JP3277239B2 - Topical patch for eperisone or tolperisone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external patch for transdermal administration of eperisone, tolperisone or a salt thereof, and more particularly, to an excellent patch and excellent feeling upon use.
In addition, the present invention relates to an external patch which does not impair the commerciality by causing the drug in the base layer to migrate in the support and precipitate on the surface on the opposite side of the base layer during storage of the preparation.

[0002]

2. Description of the Related Art Eperisone, tolperisone, or a salt thereof is an agent for improving various symptoms based on spastic paralysis, or
It has been applied as an agent for improving muscle tone due to diseases such as cervical-shoulder-arm syndrome, shoulder periarthritis, and low back pain.

[0003] Usually, eperisone, tolperisone or salts thereof are administered orally. However, in general, when a drug is administered orally, a considerable amount of the drug is broken down in the liver before the drug takes effect in the affected area because the drug absorbed in the intestine is metabolized in the liver. In addition, side effects are likely to occur because the drug is absorbed in a short time.

[0004] On the other hand, drugs have been absorbed into the circulatory system through the skin using transdermal preparations. In general, transdermal administration has the following advantages.
That is, in transdermal administration, the absorbed drug reaches the affected site without being decomposed by metabolism in the liver. In addition, transdermal administration is unlikely to cause gastrointestinal disorders as seen in oral administration. Further, by adjusting the release amount of the drug by transdermal administration, it is possible to reduce, for example, side effects caused by a large amount of the drug being absorbed in a short time. In transdermal administration, a constant drug release rate can be maintained for a long time, and the number of drug administrations can be reduced.

[0005] As a transdermal preparation, a patch in which a base layer containing a drug is formed on one surface of a support is desirable in view of the accuracy of administration and the ease of use.

As the support for supporting the drug-containing base layer, it is desirable to use a flexible and stretchable support from the viewpoint of sticking properties such as peeling, stretching, and foreign substances during use and feeling of use.

[0007] If the permeability of the drug to the support is high, the drug in the base layer migrates through the support and precipitates on the surface on the opposite side of the base layer during storage of the preparation. Therefore, it is desirable to use a drug-impermeable material as the support.

[0008] Supports that are impermeable to eperisone, tolperisone, or salts thereof include, for example,
JP-A-3-141223 discloses polyester film, Teflon (registered trademark of DuPont) film, polyester-polyethylene laminated film, polyester-ethylene / vinyl acetate copolymer laminated film, Teflon-
A polyethylene laminated film and the like are disclosed.

As a flexible and stretchable support, polyurethane films and ethylene / vinyl acetate copolymer films are widely known.

[0010]

However, the former support is insufficient in flexibility and stretchability, and has problems such as peeling during use, feeling of tension, and feeling of foreign matter.

The latter support has a high permeability to eperisone, tolperisone, or a salt thereof, and during storage of the preparation, the drug in the base layer migrates through the support and opposes the base layer. Precipitation on the side surface has the problem of impairing commercial properties.

[0012] The present invention has been made in view of the above-mentioned points, and has as its object to be excellent in sticking property and feeling upon use, and further, during storage of the preparation, the drug is supported on the side opposite to the base layer. It is an object of the present invention to provide an external patch containing eperisone, tolperisone, or a salt thereof, which does not impair commercial properties due to precipitation on the body surface.

[0013]

DISCLOSURE OF THE INVENTION The present invention has been devised in order to achieve the above-mentioned object, and a drug containing eperisone, tolperisone, or a salt thereof on one surface of a support.
The present invention provides an external patch for eperisone or tolperisone, characterized in that the support comprises an ethylene / methyl acrylate copolymer film in a patch provided with a substance-containing base layer.

In a preferred embodiment of the present invention, the drug-containing base layer further contains crospovidone and lactate ester, and the adhesive base of the base layer is acrylic acid-2-
Ethylhexyl at a rate of 45 to 80 mol % and N-
A copolymer containing vinyl-2-pyrrolidone in a proportion of 25 to 55 mol% as a main component, and a nonwoven fabric is provided on the surface of the support opposite to the base layer-attached surface of the ethylene / methyl acrylate copolymer film. It is laminated.

Hereinafter, each component of the patch according to the present invention and its production method will be described in detail.

