is soluble in water.

In addition to the pressure-sensitive adhesive, the transdermally absorbable drug tulobuterol and the plasticizer, the adhesive layer of the patch of the present invention may further contain a solubility agent for tulobuterol, an absorption enhancer, a tackifier such as ester rubber, a fragrance, a colorant, and the like as additives, if necessary. The tulobuterol dissolving agent is a solvent for dissolving tulobuterol, and can be used as long as it is a solvent without skin irritation. For example, lower alcohols such as ethanol, propanol and isopropanol, medium-chain alcohols such as hexanol and octanol, polyhydric alcohols such as glycerol, ethylene glycol and diethylene glycol, higher fatty acid esters, polyvinyl alcohol, N-methylpyrrolidone and crotamiton can be used, and these solvents can be used alone or in combination as a dissolving agent.

Examples of the percutaneous absorption enhancer for tulobuterol include: fatty acid esters such as isopropyl myristate, isopropyl palmitate, and diethyl adipate, fatty acid polyol esters such as caprylic monoglyceride, caprylic triglyceride, and sorbitan fatty acid ester, and terpenes such as 1-menthol, peppermint oil, and limonene.

Examples of other additives are: silicon compounds such as silicic anhydride and light silicic anhydride, cellulose derivatives such as ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose, water-soluble polymers such as polyvinyl alcohol, antioxidants such as dibutylhydroxytoluene, kaolin, titanium oxide, and the like.

The method for producing the tulobuterol adhesive patch of the present invention comprises mixing a pressure-sensitive adhesive, tulobuterol, and a plasticizer and additives as needed to obtain a solution in which tulobuterol is dissolved, uniformly coating the solution on the surface of a release liner so that the thickness of the dried adhesive layer becomes 15 to 80 μm, heating and drying the adhesive layer, attaching a support to the surface of the adhesive layer, and cutting the adhesive layer into a desired size. Alternatively, the tulobuterol adhesive patch of the present invention may be produced by first applying a dry adhesive to a support to form an adhesive layer, then attaching a release liner, and cutting the release liner into a desired size.

Examples

The following further specifically describes the nonaqueous acrylic pressure-sensitive adhesive for a medical percutaneous absorption tape preparation and the medical percutaneous absorption tape preparation of the present invention based on examples and test examples, but the present invention is not limited thereto.

Production example of adhesive

Production of non-aqueous acrylic pressure-sensitive adhesive

A monomer solution was prepared by uniformly dissolving 158g of 2-ethylhexyl acrylate, 35.1g of 2-acetoacetoxyethyl methacrylate, 76.2g of methyl methacrylate, 80.3g of diacetone acrylamide and 1.0g of tetraethyleneglycol dimethacrylate. 100g of the monomer solution was charged into a 2 liter 4-necked flask equipped with a Dimero reflux condenser, a thermometer, a nitrogen-blowing tube and a stirring paddle, and 350g of ethyl acetate was added as a solvent. While nitrogen gas was blown at a flow rate of 100 ml/min, the temperature was raised to 75 ℃ and maintained at 75 ℃ for 30 minutes, 0.35g of benzoyl peroxide was dissolved in 5g of ethyl acetate and added as an initiator, and the external temperature was set at 85 ℃. After confirming the reflux of the solvent, the remaining monomer solution was continuously added over 3 hours. After 1 hour from the start of the continuous addition of the monomer solution, 500g of ethyl acetate was continuously added over 3 hours. After adding ethyl acetate, stirring was continued for 12 hours, and then 0.5g of benzoyl peroxide was added as an additional catalyst, followed by heat treatment for 12 hours and cooling to prepare a non-aqueous acrylic pressure-sensitive adhesive solution.

