JPH08291069A - Eperiosone plaster for external use - Google Patents

Abstract

PURPOSE: To produce a plaster, containing eperisone and a basic substance in a base, capable of effectively percutaneously administering the eperisone or its salt and useful as an ameliorant for various symptoms such as spastic paralysis. CONSTITUTION: This plaster contains (A) eperisone or its salt and (B) a basic substance (e.g. sodium hydroxide) in a base. Furthermore, e.g. the amount of the ingredient (A) is 0.1-20wt.% and that of the ingredient (B) is 0.1-10wt.% and especially an amount ioniziably equal to the ingredient (A) in the base. When the plaster is formed into a tape pharmaceutical preparation, an acrylic tacky agent, etc., such as an alkyl (meth)acrylate polymer obtained from a 4-18C aliphatic alcohol and (meth)acrylic acid are preferably used as the base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an eperisone external patch.

[0002]

2. Description of the Related Art Eperisone or a salt thereof is an agent for improving various symptoms based on spastic paralysis, cervical-shoulder-arm syndrome, shoulder periarthritis,
It is used as an agent for improving muscle tone caused by diseases such as low back pain. Usually, eperisone or a salt thereof is orally administered. However, in general, when a drug is orally administered, a drug absorbed in the intestine is metabolized in the liver, so that a considerable amount of the drug is decomposed before reaching the affected area. Further, since the drug is absorbed in a short time, side effects are likely to occur.

In order to solve these problems, transdermal administration has been carried out in which a drug is absorbed through the skin using a transdermal absorption preparation. In the transdermal administration, the absorbed drug reaches the affected area without being decomposed in the liver, so that the gastrointestinal disorder as seen in the oral administration is unlikely to occur. In addition, by adjusting the drug release amount, it becomes possible to reduce side effects caused by a large amount of drug being absorbed in a short time. Furthermore, if a constant drug release rate can be maintained over a long period of time, the frequency of drug administration can be reduced.

However, since the stratum corneum on the skin surface has a barrier function for preventing the invasion of foreign substances into the body, even if transdermal administration of eperisone or a salt thereof is carried out as it is, an amount sufficient for exerting a medicinal effect is obtained. Since drugs are not absorbed through the skin, increasing transdermal absorbability has become an issue. For example, JP-A-2-255611 discloses a technique relating to a tape preparation containing a basic drug having a free base structure such as eperisone in a non-functional adhesive. However, this technique is insufficient in improving transdermal absorbability. Further, JP-A-6-40888 discloses a technique relating to a transdermal preparation containing a basic drug and a basic polymer substance. However, basic polymers are expensive and require careful handling.

[0005]

SUMMARY OF THE INVENTION In view of the above, an object of the present invention is to provide an eperisone external patch having good transdermal absorbability of eperisone or a salt thereof.

[0006]

The present invention resides in that the external patch for eperisone is composed of eperisone or a salt thereof, and a base containing a basic substance.

The content of eperisone or its salt used in the present invention in the base is preferably 0.05 to 30% by weight. If the amount is less than 0.05% by weight, the percutaneous absorption effect of the drug per unit area is insufficient, and a blood concentration sufficient to exert a drug effect in a practical administration area (150 cm ² or less) is obtained. If it exceeds 30% by weight,
The base material of the preparation is liable to be cracked and the sticking property is deteriorated. It is preferably 0.1 to 20% by weight.

The salt of eperisone is not particularly limited, and examples thereof include hydrochloride, phosphate, methanesulfonate and the like.

The basic substance used in the present invention is not particularly limited, and examples thereof include sodium hydroxide, potassium hydroxide, calcium hydroxide, monoethanolamine, triethanolamine, diisopropanolamine and triisopropanolamine. To be

Although the content of the above basic substance in the base depends on the content of eperisone or its salt,
Preferably it is 10% by weight. If it is less than 0.1% by weight, the effect of promoting percutaneous absorption is not sufficient, and if it exceeds 10% by weight, the physical properties of the base material may be significantly changed and skin irritation by the basic substance itself becomes a problem. . It is preferably ionically equivalent to eperisone or its salt in the base.