A) The ethylene / methyl acrylate copolymer film used for the support in the present invention is formed into a film by various known methods such as inflation molding and extrusion molding of the ethylene / methyl acrylate copolymer resin. It was done.

The methyl acrylate content (hereinafter referred to as MA content) of the ethylene / methyl acrylate copolymer resin is not particularly limited, but is preferably 12 to 24% by weight. The thickness of the ethylene / methyl acrylate copolymer film varies depending on the purpose of use, but is preferably 5 to 200 μm.

Furthermore, various known non-woven fabrics and / or woven fabrics made of polyester, polypropylene, rayon, polyolefin, pulp, etc. may be added to the ethylene / methyl acrylate copolymer film according to the need for ease of handling and appearance. A laminate obtained by laminating cloths can also be used as a support. As such a non-woven fabric or woven fabric, a non-woven fabric obtained by a melt blow method from a mixture of a block copolymer of polystyrene and hydrogenated polyisoprene and polypropylene in order not to impair the elasticity of the ethylene-methyl acrylate copolymer film. Particularly preferably used. The ratio of polypropylene in this mixture is preferably from 10 to 50% by weight.

For laminating the ethylene / methyl acrylate copolymer film and the nonwoven fabric and / or woven fabric, various known methods such as extrusion lamination, heat lamination and dry lamination are used. In this manner, the nonwoven fabric and / or woven fabric is laminated on one side of the support, that is, on the side opposite to the side to which the base layer is to be attached.

If necessary, the base layer forming surface of the ethylene / methyl acrylate copolymer film may be coated with various commonly used primers such as 2-ethylhexyl (meth) acrylate / acrylic acid copolymer. Can be applied.

B) Drugs used in the patch of the present invention include:
Eperisone, tolperisone, or salts thereof.
These are agents for improving various symptoms based on spastic paralysis, or
It has been applied as an agent for improving muscle tone due to diseases such as cervical-shoulder-arm syndrome, shoulder periarthritis, and low back pain.

As salts of eperisone and tolperisone,
Hydrochloride, phosphate, methanesulfonate and the like are exemplified.

Eperisone, tolperisone, or a salt thereof is dissolved in a base described below, or is mixed with the base at a ratio of a saturation solubility or higher and dispersed in the base in a microcrystalline state.

The content of eperisone, tolperisone or a salt thereof is preferably 0.05 to 30% by weight, more preferably 0.1 to 20% by weight in the base.
Is the ratio of If the content of eperisone, tolperisone or a salt thereof is less than 0.05% by weight, the percutaneous absorption effect per unit area of application of the drug is not sufficient, and the practical administration area of the patch (150 cm ² In the following), it may not be possible to obtain a blood concentration sufficient to exert a drug effect. On the other hand, if the content exceeds 30% by weight, the base of the patch may be easily cracked, and the sticking property may be reduced.

C) The base used in the patch of the present invention is
It depends on the dosage form of the patch. The patch of the present invention may be a tape, a patch, a poultice, a plaster and the like.

The tape preparation is obtained by forming an adhesive base layer containing a drug and optional additives on one side of a support.

The patch is formed by sequentially laminating a non-adhesive reservoir layer and an adhesive layer on one side of a support. The reservoir layer contains a drug and additives to be added as needed. It is held on an adhesive base. This reservoir layer is adhered to the skin via the adhesive layer, and the drug in the reservoir layer is transdermally absorbed through the adhesive layer. However, the drug in the reservoir layer and the additives added as needed may be included in the pressure-sensitive adhesive layer.

The cataplasm is obtained by applying a paste-like base containing a drug and optional additives to the surface of a support in a layer form. A cataplasm is usually less adhesive than a tape or a patch, and is thus fixed to the skin surface with a bandage or the like.

The plaster preparation is obtained by applying a pressure-sensitive adhesive base containing a drug and optional additives to the surface of a support in a layer form. The pressure-bondable base is formed by kneading a specific rubber-based pressure-sensitive adhesive, a synthetic or natural resin, ZnO, or the like.

C-1) As the non-adhesive base constituting the reservoir layer of the patch, a conventionally known external base can be used, for example, white petrolatum, silicone oil, carboxyvinyl polymer, polyvinyl alcohol, polyethylene glycol, liquid paraffin And the like.