[ example 1]

35.69g of the non-aqueous acrylic pressure-sensitive adhesive prepared in the adhesive preparation example was weighed into a screw bottle, and then 3.0g of isopropyl myristate and 1.5g of tulobuterol were weighed into the bottle and stirred for 1 hour. The polyester film was coated and dried by a coating tester (LTE-S, Wener Mathis Co.) so that the mass of the dried coating film became 20mg/10cm²Then, the silicone-treated surface of the polyester release liner having one surface treated with silicone was coated by contacting the silicone-treated surface with an adhesive, and the tulobuterol adhesive patch of example 1 containing 10% by mass of tulobuterol and 20% by mass of isopropyl myristate in the adhesive layer was obtained.

[ example 2]

The same procedure as in example 1 was repeated except that 1.5g of tulobuterol and 38.69g of the nonaqueous acrylic pressure-sensitive adhesive prepared in adhesive preparation example were used, and isopropyl myristate was not used, to obtain the tulobuterol adhesive patch of example 2 in which 10 mass% of tulobuterol was contained in the adhesive layer.

[ example 3]

Using 40.0g of the nonaqueous acrylic pressure-sensitive adhesive obtained in adhesive production example, 0.5g of tulobuterol and 3.0g of isopropyl myristate, the coating film mass was adjusted to 67mg/10cm in the same manner as in example 1²In this way, the tulobuterol adhesive preparation of example 3 containing 3% by mass of tulobuterol and 20% by mass of isopropyl myristate in the adhesive layer was obtained.

[ example 4]

The same procedures as in example 3 were repeated except for using 41.5g of the nonaqueous acrylic pressure-sensitive adhesive obtained in the adhesive preparation example, 0.5g of tulobuterol, and 1.5g of isopropyl myristate, to obtain the tulobuterol adhesive patch of example 4 containing 3% by mass of tulobuterol and 10% by mass of isopropyl myristate in the adhesive layer.

[ example 5]

The same procedures as in example 3 were repeated except for using 37.75g of the nonaqueous acrylic pressure-sensitive adhesive obtained in the adhesive preparation example, 0.5g of tulobuterol, and 5.25g of isopropyl myristate, to obtain the tulobuterol patch of example 5 containing 3% by mass of tulobuterol and 35% by mass of isopropyl myristate in the adhesive layer.

Tulobuterol patch.

[ example 11]

The same procedures as in example 3 were repeated except for using 40.0g of the nonaqueous acrylic pressure-sensitive adhesive prepared in the adhesive preparation example, 0.5g of tulobuterol, and 3.0g of hexyldecanol to obtain the tulobuterol patch of example 11 in which the adhesive layer contained 3 mass% of tulobuterol and 20 mass% of hexyldecanol.

Comparative example 1

A tulobuterol patch of comparative example 1 containing 10% by mass of tulobuterol and 20% by mass of isopropyl myristate in the adhesive layer was obtained in the same manner as in example 1 except that a commercially available nonaqueous acrylic pressure-sensitive adhesive (ニツセツ PE300, manufactured by japanese カ - バイト) having a composition of 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and vinyl acetate (17: 2: 1) was used as the adhesive.

Comparative example 2

A tulobuterol patch of comparative example 2, in which 10% by mass of tulobuterol was contained in the adhesive layer, was obtained in the same manner as in example 2, except that a commercially available non-aqueous acrylic pressure-sensitive adhesive (ニツセツ PE300, manufactured by japanese カ - バイト) was used as the adhesive.

Comparative example 3

A commercially available tulobuterol patch H tape using a synthetic rubber-based pressure-sensitive adhesive was used as the tulobuterol patch of comparative example 3.