The external patch for eperisone of the present invention includes:
Examples thereof include tape preparations, patch preparations, poultice preparations, plaster preparations, and the like, but tape preparations and patch preparations are preferable from the viewpoint of ease of use.

As a base for the above-mentioned tape preparation and patch, one having an adhesive force capable of being fixed to the skin surface at room temperature for a long time is used. For example, an acrylic adhesive, a rubber adhesive, a silicone adhesive, etc. Is mentioned. Considering the adhesive physical properties and costs, acrylic adhesives and rubber adhesives are preferable.

As the above-mentioned acrylic pressure-sensitive adhesive, a polymer or copolymer of an alkyl (meth) acrylate obtained from an aliphatic alcohol having 4 to 18 carbon atoms and (meth) acrylic acid; the above (meth) acrylic A copolymer or the like of an acid alkyl ester and another functional monomer is used.

The (meth) acrylic acid alkyl ester is not particularly limited, and examples thereof include butyl acrylate,
Isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, isodecyl acrylate, lauryl acrylate, stearyl acrylate, butyl methacrylate, isobutyl methacrylate,
2-Ethylhexyl methacrylate, isooctyl methacrylate, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate, stearyl acrylate and the like can be mentioned.

The functional group monomer is not particularly limited, and examples thereof include a hydroxyl group-containing monomer, a carboxyl group-containing monomer, an amide group-containing monomer, and a pyrrolidone ring-containing monomer.

The monomer having a hydroxyl group is not particularly limited, and examples thereof include 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate. The monomer having a carboxyl group is not particularly limited, and examples thereof include α, β such as acrylic acid, methacrylic acid, maleic acid, fumaric acid and crotonic acid.
-Unsaturated carboxylic acid; maleic acid monoalkyl ester such as butyl maleate; and maleic anhydride.

The above-mentioned amide group-containing monomer is not particularly limited, and examples thereof include alkyl (meth) acrylamides such as acrylamide, dimethylacrylamide and diethylacrylamide; butoxymethylacrylamide,
Alkyl ether methylol (meth) acrylamides such as ethoxymethyl acrylamide; diacetone acrylamide and the like.

The monomer having a pyrrolidone ring is not particularly limited, and examples thereof include vinylpyrrolidone. Examples of monomers other than the above include vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene and butadiene.

The acrylic pressure-sensitive adhesive can be obtained by copolymerizing the above-mentioned monomers by a known method. The acrylic pressure-sensitive adhesive contains 50% by weight or more of the (meth) acrylic acid alkyl ester. It is preferable.

The rubber-based pressure-sensitive adhesive is not particularly limited, and examples thereof include natural rubber, synthetic isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polyisoprene, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer. , Styrene-isoprene-styrene block copolymers and the like. The silicone adhesive is not particularly limited, and examples thereof include silicone rubber such as polyorganosiloxane.

If desired, various compounding agents may be added to the above base. Such compounding agents include, for example, tackifiers such as rosin-based resins, polyterpene resins, chroman-indene resins, petroleum-based resins, terpene phenolic resins; liquid polybutene, mineral oil, lanolin, liquid isobutylene, liquid polyacrylates and the like. Plasticizer; Filler;
Antiaging agent etc. are mentioned.

When the external patch of eperisone of the present invention is a poultice, its base is not particularly limited, and examples thereof include natural polymers such as sodium alginate, gelatin, corn starch and tragacanth gum; methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and the like. And cellulose-based polymers such as dextrin and carboxymethyl starch; and synthetic polymers such as polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, and polyvinylpyrrolidone.