C-2) The adhesive base of the tape or the adhesive of the adhesive layer of the patch is excellent in compatibility with the above-mentioned drugs, and can fix the patch on the skin surface at room temperature for a long time. There is no particular limitation as long as it has adhesive strength. Preferred examples of the pressure-sensitive adhesive include an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, and a silicone-based pressure-sensitive adhesive.

As the acrylic pressure-sensitive adhesive, in particular, a homopolymer or copolymer of an alkyl (meth) acrylate having 4 to 18 carbon atoms in the alkyl group and / or the above-mentioned alkyl (meth) acrylate and other alkyl A copolymer with a functional monomer is preferably used.

As the above (meth) acrylate, butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, acrylic acid-2-
Ethylhexyl, isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate,
Stearyl acrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate,
Examples thereof include isooctyl methacrylate, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate, and stearyl methacrylate.

Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group,
Examples include a monomer having an amide group, a monomer having an amino group, and a monomer having a pyrrolidone ring.
Examples of the monomer having a hydroxyl group include 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth).
Examples include hydroxyalkyl (meth) acrylates such as acrylates. Examples of monomers having a carboxyl group include α, β such as acrylic acid and methacrylic acid.
-Unsaturated carboxylic acid: monoalkyl maleate such as butyl maleate: maleic acid: fumaric acid: crotonic acid and the like. Maleic anhydride also provides the same (co) polymerization component as maleic acid. Examples of the monomer having an amide group include alkyl (meth) such as acrylamide, dimethylacrylamide, and diethylacrylamide.
Acrylamide: Examples thereof include alkyl ether methylol (meth) acrylamide such as butoxymethylacrylamide and ethoxymethylacrylamide, and diacetone acrylamide. Examples of the monomer having an amino group include dimethylaminoethyl acrylate. Examples of the monomer having a pyrrolidone ring include N-vinyl-2-pyrrolidone.

As copolymerizable monomers other than those described above, vinyl acetate, vinyl alcohol, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene and the like can also be used.

In order to produce a copolymer of an alkyl (meth) acrylate, it is preferable that the alkyl (meth) acrylate is contained in an amount of not less than 45% by weight in all the copolymerized monomer components.

More preferably, a copolymer containing 2-ethylhexyl acrylate and N-vinyl-2-pyrrolidone as copolymerization components is used. The content of 2-ethylhexyl acrylate is 45 to 80 mol%, preferably 55 to 70 mol%, and the content of N-vinyl-2-pyrrolidone is 20 to 55 mol%, preferably 30 to 45 mol%. It is.

A polyfunctional monomer is further added to the monomer component for producing an acrylic pressure-sensitive adhesive, if necessary.
It is copolymerized with the above monomer components. The addition of this polyfunctional monomer causes only slight crosslinking between the resulting polymers, thereby increasing the internal cohesion of the adhesive. Therefore, the so-called glue residue phenomenon at the time of peeling the patch is almost eliminated irrespective of the properties of the pasted skin and the amount of perspiration. In addition, the addition of the polyfunctional monomer has no adverse effect on the drug release and low skin irritation. Examples of such a polyfunctional monomer include, but are not limited to, di (meth) acrylate, tri (meth) acrylate, and tetra (meth) acrylate. More specifically, di (meth) acrylate obtained by combining polymethylene glycols such as hexamethylene glycol and octamethylene glycol with (meth) acrylic acid; polyalkylene glycols such as polyethylene glycol and polypropylene glycol; Di (meth) obtained by bonding with (meth) acrylic acid
Acrylates; tri (meth) acrylates such as trimethylolpropane tri (meth) acrylate and glycerin tri (meth) acrylate; and tetra (meth) acrylates such as pentaerythritol tetra (meth) acrylate
Acrylates are exemplified. These polyfunctional monomers may be used in combination of two or more. The polyfunctional monomer has a content of 0.005 in all monomers used for the production of the adhesive.
Used at a rate of .about.0.5% by weight. If the amount of the polyfunctional monomer is less than 0.005% by weight, the effect of improving the internal cohesive force by crosslinking is small, and if it exceeds 0.5% by weight, the pressure-sensitive adhesive obtained by polymerization tends to gel. In addition, the effect also appears on the diffusion and release of drugs.