Comparative example 4

With 90g of 2-ethylhexyl acrylate, 90g of n-butyl acrylate, 80.5g of diacetoneacrylamide, 87.5g of methyl methacrylate and 0.3g of diethylene glycol dimethacrylate

The test described above was carried out using the tulobuterol patches of examples 1 and 2 and comparative examples 1 and 2, and the results shown in the following table (table 1) were obtained. That is, the formulation of example 1 of the present invention, namely, the tulobuterol patch having an adhesive layer in which tulobuterol and plastic are mixed in an acrylic pressure-sensitive adhesive containing a 2-acetoacetoxyethyl methacrylate monomer is superior in release rate, flux value, cumulative permeation rate, and delay time to those of comparative example 1, namely, the tulobuterol patch having an adhesive layer in which tulobuterol and a plasticizer are mixed in a commercially available acrylic pressure-sensitive adhesive not containing a 2-acetoacetoxyethyl methacrylate monomer. Also, the release rate, flux value, cumulative permeation amount and delay time of the tulobuterol patch of example 2 of the present invention containing no plasticizer composition were superior to those of comparative example 2 containing no plasticizer composition, respectively.

[ Table 1]

Table 1: drug delivery from tulobuterol patch and nude mouse skin permeation

Patch preparation

Content (%)

The weight of the ointment is mg/10cm2

Release Rate%/24 hr

Delay time hr

Flux μ g/cm2/hr

Cumulative permeation quantity mug/cm2/24hr

Myristic acid isopropyl ester

Tulobuterol

Example 1

20

10

20

96.1±0.3

0.17±0.17

3.620±0.057

29.40±1.23

Example 2

0

10

20

95.7±0.8

2.31±0.98

1.757±0.398

17.71±4.27

Comparative example 1

20

10

20

83.0±0.4

1.10±0.28

2.238±0.008

20.98±2.24

Comparative example 2

0

10

20

88.9±0.2

5.14±1.93

0.335±0.133

3.30±1.12

The amount of plasticizer and drug means% by weight when the total weight of the adhesive layer is taken as 100.

2-2) Wistar rat extirpation skin permeability test method

The flux value was determined in the same manner as in the 2-1 test method except that Wistar rats were used to extract skin instead of nude mice.

The test was carried out using the tulobuterol patch of example 3 in which tulobuterol was mixed with the acrylic pressure-sensitive adhesive containing a 2-acetoacetoxyethyl methacrylate monomer according to the present invention and the tulobuterol patch of comparative example 3 in which tulobuterol was mixed with the synthetic rubber adhesive, and the results of table 2 were obtained.

[ Table 2]

Table 2: wistar rat skin permeability from tulobuterol patch

	Tulobuterol content (%)	Paste weight (mg/10 cm)2)	Flux (μ g/cm)2/hr)
				Example 3	3	67	15.9
Comparative example 3	10	20	6.3

From the above results, it is understood that the skin permeability of rats in the patch containing tulobuterol mixed in the acrylic pressure-sensitive adhesive containing 2-acetoacetoxyethyl methacrylate monomer of example 3 of the present invention is superior to the skin permeability of the tulobuterol patch of comparative example 3 in which tulobuterol is mixed in the synthetic rubber adhesive.

[ test example 2]

Skin irritation test

The tulobuterol patch of example 3 according to the present invention and the tulobuterol patch of comparative example 3 were evaluated for safety using a single skin irritation test using rabbits.

1) One-time skin irritation test method (rabbits)

Before the test, the hair of the rabbit was shaved off by using an electric hair cutter and used for the test. The preparation is applied to the back of rabbit, covered with impermeable oil paper, and fixed thereon by using non-woven adhesive bandage (mesh, ニチバン), and the whole applied part is covered with gauze, and covered with adhesive elastic bandage (elastic hole, ニチバン). After 24 hours, the test preparation was removed, and the application site was gently wiped with absorbent cotton moistened with warm water, left for 30 minutes, and then observed. Further, the site of application was observed in the same manner at 48 and 72 hours after the preparation application, and the primary irritation index (p.i.i.) was calculated from the scores at 24 and 72 hours after the application on the basis of the evaluation criteria such as Draize described below.

