JPH06211696A - Percutaneous absorption pharmaceutical preparation of eperisone or tolperisone - Google Patents

Abstract

PURPOSE:To obtain a percutaneous absorption pharmaceutical preparation of eperisone or tolperisone, capable of effectively suppressing hydrolysis of eperisone, tolperisone or salts thereof with water and excellent in preservation stability. CONSTITUTION:This eperisone of tolperisone percutaneous absorption pharmaceutical preparation is characterized by including a dicarboxylic acid or a tricarboxylic acid having pKa of >=3.5 in a base containing eperisone, tolperisone or its salt or regulating the moisture content in the base containing the eperisone, tolperisone or salts thereof and crosspovidone to <=0.2wt.%.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a percutaneous absorption preparation for transdermal administration of eperisone, tolperisone, or a salt thereof, and more particularly to a percutaneous absorption preparation excellent in storage stability of a drug. .

[0002]

2. Description of the Related Art Eperisone, tolperisone, or a salt thereof is an agent for improving various symptoms caused by spastic paralysis, or
It is used as an agent for improving muscle tone caused by diseases such as cervical-shoulder-arm syndrome, periarthritis of the shoulder, and low back pain.

Usually, eperisone, tolperisone, or their salts are orally administered. However, in general, when a drug is orally administered, the drug absorbed in the intestine is metabolized in the liver, so that a considerable amount of the drug is decomposed in the liver before the drug is effective in the affected area. Furthermore, since the drug is absorbed in a short time, side effects are likely to occur.

On the other hand, a transdermal preparation is used to absorb a drug into the circulatory system through the skin. Generally, the transdermal administration method has the following advantages.
That is, in transdermal administration, the absorbed drug reaches the affected area without being decomposed by metabolism in the liver. In addition, transdermal administration is unlikely to cause gastrointestinal disorders as seen in oral administration. Furthermore, by adjusting the amount of drug released by transdermal administration, it is possible to reduce side effects due to, for example, a large amount of drug being absorbed in a short time.
In addition, transdermal administration can maintain a constant drug release rate over a long period of time, and the number of drug administrations can be reduced.

It is known that eperisone, tolperisone, or salts thereof are percutaneously absorbed drugs. A transdermal preparation containing this drug is disclosed in JP-A-64
No. 52,716, a fatty acid monoglyceride having 8 to 12 carbon atoms and /
Alternatively, a percutaneous absorption preparation in which the lactate ester of a fatty acid alcohol having 12 to 18 carbon atoms is contained to remarkably improve the percutaneous absorption of the drug is described. Also,
JP-A-3-199363 describes a transdermal preparation capable of effectively percutaneously absorbing the drug by including a water-swellable crosslinked polyvinylpyrrolidone (crospovidone) in a base. .

[0006]

Eperisone, tolperisone, or a salt thereof is a substance that is easily hydrolyzed by water in a percutaneous absorption preparation. Therefore, JP-A-6
In the percutaneously absorbable preparation of No. 4-52716, the drug is decomposed under severe storage conditions, which may impair the quality of the preparation.

Further, the transdermal preparation of JP-A-3-199363 has good transdermal absorbability of a drug because it contains crospovidone, but on the other hand, it tends to retain water and is obtained by a usual production method. The ones have a high water content. As a result, the drug may be hydrolyzed by water during storage of the preparation, which may impair the quality of the preparation.

The present invention has been made in view of the above points, and an object of the present invention is to prevent eperisone, tolperisone, or salts thereof from being hydrolyzed by water and to have excellent storage stability. To provide a percutaneous absorption preparation.

[0009]

The percutaneous absorption preparation according to the present invention has been devised to achieve the above object. The first one is eperisone, tolperisone, or a group containing a salt thereof. A percutaneous absorption preparation of eperisone or tolperisone, characterized in that a dicarboxylic acid or tricarboxylic acid having a pKa of 3.5 or less is contained in the agent.