If necessary, purified water; a moisturizing agent composed of polyhydric alcohol such as glycerin or propylene glycol; an inorganic filler such as kaolin, pentonite, zinc white, or titanium dioxide; viscosity. A regulator, a cross-linking agent, an antiaging agent and the like may be added.

In order to further improve the percutaneous absorption of the drug, the external patch of eperisone of the present invention may be added with an appropriate absorption promoter, if necessary.

The absorption promoter is not particularly limited,
For example, sodium lauryl sulfate, lauryl ether,
Examples include lauromacrogol, lactate ester, lauroyl diethanolamide, lauroyl sarcosine, sodium lauroyl sarcosine, and the like. The amount of the absorption enhancer added is preferably 10% by weight or less based on the total weight of the drug-containing layer. When it exceeds 10% by weight, the skin irritation of the obtained preparation becomes large. It is preferably 0.1 to 10% by weight.

The external patch for eperisone is prepared by laminating a drug-containing layer containing eperisone or a salt thereof, a basic substance, a base, and, if necessary, an absorption promoter, on the surface of a support.

As the above-mentioned support, any support that is usually used for patches can be used. The material of the support is not particularly limited, and examples thereof include cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, Examples thereof include polyvinylidene chloride and aluminum. These materials may be used as a single layer sheet or a laminate of two or more sheets. Materials other than aluminum can be used as woven and non-woven fabrics.

The method for forming the drug-containing layer on the surface of the support is not particularly limited, and examples thereof include a solution coating method, a hot melt coating method, and an electron beam curing emulsion coating method. In the present invention, the solvent coating method can be preferably used. In the solvent coating method, the drug-containing layer is prepared by diluting the above-mentioned base with an appropriate solvent, adding a drug, and, if necessary, an absorption promoter and various compounding agents to a support. It is formed by coating the surface and drying to remove the solvent. After coating the dispersion on a release paper and drying,
It is also possible to transfer to a support.

The thickness of the drug-containing layer varies depending on the purpose of use, but is usually 30 to 2000 μm. 30 μm
When it is less than the above range, the desired amount of drug cannot be contained in the base material having a predetermined area of the patch. Further, in the case of tape preparations and patch preparations, sufficient tackiness cannot be obtained. 20
When it exceeds 00 μm, it becomes difficult for the drug contained in the drug-containing layer near the support to reach the skin surface.
The drug in the formulation is not used effectively. In the present invention, a release paper may be attached to the support until the time of use in order to protect the drug-containing layer. The eperisone external-use patch thus prepared is used by being applied to an affected area.

[0030]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 65 mol% of 2-ethylhexyl acrylate, 35 mol% of vinylpyrrolidone and 0.02% by weight of hexamethylene glycol dimethacrylate were charged in a separable flask so that the monomer concentration at the initial stage of polymerization was 85% by weight. Ethyl acetate was added. This solution is placed under a nitrogen atmosphere at 60 ° C.
After heating, the polymerization initiator lauroyl peroxide and ethyl acetate were sequentially added little by little, and polymerization was carried out for 32 hours. Ethyl acetate was added to the obtained polymer for dilution to obtain a base solution having a solid content concentration of 36% by weight. To 100 parts by weight of this base solution, 9.4 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) and 1.4 parts by weight of sodium hydroxide (manufactured by Wako Pure Chemical Industries) previously dissolved in ethanol were added, and the mixture was dissolved in a dissolver. After sufficiently stirring, it was coated on a polyester release paper having a thickness of 75 μm and dried at 60 ° C. for 20 minutes to form a drug-containing layer.

30 μm thick polyester-ethylene
The above drug-containing layer was transferred onto a vinyl acetate copolymer laminated film (manufactured by Nippon Matai Co., Ltd.) to give a thickness of 50 wt% eperisone hydrochloride and 3 wt% sodium hydroxide.
A tape preparation having a drug-containing layer of μm laminated was obtained.