If necessary, a tackifier such as a rosin resin, a polyterpene resin, a coumarone-indene resin, a petroleum resin, or a terpene-phenol resin may be added to the acrylic pressure-sensitive adhesive.

To prepare an acrylic pressure-sensitive adhesive,
Solution polymerization of the required monomer is carried out in the presence of a polymerization initiator. However, the polymerization form is not limited to this. The polymerization reaction conditions are appropriately selected mainly depending on the type of the monomer.

Examples of the rubber-based adhesive include natural rubber, synthetic isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polyisoprene, polybutadiene,
100 parts by weight of a rubber elastic material such as a styrene-butadiene copolymer, a styrene-isoprene copolymer, a styrene-isoprene-styrene block copolymer, for example, a rosin resin, a polyterpene resin, a coumarone-indene resin, a petroleum resin, 20 to 200 parts by weight of a tackifier such as a terpene-phenol resin, and if necessary,
Liquid softeners such as liquid polybutene, mineral oil, lanolin, liquid polyisoprene, and liquid polyacrylate: fillers such as titanium oxide; antioxidants such as butylhydroxytoluene;

As the silicone-based pressure-sensitive adhesive, one containing polyorganosiloxane or the like as a main component is used.

Compounding agents such as a plasticizer, a filler, and an antioxidant are added to each of the pressure-sensitive adhesives as needed.

C-3) When the patch of the present invention is a poultice, bases include natural polymers such as alkali metal alginate, gelatin, corn starch and tragacanth gum; and cellulose such as methylcellulose, hydroxyethylcellulose and carboxymethylcellulose. Starch polymers such as dextrin and carboxymethyl starch; and synthetic polymers such as polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, and polyvinylpyrrolidone.

The paste-like base used in the production of the cataplasm comprises, in addition to the compounding agent such as a drug and an absorption promoter added as needed, further purified water, a humectant, an inorganic filler, and a viscosity adjusting agent. Agents, a cross-linking agent, an antioxidant, and the like may be appropriately contained. As the humectant, glycerin, propylene glycol or the like is used, and as the inorganic filler,
Kaolin, bentonite, zinc white, titanium dioxide and the like are used.

C-4) When the patch of the present invention is a plaster, a pressure-sensitive adhesive base obtained by kneading a specific rubber-based adhesive, a synthetic or natural resin, ZnO or the like is used as the base. Is done.

D) The patch of the present invention may contain a suitable absorption enhancer, if necessary, for the purpose of improving the transdermal permeability of the drug. Examples of the absorption enhancer include isopropyl myristate, diethyl sebacate, sorbitan monolaurate, glycerin monooleate, sodium oleyl phosphate, sodium lauryl sulfate, octylphenyl ether, octylphenyl ether with polyethylene glycol, lauryl ether, lauryl ether with polyethylene glycol. , Sorbitan monooleate,
Sorbitan monooleate with polyethylene glycol,
Lauroyl diethanolamide, lauroyl sarcosine, oleoyl sarcosine sugar ester, lecithin, glycyrrhetin, urea, salicylic acid, calcium thioglycolate, lactic acid, crospovidone, lactate ester, olive oil, squalene, lanolin, liquid paraffin, glycerin and the like are used.

Particularly preferred absorption promoters are crospovidone and esters of aliphatic alcohols having 12 to 18 carbon atoms with lactic acid.

Such lactate esters include myristyl lactate, lauryl lactate, and cetyl lactate.

In the patch according to the present invention, crospovidone contained in the base layer is selected from US Pharmacopeia NF X
As described in VII (the compendium), it is a crosslinked homopolymer of N-vinyl-2-pyrrolidone,
It is a substance containing a nitrogen atom in the range of １２12.8% by weight (in an anhydrous state).

Preferred examples of commercially available crospovidone include Kollidon CL (registered trademark) manufactured by BASF,
Kolydone CL-M (registered trademark), polyplasdone XL (registered trademark) manufactured by GAF, polyplasdone INF-10
(Registered trademark). Methods for producing these compounds are described in U.S. Pat. Nos. 3,759,880 and 3,933,766.
Nos. 3,689,439, 4,139,688 and 4,
No. 180633.