The second percutaneous absorption preparation according to the present invention has a water content of 0.2 in a base containing eperisone, tolperisone, or a salt thereof and crospovidone.
It is an eperisone or tolperisone percutaneous absorption preparation characterized by being made up to a weight% or less.

The percutaneous absorption preparation according to the present invention may optionally contain a percutaneous absorption enhancer.

As a base for the percutaneous absorption preparation according to the present invention, an adhesive base is used in the case of tapes and poultices,
In the case of ointments, creams and patches, non-stick base is used.

The contents of eperisone, tolperisone, or salts thereof, dicarboxylic acid or tricarboxylic acid, crospovidone, and transdermal absorption promoter contained in the base are
For ointments and creams, the content corresponds to the content of the preparation itself. For patches such as tapes and poultices, the part excluding the support and release paper from the preparation, that is, the drug-containing adhesive layer (paste layer) part And the patch agent corresponds to the content with respect to the base contained in the reservoir layer. This point is common throughout the specification.

Hereinafter, each component of the percutaneous absorption preparation according to the present invention and the production method will be described in detail.

A) The drug used in the percutaneous absorption preparation of the present invention is eperisone, tolperisone, or a salt thereof. These are applied as agents for improving various symptoms based on spastic paralysis or agents for improving muscle tone caused by diseases such as cervical-shoulder-arm syndrome, periarthritis of the shoulders, and low back pain.

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

Eperisone, tolperisone, or a salt thereof is dissolved in a base material described below, or is mixed in the base material at a ratio of saturated solubility or more and dispersed in the base material 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. If the content of eperisone, tolperisone, or a salt thereof is less than 0.05% by weight, the percutaneous absorption effect of the drug per unit area of administration is insufficient, and the practical administration area of percutaneous absorption preparation ( In some cases, it may not be possible to obtain a blood concentration sufficient to exert a drug effect at 150 cm ² or less). On the other hand, if the content exceeds 30% by weight, cracking of the base of the preparation is likely to occur, and for example, in the case of patches, the sticking property may deteriorate.

B) The percutaneous absorption preparation of the present invention may contain an appropriate absorption enhancer, if necessary, for the purpose of improving the transdermal permeability of the drug. As the absorption enhancer, isopropyl myristate, diethyl sebacate, sorbitan monolaurate, glycerin monooleate, sodium oleyl phosphate, sodium lauryl sulfate, octylphenyl ether, polyethylene glycol-added octylphenyl ether, lauryl ether, polyethylene glycol-added lauryl ether. , Sorbitan monooleate, polyethylene glycol-added sorbitan monooleate, lauroyl diethanolamide, lauroyl sarcosine, oleoyl sarcosine sugar ester, lecithin, glycyrrhetin, urea, salicylic acid, calcium thioglycolate, lactic acid, lactate ester, olive oil,
Squalene, lanolin, liquid paraffin, glycerin, etc. are used.

Particularly preferred absorption promoters have 12 to 12 carbon atoms.
It is an ester of 18 fatty alcohols and lactic acid. Examples of such lactic acid ester include myristyl lactate, lauryl lactate, cetyl lactate and the like.

The content of the absorption promoter is 10% by weight or less, preferably 0.1 to 10% by weight. When the content of the absorption enhancer exceeds 10% by weight, the resulting preparation has a high skin irritation, and when administered to the skin, redness and itching occur.

C) In the first transdermal preparation according to the present invention, a dicarboxylic acid or tricarboxylic acid having a pKa of 3.5 or less in an aqueous solution at a temperature of 25 ° C. is contained in the base. Examples of such dicarboxylic acid or tricarboxylic acid include fumaric acid (PKa3.03), maleic acid (PKa3.4), citric acid (PKa3.13), and the like, and fumaric acid is particularly preferably used. PK
The content of the dicarboxylic acid or tricarboxylic acid having a of 3.5 or less is preferably 0.3 to 15% by weight, particularly preferably 1 to 6% by weight. If the content is too small, the stabilizing effect of the drug is not sufficient, and if the content is too large, the shapeability of the base material becomes problematic.