Evaluation criteria of Draize et al

A: erythema and scabbing

No erythema: 0. very mild erythema: 1. marked erythema: 2. moderate to severe erythema: 3. severe erythema to mild scab formation: 4

B: formation of edema

No edema: 0. very mild edema: 1. mild edema: 2. moderate edema (approximately 1mm swelling): 3. severe edema: 4

2) Evaluation of test

Using the tulobuterol patch of example 3 of the present invention and the tulobuterol patch of comparative example 3, a rabbit skin irritation test was performed once using the method of test example 2, and the skin irritation index of table 3 was determined once. As a result, the tulobuterol patch of example 3 according to the present invention showed less skin irritation than the tulobuterol patch of comparative example 3.

[ Table 3]

Table 3: skin one time irritation index of tulobuterol patch

	Index of skin Primary irritation
		Example 3	1.25
Comparative example 3	2.19

[ test example 3]

Adhesion Property test

The adhesive properties of the tulobuterol adhesive patches of examples 1-11 of the present invention and the tulobuterol adhesive patches of comparative examples 1-4 were evaluated by the following (functional) test methods from the three viewpoints of adhesive strength, and self-adhesiveness.

1) Adhesion property test method

1-1) adhesive force

The liner of the formulation was peeled off, and the adhesive face was touched with a finger, and evaluated according to the following evaluation standards.

Evaluation criteria

O: (excellent) the adhesive force is equivalent to that of a commercially available anti-inflammatory-pain-containing adhesive tape agent S and a commercially available フエルビナクル -containing adhesive tape agent F which use natural rubber latex;

and (delta): (good) has the same degree of adhesive force with a commercially available adhesive tape agent M containing ketoprofen and a commercially available adhesive tape agent Y containing flurbiprofen, both of which use a styrene-isopropenyl-styrene copolymer;

x: (poor) adhesion of commercial products or less;

-: since the adhesion was remarkably low (semi-solid state), it could not be evaluated.

1-2) adhesion

The liner of the preparation was peeled off, and the adhesive surface was touched with a finger, and evaluated based on the following evaluation criteria.

Evaluation criteria

O: (excellent) the adhesive force is equivalent to that of a commercially available adhesive tape agent M containing ketoprofen and a commercially available adhesive tape agent Y containing flurbiprofen, both of which use a styrene-isopropenyl-styrene copolymer;

and (delta): (good) has the same degree of adhesion with a commercially available indomethacin-containing adhesive tape agent S and a commercially available フエルビナクル -containing adhesive tape agent F using a natural rubber latex;

x: (poor) adhesion of commercial products or less

-: since the adhesion force was remarkably low (semi-solid state), it could not be evaluated.

1-3) self-adhesion

The ease of peeling when the adhesive faces of the formulations were adhered to each other was evaluated according to the following evaluation criteria.

Evaluation criteria

O: (excellent) no resistance, easy peeling;

and (delta): (good) slightly resistant, still peelable;

x: (poor) has a certain resistance and is difficult to peel

2) Evaluation results

The above adhesion property test was carried out using the tulobuterol patches of examples 1-11 of the present invention and the tulobuterol patches of comparative examples 1-4. The results are shown in Table 4.

[ Table 4]

Table 4: adhesive properties of tulobuterol patches

Patch preparation

Plasticizer content (%)

Tulobuterol content (%)

Paste weight (mg/10 cm)2)