Crospovidone has a moderate swelling property in water. Therefore, when a preparation containing crospovidone is administered to the skin, it absorbs water such as sweat and swells, thereby improving drug release. The crospovidone content is preferably in the range from 0.5 to 20% by weight.
When the content of crospovidone is less than 0.5% by weight,
A sufficient promoting effect on drug release cannot be obtained. When the content of crospovidone exceeds 20% by weight, for example, when the preparation of the present invention is a tape or the like, the adhesiveness of the preparation decreases.

The above-mentioned absorption promoter is contained in the base of the present invention in an amount of 10%.
% By weight, preferably 0.1 to 10%.
% By weight. When the content of the absorption promoter is 10
If the content exceeds% by weight, the resulting preparation becomes too irritating to the skin, and when it is applied to the skin, redness and itching occur.

E) The tape preparation is usually provided with a release paper on its sticking surface in order to protect the surface of the adhesive base layer until use. The patch is also provided with a release paper for protecting the pressure-sensitive adhesive layer. As the release paper, one obtained by subjecting a polyethylene terephthalate film to a silicon treatment is often used, but the release paper is not limited to this. The thickness of the release paper is 100 μm or less, preferably 5 to 50 μm
It is.

F) To produce the patch of the present invention, one side of the ethylene / methyl acrylate copolymer film is
A base layer containing a compounding agent such as eperisone, tolperisone, or a salt thereof, and an absorption enhancer added as needed is formed.

In order to form a base layer on the surface of a support, an ordinary method for producing a pressure-sensitive adhesive tape can be applied. A typical example thereof is a solvent coating method, and in addition, a hot melt coating method, an electron beam curing emulsion coating method and the like are used. To form a base layer on a support by a solvent coating method, for example, eperisone, tolperisone, or a salt thereof, and a base,
With compounding agents such as absorption enhancers added as needed,
It is dissolved or dispersed in an appropriate solvent, and the resulting solution or dispersion is directly applied to the surface of the support and dried to form a drug-containing base layer having a required thickness. This base layer is brought into close contact with a protective release paper to obtain a desired tape. Alternatively, this solution or dispersion may be coated on a protective release paper, and the base layer obtained after drying may be adhered to a support.

The thickness of the base layer varies depending on the purpose of use, but is usually in the range of about 30 μm to about 2000 μm. If the thickness is less than 30 μm, a desired amount of the drug cannot be contained in the base having a predetermined area of the patch.
Furthermore, in the case of tapes and patches, sufficient tackiness cannot be obtained. If the thickness exceeds 2000 μm, it becomes difficult for the drug contained in the drug-containing layer near the support to diffuse and reach the skin surface, and the drug in the preparation is not effectively used. A release paper is stuck on the drug-containing layer until the time of use for the purpose of protecting this layer depending on the dosage form.

The patch obtained in this manner has a moderate O
In order to have a DT (sealing) effect and prevent rash and peeling due to stuffiness, the water vapor permeability of the preparation is preferably 5
~500g / m ^2/24 hours (temperature 37 °, relative humidity 9
0%), more preferably 30~100g / m ^2/24 hours (temperature 37 °, relative humidity of 90%).

The patch thus prepared is used by sticking it to the affected area.

[0060]

Next, in order to specifically explain the present invention,
Examples showing one example of the present invention and some comparative examples showing a comparison with the examples are given, and the evaluation test results of the obtained patches are shown.

Example 1 75.5% by weight of 2-ethylhexyl acrylate and N-
24.5% by weight of vinyl-2-pyrrolidone and 0.04 part by weight of hexamethylene glycol dimethacrylate based on 100 parts by weight of the former were charged into a separable flask, and the monomer concentration at the beginning of polymerization was 85% by weight. Ethyl acetate was added. This solution is heated to 60 ° C under a nitrogen atmosphere.
, And lauroyl peroxide and ethyl acetate as polymerization initiators were sequentially added little by little, and a polymerization reaction was carried out for 32 hours. Ethyl acetate was added to the obtained polymer to dilute the reaction solution to obtain a base solution having a solid content of 36% by weight.

Then, 4 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) was added to 100 parts by weight of the base solution, and the solution was sufficiently stirred in a dissolver.
m on a release paper made of polyethylene terephthalate and dried at 60 ° C. for 20 minutes to form a drug-containing base layer.