D) In the second percutaneous absorption preparation according to the present invention, crospovidone contained in the base is
As described in Pharmacopeia NF XVII (official compendial), it is a cross-linked homopolymer of N-vinyl-2-pyrrolidone, containing nitrogen atoms in the range of 11.0 to 12.8% by weight (anhydrous state). It is a substance containing.

Suitable examples of commercially available crospovidone are Kollidon CL (registered trademark) manufactured by BASF,
Kollidon CL-M (registered trademark), Polyplusdon XL (registered trademark) manufactured by GAF, Polyplusdon INF-10
(Registered trademark). Methods for producing these compounds are described in US Pat. Nos. 3,759,880 and 3,933,766.
Nos. 3689439, 4139688 and 4
180633.

Crospovidone exhibits a moderate swelling property in water. Therefore, when a formulation containing crospovidone is administered to the skin, it absorbs water such as sweat,
Swells and improves drug release. The content of crospovidone is preferably in the range of 0.5 to 20% by weight. If the content of crospovidone is less than 0.5% by weight, a sufficient accelerating effect on drug release cannot be obtained. When the content of crospovidone exceeds 20% by weight, when the preparation of the present invention is a tape preparation or the like, the tackiness of the preparation decreases.

E) In the second percutaneous absorption preparation according to the present invention, in order to enhance drug stability, the water content in the base is suppressed to 0.2% by weight or less. For example, in the tape preparation among the preparations of the present invention, the water content in the base is usually 0.3 to 0.7%.
The amount of the decomposed product of the drug when stored for a day reaches about 0.9% in the case of a large amount. On the other hand, in a transdermal preparation with a water content of 0.2% or less in the base, the amount of the decomposed substance of the drug is about 0.4% even under the same conditions as described above, It is less than about half.

In order to adjust the water content in the transdermal preparation of the present invention to 0.2% by weight or less, the following method can be adopted.

A base containing eperisone, tolperisone, or a salt thereof and crospovidone is prepared by an ordinary method, and the obtained transdermal preparation is placed in an aluminum bag together with a known desiccant such as silica gel, alumina, or a phosphorus compound. How to store it in a moisture-proof bag or box.

A base containing eperisone, tolperisone, or a salt thereof and crospovidone is prepared by an ordinary method, and the obtained transdermal absorption preparation is sealed with a known desiccant such as silica gel, alumina, or a phosphorus compound. A method of dehumidifying inside and then storing the dehumidified percutaneous absorption preparation in a moisture-proof bag or box such as an aluminum bag for storage.

First, a base containing eperisone, tolperisone, or a salt thereof and crospovidone is prepared by a usual method, and this is used as it is or after being processed, in a dehumidified environment and at a normal pressure of 40 to 60 ° C. A method of packaging a moisture-reduced percutaneous absorption preparation in a moisture-proof packaging material such as an aluminum bag after setting the moisture content to 0.2% by weight or less under mild heating or under reduced pressure at room temperature.

When the transdermal preparation of the present invention is a patch, in the step of forming an adhesive layer containing eperisone, tolperisone, or a salt thereof and crospovidone on one surface of a support, Moisture content is 0.2
The pressure-sensitive adhesive layer was dried at a sufficient temperature and for a time of not more than 10% by weight, and was quickly formulated to avoid moisture absorption and packaged in a moisture-proof packaging material such as an aluminum bag or dehumidified. A method of packaging in a moisture-proof packaging material such as an aluminum bag under the environment.

According to the methods (1) and (2), even if the moisture content is adjusted to 0.2% by weight or less at the time of preparation of the preparation, moisture absorption is likely to occur in the subsequent processing or packaging process, which may cause variations in quality. Therefore, it is desirable to take measures to deal with these points.

F) The dosage forms of the transdermal preparation according to the present invention include tapes, patches, poultices, creams,
There are ointments and the like.

The tape preparation contains the adhesive base layer containing the drug and dicarboxylic acid or tricarboxylic acid in the first transdermal preparation, and the drug and crospovidone in the second transdermal preparation. An adhesive base layer is provided on one side of the support.