Example 2 100 parts by weight of a base solution obtained in the same manner as in Example 1 was added with 11.6 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.).
5.8 parts by weight of propylene glycol (manufactured by Wako Pure Chemical Industries), 1.7 parts by weight of potassium hydroxide (manufactured by Wako Pure Chemical Industries) previously dissolved in ethanol, and 2.9 parts by weight of cetyl lactate (manufactured by Nippon Chemicals Co., Ltd.). Was added, and the mixture was sufficiently stirred in a dissolver, then coated on a polyester release paper having a thickness of 75 μm, and dried at 60 ° C. for 20 minutes to form a drug-containing layer. The above drug-containing layer was transferred onto a polyester-ethylene / vinyl acetate copolymer laminated film (manufactured by Nippon Matai Co., Ltd.) having a thickness of 30 μm to obtain 20% by weight of eperisone hydrochloride, 10% by weight of propylene glycol, and 5% by weight of Thickness 5 containing cetyl lactate and 3% by weight potassium hydroxide
A tape preparation having a drug-containing layer of 0 μm laminated was obtained.

Example 3 To 100 parts by weight of a base solution obtained in the same manner as in Example 1, 4.1 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) and 0.8 parts of triethanolamine (manufactured by Wako Pure Chemical Industries, Ltd.) were added. After adding 1 part by weight and thoroughly stirring in a dissolver, a thickness of 7
It was applied on a 5 μm polyester release paper and dried at 60 ° C. for 20 minutes to form a drug-containing layer. Thickness 30
The above drug-containing layer was transferred to a polyester-ethylene / vinyl acetate copolymer laminated film (made by Nippon Matai Co., Ltd.) having a thickness of 50 μm containing 10% by weight of eperisone hydrochloride and 2% by weight of triethanolamine. A tape preparation in which the drug-containing layer of was laminated was obtained.

Example 4 80 mol% of 2-ethylhexyl methacrylate, 10 mol% of 2-ethylhexyl acrylate, 10 mol% of dodecyl methacrylate and 0.02% by weight of hexamethylene glycol dimethacrylate were charged in a separable flask to start the polymerization. Ethyl acetate was added so that the monomer concentration of was about 85% by weight. This solution was heated to 60 ° C. under a nitrogen atmosphere, lauroyl peroxide and ethyl acetate as polymerization initiators were successively added little by little, and polymerization was carried out for 24 hours. Ethyl acetate was added to the obtained polymer to dilute it to obtain a base solution having a solid content concentration of 45% by weight. To 100 parts by weight of the obtained base solution, 5.8 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.),
5.8 parts by weight of propylene glycol (manufactured by Wako Pure Chemical Industries) and 1.8 parts by weight of sodium hydroxide (manufactured by Wako Pure Chemical Industries) previously dissolved in ethanol were added, and in a dissolver,
After sufficiently stirring, it was applied onto a 75 μm-thick polyester release paper and dried at 60 ° C. for 20 minutes to form a drug-containing layer.

Polyester-ethylene having a thickness of 30 μm
A thickness containing 10% by weight of eperisone hydrochloride, 10% by weight of propylene glycol and 3% by weight of sodium hydroxide by transferring the above drug-containing layer to a vinyl acetate copolymer laminated film (manufactured by Nippon Matai Co., Ltd.) A tape preparation having a drug-containing layer of 50 μm laminated was obtained.

Comparative Example 1 9 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) was added to 100 parts by weight of the base solution obtained in the same manner as in Example 1, and the mixture was thoroughly stirred in a dissolver to give a thickness. 75μ
m polyester release paper and apply at 60 ℃ for 20
It was dried for a minute to form a drug-containing layer. Thickness 30 μm
The polyester-ethylene / vinyl acetate copolymer laminated film (made by Nippon Matai Co., Ltd.) was used to transfer the above-mentioned drug-containing layer, and a thickness of 50 μm containing 20% by weight of eperisone hydrochloride.
A tape preparation in which m drug-containing layers were laminated was obtained.