Ethylene / methyl acrylate copolymer resin (trade name “Nisseki Lexpearl RB” manufactured by Nippon Petrochemical Co., Ltd.)
A support consisting of a film having a thickness of 60 μm and obtained by inflation molding of “3240” (registered trademark, MA content; 24% by weight) was adhered to the drug-containing base layer.
Thus, a tape preparation having a drug-containing base layer containing 80% of eperisone hydrochloride and having a thickness of 80 μm on one surface of the support was prepared.

Example 2 As a support, ethylene-methyl acrylate copolymer resin (trade name "Nisseki Lexpearl C" manufactured by Nippon Petrochemical Co., Ltd.)
RB315R5® (registered trademark, MA content; 15% by weight), a film having a thickness of 40 μm obtained by inflation molding, and otherwise the same as in Example 1, 10% by weight of eperisone hydrochloride And a tape preparation having a drug-containing base layer having a thickness of 80 μm on one surface of a support was prepared.

Example 3 A support was obtained by a melt blow method from a mixture of 80% by weight of a block copolymer of polystyrene and hydrogenated polypropylene (trade name "Septon", trade name, manufactured by Kuraray Co., Ltd.) and 20% by weight of polypropylene. Non-woven fabric (weight 50
g / m ² ), and ethylene-methyl acrylate copolymer resin (trade name “Nisseki Lexpearl” manufactured by Nippon Petrochemical Co., Ltd.)
"CRB315R5" registered trademark, MA content; 15% by weight)
Using a laminate obtained by lamination by extrusion lamination so that the thickness of the ethylene-methyl acrylate copolymer film is 40 μm, and the film surface of this laminate is obtained in the same manner as in Example 1. The substrate was brought into close contact with the drug-containing base layer. Thus, a tape preparation having a drug-containing base layer containing 80% of eperisone hydrochloride and having a thickness of 80 μm on one surface of the support was prepared.

Example 4 100 parts by weight of a styrene-isoprene-styrene block copolymer (KRATON D1107, manufactured by Ciel)
15% by weight of polybutene (HV-300, manufactured by Nippon Petrochemical), 160 parts by weight of alicyclic saturated hydrocarbon resin (Alcon P-90, manufactured by Arakawa Chemicals) and 3 parts by weight of butylhydroxytoluene were added to cyclohexane. By mixing, a base solution having a solid concentration of 45% by weight was obtained.

Then, 5 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) was added to 100 parts by weight of the base solution, and the solution was sufficiently stirred in a dissolver.
m of a polyethylene terephthalate film and dried at 60 ° C. for 20 minutes to form a drug-containing base layer.

Ethylene / methyl acrylate copolymer resin (trade name “Nisseki Lexpearl RB” manufactured by Nippon Petrochemical Co., Ltd.)
A support made of a film having a thickness of 20 μm and obtained by inflation molding of “5120” (registered trademark, MA content; 12% by weight) was adhered to the drug-containing base layer.
Thus, a tape preparation having a drug-containing base layer having a thickness of 80 μm and containing 10% by weight of eperisone hydrochloride on one surface of the support was prepared.

Example 5 To 100 parts by weight of the base solution obtained in the same manner as in Example 1, 4 parts by weight of tolperisone hydrochloride (manufactured by Sigma) was added, and the solution was thoroughly stirred in a dissolver. 75μ
m of a polyethylene terephthalate film and dried at 60 ° C. for 20 minutes to form a drug-containing base layer.

Ethylene / methyl acrylate copolymer resin (trade name “Nisseki Lexpearl RB” manufactured by Nippon Petrochemical Co., Ltd.)
A support consisting of a film having a thickness of 60 μm and obtained by inflation molding of “3240” (registered trademark, MA content; 24% by weight) was adhered to the drug-containing base layer.
Thus, a tape preparation having a drug-containing base layer containing 80% of eperisone hydrochloride and having a thickness of 80 μm on one surface of the support was prepared.