The patch is composed of a non-adhesive reservoir layer and an adhesive layer which are sequentially laminated on one side of a support, and the reservoir layer is composed of a drug and a dicarboxylic acid in the first transdermal preparation. Alternatively, the tricarboxylic acid, and in the second transdermal preparation, the drug and crospovidone are held on a non-adhesive base. This reservoir layer is attached to the skin via the adhesive layer, and the drug in the reservoir layer is transdermally absorbed through the adhesive layer. However, the drug, crospovidone, dicarboxylic acid or tricarboxylic acid in the reservoir layer may be contained in the adhesive layer.

The poultice is a paste-like base containing the drug and dicarboxylic acid or tricarboxylic acid in the first transdermal preparation, and the drug and crospovidone in the second transdermal preparation. It is applied in layers on the surface. Since patches are less sticky than tapes and patches, they are fixed to the skin surface with a bandage.

The creams and ointments have a non-adhesive base containing the drug and dicarboxylic acid or tricarboxylic acid in the first transdermal preparation and the drug and crospovidone in the second transdermal preparation. It is a drug-containing paste or slurry that is uniformly mixed.

G) A detailed description will be given of the structure of the patch such as tape and poultice.

G-1) The adhesive base of the tape or the adhesive of the adhesive layer of the patch is excellent in compatibility with the above-mentioned drug, and is capable of fixing the preparation on the skin surface at room temperature for a long time. There is no particular limitation as long as it has strength. Examples of preferable adhesives include acrylic adhesives, rubber adhesives, silicone adhesives and the like.

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

Examples of the (meth) acrylic acid ester include butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, and acrylic acid-2-
Ethylhexyl, isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate,
Stearyl acrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate, stearyl methacrylate and the like are exemplified. It

Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group,
Examples thereof include monomers having an amide group, monomers having an amino group, and monomers having a pyrrolidone ring.
Examples of the monomer having a hydroxyl group include 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth).
Examples thereof include hydroxyalkyl (meth) acrylates such as acrylates. Examples of the monomer having a carboxyl group include α, β such as acrylic acid and methacrylic acid.
-Unsaturated carboxylic acid: maleic acid monoalkyl ester such as butyl maleate: maleic acid: fumaric acid: crotonic acid. Maleic anhydride also gives the same (co) polymerization components as maleic acid. Examples of the amide group-containing monomer include acrylamide, dimethyl acrylamide, and diethyl acrylamide (alkyl (meth))
Acrylamide: N-butoxymethyl acrylamide,
Examples include N-alkoxymethyl (meth) acrylamides such as N-ethoxymethylacrylamide, diacetone acrylamide, and the like. 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 the above, vinyl acetate, vinyl alcohol, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene and the like can be used.

In order to produce a copolymer of (meth) acrylic acid alkyl ester, it is preferable that the total amount of the copolymerized monomer components contains (meth) acrylic acid alkyl ester in an amount of 50% by weight or more.

If necessary, a polyfunctional monomer is added to the monomer component for producing the acrylic pressure-sensitive adhesive,
Copolymerized with the above monomer components. The addition of this polyfunctional monomer causes only slight cross-linking between the resulting polymers, which increases the internal cohesive strength of the adhesive. Therefore, the so-called adhesive residue phenomenon at the time of peeling off the patch can be almost eliminated irrespective of the property of the applied skin and the amount of perspiration. Moreover, the addition of this polyfunctional monomer does not have any adverse effect on 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 combining with (meth) acrylic acid
Acrylate; tri (meth) acrylates such as trimethylolpropane tri (meth) acrylate and glycerin tri (meth) acrylate; and tetra (meth) acrylates such as pentaerythritol tetra (meth) acrylate
Acrylate is exemplified. You may use these polyfunctional monomers in combination of 2 or more types. The polyfunctional monomer is used in the production of the pressure-sensitive adhesive in an amount of 0.005 to 0.5 based on 100 parts by weight of all monomers other than the polyfunctional monomer.
Used in parts by weight. If the amount of the polyfunctional monomer used is less than 0.005 parts by weight, the effect of improving the internal cohesive force due to crosslinking is small, and if it exceeds 0.5 parts by weight, the pressure-sensitive adhesive obtained by polymerization easily causes gelation. It also affects 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 kind of the monomer.