Comparative Example 2 11.1 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) was added to 100 parts by weight of the base solution obtained in the same manner as in Example 1.
5.5 parts by weight of propylene glycol (manufactured by Wako Pure Chemical Industries, Ltd.) and 2.8 parts by weight of cetyl lactate (manufactured by Nippon Chemicals Co., Ltd.) previously dissolved in ethanol were added, and in a dissolver,
After sufficiently stirring, it was applied onto a 75 μm-thick polyester release paper and dried at 60 ° C. for 20 minutes to form a drug-containing layer. The above drug-containing layer was transferred onto a polyester-ethylene / vinyl acetate copolymer laminated film (manufactured by Nippon Matai Co., Ltd.) having a thickness of 30 μm to obtain 20% by weight of eperisone hydrochloride, 10% by weight of propylene glycol, and 5% by weight of A 50 μm-thick drug-containing layer containing cetyl lactate was laminated to obtain a tape preparation.

Comparative Example 3 4 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) was added to 100 parts by weight of the base solution obtained in the same manner as in Example 1, and the mixture was thoroughly stirred in a dissolver and then the thickness was increased. 75μ
m polyester release paper and apply at 60 ℃ for 20
It was dried for a minute to form a drug-containing layer. Thickness 30 μm
The above-mentioned drug-containing layer was transferred to a polyester-ethylene / vinyl acetate copolymer laminated film (made by Nippon Matai Co., Ltd.), and a thickness of 50 μm containing 10% by weight of eperisone hydrochloride.
A tape preparation in which m drug-containing layers were laminated was obtained.

Comparative Example 4 100 parts by weight of the base solution obtained in the same manner as in Example 4 was added to 11.3 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.).
11.3 parts by weight of propylene glycol (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and after sufficiently stirring in a dissolver, coated on a polyester release paper having a thickness of 75 μm, and at 60 ° C.
And dried for 20 minutes to form a drug-containing layer. Thickness 3
The above drug-containing layer was transferred to a 0 μm polyester-ethylene / vinyl acetate copolymer laminated film (manufactured by Nippon Matai Co., Ltd.) to contain 10% by weight of eperisone hydrochloride, 10% by weight of propylene glycol and having a thickness of 50 μm. A tape preparation in which a drug-containing layer was laminated was obtained.

Comparative Example 5 Preparation was carried out in the same manner as in Example 1 except that fumaric acid was added instead of sodium hydroxide, containing 20% by weight of eperisone hydrochloride and 3% by weight of fumaric acid and containing a drug having a thickness of 50 μm. A layered tape formulation was obtained.

Comparative Example 6 20% by weight of eperisone hydrochloride was prepared in the same manner as in Example 2 except that citric acid was added instead of potassium hydroxide.
A tape preparation was obtained in which a drug-containing layer having a thickness of 50 μm and containing 10% by weight of propylene glycol, 5% by weight of cetyl lactate and 3% by weight of citric acid was laminated.

The tape preparations of Examples 1 to 4 and Comparative Examples 1 to 6 were subjected to a hairless mouse skin permeation test. Fr
The skin removed from the back of a hairless mouse was fixed to a diffusion cell of anz, and a 3.14 cm ² sample was attached to the upper side of the skin. Twenty-four hours after application, the receptor fluid under the skin was sampled and the amount of eperisone was measured by HPLC.
The diffusion cell is kept at a constant temperature of 37 ° C, and the pH of the receptor solution is
A phosphate buffer adjusted to 7.2 was used. Table 1 shows the above results.

[0044]

[Table 1]

[0045]

Since the external patch of eperisone of the present invention has the above-mentioned constitution, eperisone or its salt can be effectively transdermally administered.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 47/02 A61K 47/02 E 47/18 47/18 E

Claims (2)

[Claims] 1. An external patch for eperisone, which comprises eperisone or a salt thereof and a basic substance in a base. 2. The external patch for eperisone according to claim 1, wherein the basic substance is dissolved in a base.