Example 6 78.3% by weight of 2-ethylhexyl methacrylate, 9.1% by weight of 2-ethylhexyl acrylate, 12.6% by weight of dodecyl methacrylate, and 100 parts by weight of the former three 0.04 parts by weight of hexamethylene glycol dimethacrylate was charged into a separable flask, and ethyl acetate was added so that the monomer concentration in the initial stage of the polymerization was 85% by weight. This solution was heated to 60 ° C. under a nitrogen atmosphere, and lauroyl peroxide and ethyl acetate, which are polymerization initiators, were sequentially added little by little to carry out a polymerization reaction for 24 hours.
Ethyl acetate was added to the obtained polymer to dilute the reaction solution,
A base solution having a solid content of 45% by weight was obtained.

Next, 5 parts by weight of tolperisone hydrochloride (manufactured by Sigma) was added to 100 parts by weight of the base solution, and the solution was sufficiently stirred in a dissolver, and then was placed on a release paper made of a 75 μm-thick polyethylene terephthalate film. And dried at 60 ° C. for 20 minutes to form a drug-containing base layer.

Ethylene / methyl acrylate copolymer resin (trade name “Nisseki Lexpearl CR” manufactured by Nippon Petrochemical Co., Ltd.)
A support consisting of a film having a thickness of 40 μm and obtained by inflation molding of B315R5® (registered trademark, MA content; 15% by weight) was adhered to the drug-containing base layer. In this way, a tape preparation having a drug-containing base layer containing 10% by weight of tolperisone hydrochloride and having a thickness of 80 μm on one surface of the support was prepared.

Example 7 To 115 parts by weight of the base solution obtained in the same manner as in Example 1, 5 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) and polyplasdone INF-10 (crospovidone, manufactured by GAF)
1 part by weight and cetyl lactate (manufactured by VAN DYK)
After 5 parts by weight of the solution was sufficiently stirred in a dissolver, the solution was coated on a 75 μm-thick polyethylene terephthalate release paper and dried at 60 ° for 20 minutes to form a drug-containing base layer.

Ethylene / methyl acrylate copolymer resin (Nippon Petrochemical Co., Ltd., Nisseki Lexpearl CRB315R)
5 (registered trademark), methyl acrylate content; 15% by weight)
Of a film having a thickness of 40 μm obtained by inflation molding was adhered to the drug-containing base layer. Thus, a tape preparation having a drug-containing base layer having a thickness of 80 μm on one side of a support, containing 10% by weight of eperisone hydrochloride, 2% by weight of polyplasdone INF-10 and 5% by weight of cetyl lactate was prepared. did. Fine particles of polyplasdone INF-10 and microcrystals of eperisone hydrochloride were dispersed in the drug-containing base layer of this tape preparation.

Example 8 As a support, a block copolymer of polystyrene and hydrogenated polyisoprene (Septon (registered trademark) manufactured by Kuraray Co., Ltd.)
A nonwoven fabric obtained by a melt blowing method from a mixture of 80% by weight and 20% by weight of polypropylene (a basis weight of 50 g /
m ² ), an ethylene-methyl acrylate copolymer resin (Nippon Petrochemical Co., Ltd., Nisseki Lexpearl CRB315R5 (registered trademark), so that the thickness of the ethylene-methyl acrylate copolymer film becomes 40 μm, (Methyl acrylate content; 15% by weight), and the film surface of the laminated support was adhered to the drug-containing base layer obtained in the same manner as in Example 7 by using a laminate obtained by lamination by extrusion lamination. I let it. Thus, a tape preparation having a drug-containing base layer having a thickness of 80 μm and containing 10% by weight of eperisone hydrochloride, 2% by weight of polyplasdone INF-10 and 5% by weight of cetyl lactate on the film surface of the laminated support Was prepared. Fine particles of polyplasdone INF-10 and microcrystals of eperisone hydrochloride were dispersed in the drug-containing base layer of this tape preparation.

Comparative Example 1 A 30 μm-thick polyester-ethylene / vinyl acetate copolymer laminated film (manufactured by Nippon Mattai Co., Ltd.) was used as a support.
In the same manner as in Example 1, but containing 10% by weight of eperisone hydrochloride,
A tape preparation having a μm drug-containing base layer on one side of the support was prepared.

Comparative Example 2 A 100 μm-thick polyurethane film (manufactured by Okura Industry Co., Ltd.) was used as a support, and in the same manner as in Example 1 except that the support contained 10% by weight of eperisone hydrochloride. A tape preparation having a drug-containing base layer having a thickness of 80 μm on one surface of a support was prepared.