As the rubber-based adhesive, natural rubber, synthetic isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polyisoprene, polybutadiene,
100 parts by weight of rubber elastic body such as styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-styrene block copolymer, for example, rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin, 20 to 200 parts by weight of a tackifier such as a terpene-phenol resin, and if necessary,
A softening agent such as liquid polybutene, mineral oil, lanolin, liquid polyisoprene, and liquid polyacrylate: a filler such as titanium oxide: an antioxidant such as butylhydroxytoluene is used in an appropriate amount.

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

Compounding agents such as a plasticizer, a filler, and an anti-aging agent are added to each of the above pressure-sensitive adhesives, if necessary.

G-2) As a support for tapes and patches, it is flexible, but imparts self-supporting property to the transdermal preparation,
Moreover, a substance that plays a role of preventing volatilization and migration of the drug in the adhesive base layer or the reservoir layer is used. As the material of the support, cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride, Examples include polypropylene, ethylene vinyl alcohol, ethylene / methyl methacrylate copolymer, ethylene / ethyl acrylate copolymer, and aluminum. These materials are used, for example, as a single layer sheet or film or a laminate of two or more sheets. Materials other than aluminum may be used as woven or non-woven fabrics. As the support, one made of a material having an appropriate conformability to the skin surface is preferably used, and a laminate film of polyethylene terephthalate and ethylene-vinyl acetate copolymer is particularly preferable. The thickness of the support is 500 μm or less, preferably 5 to 150 μm.

An adhesive base layer is formed on the surface of the support to form a tape preparation. Also, a reservoir layer and an adhesive layer are sequentially laminated on one surface of the support to form a patch. In the patch agent, a suitable drug release controlling film may be present between the reservoir layer and the adhesive layer.

G-3) In the preparation of the tape agent, the usual method for producing an adhesive tape can be applied to form the adhesive base layer. A typical example thereof is a solvent coating method, and in addition to this, a hot melt coating method, an electron beam curing emulsion coating method and the like are used. To form the adhesive base layer by a solvent coating method, for example, in the first percutaneous absorption preparation, a drug and a dicarboxylic acid or tricarboxylic acid and a compounding agent such as an absorption enhancer which is optionally added, In the second percutaneous absorption preparation, the drug, crospovidone, and a compounding agent such as an absorption promoter, which is added as necessary, are dissolved or dispersed in an appropriate solvent, and the obtained solution or dispersion is used as the surface of the support. Is directly applied to and dried on to form an adhesive base layer having a required thickness.
The base layer is brought into close contact with a protective release paper to obtain the target tape preparation. Further, this solution or dispersion may be coated on a protective release paper, and the adhesive base layer obtained after drying may be brought into close contact with the support. The thickness of the adhesive base layer varies depending on the purpose of use, but is usually in the range of 30 to 200 μm. If this thickness is less than 30 μm, a desired amount of drug cannot be contained in the base material having a predetermined area of the tape preparation, and sufficient adhesiveness cannot be obtained. When the thickness exceeds 200 μm, it becomes difficult for the drug contained in the drug-containing base layer near the support to diffuse and reach the skin surface,
The drug in the base is not used effectively.

The adhesive patch thus obtained has a suitable O content.
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%).

G-4) 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 protection of the adhesive layer. As the release paper, a polyethylene terephthalate film treated with silicon 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
Is.

G-5) As the non-adhesive base material forming the reservoir layer of the patch, a conventionally known base material for external use can be used. For example, white petrolatum, silicone oil, carboxyvinyl polymer, polyvinyl alcohol, polyethylene glycol, liquid paraffin. Are exemplified.