Presence or absence of crystallization

Adhesive force

Adhesion force

Self-adhesive property

Example 1

Isopropyl myristate: 20

10

20

Is free of

○

○

○

Example 2

-

10

20

Is free of

○

○

○

Example 3

Isopropyl myristate: 20

3

67

Is free of

○

○

○

Example 4

Isopropyl myristate: 10

3

67

Is free of

○

○

○

Example 5

Isopropyl myristate: 35

3

67

Is free of

○

○

○

Example 6

Diethyl sebacate: 20

3

67

Is free of

○

○

○

Example 7

Diethyl sebacate: 30

3

67

Is free of

○

○

○

Example 8

Isopropyl palmitate: 20

3

67

Is free of

○

○

○

Example 9

Medium-chain fatty acid triglycerides: 20

3

67

Is free of

○

○

○

Example 10

Castor oil: 20

3

67

Is free of

○

○

○

Example 11

Hexyldecanol: 20

3

67

Is free of

○

○

○

Comparative example 1

Isopropyl myristate: 20

10

20

Is free of

×

-

-

Comparative example 2

-

10

20

Is free of

×

-

-

Comparative example 3

-

10

20

Is provided with

○

△

×

Comparative example 4

Isopropyl myristate: 20

10

20

Is free of

×

-

-

-: adhesion was insufficient, and therefore, it could not be evaluated

The amounts of the plasticizer and the drug represent% by weight when the total weight of the adhesive layer is taken as 100.

The tulobuterol patches of examples 1 to 11, in which tulobuterol was mixed in the acrylic pressure-sensitive adhesive containing the copolymer containing 2-acetoacetoxyethyl methacrylate as a monomer component, were superior in terms of three points of adhesion, and self-adhesiveness to the tulobuterol patches of comparative examples 1, 2, and 4, in which tulobuterol was mixed in the acrylic pressure-sensitive adhesive containing the copolymer not containing 2-acetoacetoxyethyl methacrylate as a monomer component. The tulobuterol adhesive patches of examples 1 to 11 according to the present invention had the same adhesive strength as the tulobuterol adhesive patch of comparative example 3 in which tulobuterol was mixed with a synthetic rubber adhesive, but had excellent adhesive strength and self-adhesiveness.

Industrial applicability

By using a copolymer obtained by copolymerizing an acrylic monomer of acetoacetoxyalkyl (meth) acrylate with one or more monomers of other vinyl monomers as a pressure-sensitive adhesive, a tulobuterol patch excellent in adhesion, cohesive force, self-adhesiveness, tulobuterol release from the adhesive layer and skin permeability, little skin irritation, and high safety can be provided.

Claims (8)

1. A tulobuterol patch characterized in that: the adhesive patch is formed by sequentially laminating (a) a support, (b) an adhesive layer and (c) a release liner, wherein the adhesive layer of (b) contains a plasticizer and tulobuterol as a percutaneous absorption medicament, and the adhesive is an acrylic pressure-sensitive adhesive which is a copolymer obtained by copolymerizing 2-acetoacetoxyethyl methacrylate, diacetone acrylamide, tetraethyleneglycol dimethacrylate, 2-ethylhexyl acrylate and methyl methacrylate.

2. The tulobuterol patch according to claim 1, wherein the 2-acetoacetoxyethyl methacrylate content is 10 to 45% by mass, based on 100% by mass of the total copolymer.

3. The tulobuterol patch according to claim 1, wherein the plasticizer is one or more lipophilic oils selected from the group consisting of fatty acid esters having 6 to 18 carbon atoms, dibasic acid esters having 6 to 10 carbon atoms, higher alcohols having 10 to 18 carbon atoms, and oils and fats that are liquid at room temperature.

4. Tulobuterol patch according to claim 3, wherein the plasticizer is one or more plasticizers selected from the group consisting of isopropyl myristate, diethyl sebacate, isopropyl palmitate, medium chain fatty acid triglycerides and hexyldecanol.

5. Tulobuterol patch according to claim 4, wherein the plasticizer is isopropyl myristate.

6. The tulobuterol patch according to claim 4 or 5, wherein the plasticizer is mixed in an amount of 10 to 35% by mass based on the total mass of the adhesive layer.

7. The tulobuterol patch according to claim 1, wherein 1 to 10% by mass of tulobuterol based on the total mass of the adhesive layer is contained in the adhesive layer in a dissolved state.

8. Tulobuterol patch according to claim 1, wherein the adhesive layer is a non-aqueous adhesive.