Comparative Example 3 As a support, a polyester film having a thickness of 12 μm (manufactured by Toyobo Co., Ltd.) was used. A tape preparation having a drug-containing base layer having a thickness of 80 μm on one surface of a support was prepared.

Comparative Example 4 A 70 μm-thick ethylene-vinyl acetate copolymer film (manufactured by Tamapoli) was used as a support.
Otherwise in the same manner as in Example 4, a tape preparation containing a drug-containing base layer containing 10% by weight of eperisone hydrochloride and having a thickness of 80 μm on one side of a support was prepared.

Comparative Example 5 A 60 μm thick ethylene / methyl methacrylate copolymer film (manufactured by Okura Industries Co., Ltd.) was used as a support. A tape preparation having a drug-containing base layer having a thickness of 80 μm on one surface of a support and containing tolperisone hydrochloride was prepared.

Comparative Example 6 A 60 μm-thick ethylene-ethyl acrylate copolymer film (manufactured by Mitsui DuPont Polychemicals) was used as a support. A tape preparation having an 80 μm-thick drug-containing base layer containing 1% by weight of tolperisone hydrochloride on one surface of a support was prepared.

Evaluation Test Test 1 Each of the tape preparations obtained in Examples 1, 2, 3, 4, 5, 6, 7, 8 and Comparative Examples 1, 2, 3, 4, 5, 6 was 50 cm
² Cut to a size of (71 mm x 71 mm), the obtained test pieces were stuck on the backs of 10 healthy males for 24 hours each, and the ease of sticking, sticking property (peeling), feeling of use (feeling of foreign matter,
Each test piece was evaluated for a sense of tension. The evaluation criteria are as follows. Table 1 shows the number of testees.

Evaluation criteria for ease of sticking Easy to stick: ○ Neither can be said: △ Difficult to stick: × Evaluation criteria for peeling: Not peeling at all: ○ Peeling 10% portion: △ Peeling 20% or more: x , Evaluation criteria of the feeling of tension Not felt: ○ Felt a little: 感 じ る Feel strongly: ×

[Table 1] Test 2 Example 1, 2, 3, 4, 5, 6, 7, 8 and Comparative Example 1, 2, 3, 4, 5, 6 Tape 50 cm in size
² (71 mm × 71 mm) test pieces were each sealed in an aluminum bag and stored at a temperature of 45 ° for 6 months, after which the surface of the support was observed.

Table 2 shows the observation results.

[0086]

[Table 2] In Table 2, no crystal precipitation of the drug was observed on the surface of the support: ○ Crystal precipitation of the drug was observed on the surface of the support: ×

[0087]

The patch for external use of eperisone or tolperisone according to the present invention, which uses an ethylene-methyl acrylate copolymer film as a support, has a good sticking property and a good feeling in use. During storage, the drug in the base layer migrates in the support and precipitates on the surface on the opposite side of the base layer, so that there is no possibility that the merchantability is impaired.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 21/02 A61P 21/02 (72) Inventor Mitsuhiro Yoshida 900-10, Honjo City, Saitama Prefecture (72) Inventor Jun Nonaka Jun Saitama 1-15-4 Midori, Honjo-shi (56) References JP-A-4-217919 (JP, A) JP-A-59-193819 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB A61K 9/70 A61K 31/445 A61K 47/12 A61K 47/32 A61P 21/02

Claims (2)

(57) [Claims] 1. A patch having a drug-containing base layer containing eperisone, tolperisone, or a salt thereof on one surface of a support, wherein the support comprises an ethylene-methyl acrylate copolymer film. An external patch for eperisone or tolperisone. 2. The drug-containing base layer further contains crospovidone and lactate ester, and the adhesive base of the base layer contains 2-ethylhexyl acrylate in a ratio of 45 to 80 mol %, and 25-N-vinyl-2-pyrrolidone
The non-woven fabric is mainly composed of a copolymer containing 55 mol%, and a nonwoven fabric is laminated on a surface of the support opposite to the base layer-attached surface of the ethylene / methyl acrylate copolymer film. 3. The external patch according to item 1.