H) As a poultice, in the first percutaneous absorption preparation, the drug, a dicarboxylic acid or a tricarboxylic acid, and a compounding agent such as an absorption promoter, which is optionally added, are used.
In the percutaneous absorption preparation (1), a paste-like base containing a drug, crospovidone, and a compounding agent such as an absorption promoter, which is optionally added, is applied in layers on the surface of a support.

As the support for the poultice, those described above for the tape or poultice are used. Since patches are generally less sticky than tapes and patches, they are fixed to the skin surface with a bandage or the like. As a base for poultices, alkali metal alginate, gelatin,
Natural polymers such as corn starch and tragacanth gum; methyl cellulose, hydroxyethyl cellulose,
Cellulose-based polymers such as carboxymethyl cellulose; starch-based polymers such as dextrin and carboxymethyl starch; synthetic polymers such as polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether and polyvinylpyrrolidone It is illustrated.

To produce a poultice, the first percutaneous absorption preparation contains the drug, a dicarboxylic acid or tricarboxylic acid, and a compounding agent such as an absorption promoter, which is optionally added, and the second percutaneous absorption preparation. In the preparation, the drug, crospovidone, and a compounding agent such as an absorption promoter, which is added as necessary, are uniformly mixed, and the obtained drug-containing paste is applied as a layer on one surface of the support. The drug-containing paste may further contain purified water, a moisturizer, an inorganic filler, a viscosity modifier, a cross-linking agent, an antioxidant, etc., as appropriate. Glycerin, propylene glycol, etc. are used as the moisturizer, and kaolin, bentonite, zinc white, titanium dioxide, etc. are used as the inorganic filler.

I) Creams and ointments include a non-adhesive base, a drug and a dicarboxylic acid or tricarboxylic acid in the first percutaneous absorption preparation, and a compounding agent such as an absorption enhancer which is optionally added. The second percutaneous absorption preparation is a drug-containing paste or slurry prepared by uniformly mixing a drug, crospovidone, and a compounding agent such as an absorption promoter that is added as necessary.

The bases for creams and ointments include
Beeswax, oil, lanolin, white petrolatum, paraffin,
Hydrocarbon gel (for example, registered trademark "Plastibase", manufactured by Taisho Pharmaceutical Co., Ltd.), higher fatty acid, higher alcohol, emulsifier, macrogol, carboxyvinyl polymer and the like are used.

The cream and ointment may contain a fat-soluble dissolving agent, purified water, a water-soluble dissolving agent, a pH adjusting agent and the like. As fat-soluble dissolving agents, crotamiton,
Liquid paraffin, isopropyl myristate, diethyl sebacate and the like are used, and as the water-soluble solubilizer, ethanol and polyhydric alcohols such as glycerin and propylene glycol are used.

J) The transdermal preparations of various dosage forms thus obtained are usually applied or applied directly to the skin surface for the purpose of transdermally administering the drug to the internal circulation system.

[0064]

EXAMPLES Next, in order to specifically describe the present invention,
Examples showing one example of the present invention and some comparative examples showing comparison therewith are given, and the evaluation test results of the obtained transdermal absorption preparations are shown. In addition, Examples 1 to 4 correspond to the first percutaneous absorption preparation according to the present invention, and Examples 5 to 9 correspond to the second percutaneous absorption preparation.

Example 1 1) Preparation of adhesive base 75.5% by weight of 2-ethylhexyl acrylate and N
-Vinyl-2-pyrrolidone (24.5% by weight) and hexamethylene glycol dimethacrylate (0.04 parts by weight per 100 parts by weight of the former two) were charged into a separable flask, and the monomer concentration at the initial stage of polymerization was 85% by weight. Ethyl acetate was added so that This solution is placed under a nitrogen atmosphere at 60
The mixture was heated to 0 ° C., lauroyl peroxide as a polymerization initiator and ethyl acetate were successively 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 concentration of 34% by weight.

2) Preparation of a coating liquid containing a patch formulation. To 100 parts by weight of the obtained base solution, 4 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) and 2 parts by weight of fumaric acid were added. Was thoroughly stirred in a dissolver to prepare a coating liquid in which fine crystals of eperisone hydrochloride and fumaric acid were uniformly dispersed in the solution.

3) Preparation of percutaneous absorption preparation The coating solution of step 2) was applied on a release paper made of polyethylene terephthalate film having a thickness of 38 μm, and the temperature was 60 ° C.
30 minutes in a gear oven to form a drug-containing adhesive base layer.

Then, polyethylene terephthalate, which is a support of polyethylene terephthalate and an ethylene-vinyl acetate copolymer laminated film and has a thickness of 30 μm, was adhered to the base layer.

Thus, a tape preparation having a drug-containing base layer having a thickness of 50 μm and containing 10% by weight of eperisone hydrochloride and 5% by weight of fumaric acid on one side of the support was prepared.

Example 2 1) Preparation of adhesive base 2-ethylhexyl methacrylate 78.3% by weight, 2-ethylhexyl acrylate 9.1% by weight, dodecyl methacrylate 12.6% by weight, and the above three Hexamethylene glycol dimethacrylate (0.04 parts by weight) was added to a separable flask with respect to 100 parts by weight of the total amount of ethyl acetate, and ethyl acetate was added so that the monomer concentration at the initial stage of polymerization was 85% by weight. This solution was heated to 60 ° C. under a nitrogen atmosphere, lauroyl peroxide as a polymerization initiator and ethyl acetate were successively added little by little, and a polymerization reaction was carried out for 24 hours.
Ethyl acetate was added to the obtained polymer to dilute the reaction solution,
A base solution having a solid content concentration of 59.5% by weight was obtained.

2) Preparation of a coating liquid containing a patch formulation A mixture of 7 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) and 3.5 parts by weight of citric acid was added to 100 parts by weight of the obtained base solution. These were thoroughly stirred in a dissolver to prepare a coating solution in which fine crystals of eperisone hydrochloride and citric acid were uniformly dispersed in the solution.

3) Preparation of percutaneous absorption preparation Using the coating liquid of step 2), 10% by weight of eperisone hydrochloride and 5% by weight of citric acid were prepared by the same procedure as in step 3) of Example 1. A tape preparation containing a drug-containing base layer having a thickness of 50 μm on one side of a support was prepared.

Example 3 1) Preparation of adhesive base 100 parts by weight of styrene-isoprene-styrene block copolymer (QTC3420 manufactured by Nippon Zeon Co., Ltd.), 33 parts by weight of polybutene (HV-300F manufactured by Nippon Petrochemical Co., Ltd.), 283 parts by weight of alicyclic saturated hydrocarbon resin (Arakawa Chemical Co., Alcon P-90), 250 parts by weight of liquid paraffin and 4 parts by weight of butylhydroxytoluene were added and mixed to cyclohexane to give a solid content concentration of 61% by weight. A base solution was obtained.

2) Preparation of a formulation-containing liquid for patching To 100 parts by weight of the obtained base solution, 7 parts by weight of eperisone hydrochloride and 2.0 parts by weight of maleic acid were added, and these were sufficiently stirred in a dissolver, A coating liquid was prepared in which fine crystals of eperisone hydrochloride and fine particles of maleic acid were uniformly dispersed in the solution.

3) Preparation of percutaneously absorbable preparation By the same procedure as in step 3) of Example 1 using the coating solution of step 2), 10% by weight of eperisone hydrochloride and 2.8 were used.
A tape preparation having a 50 μm thick drug-containing base layer containing 6% by weight of maleic acid on one side of a support was prepared.

Example 4 The same operation as in Example 1 was carried out except that 4 parts by weight of tolperisone hydrochloride (manufactured by Sigma) was added in place of eperisone hydrochloride in step 2) of Example 1 to obtain 10% by weight. A tape preparation having a 50 μm thick drug-containing base layer containing tolperisone hydrochloride and 5% by weight of fumaric acid on one side of a support was prepared.

Comparative Example 1 The same procedure as in Example 1 was carried out except that fumaric acid was not added in step 2) of Example 1, and the drug-containing group having a thickness of 50 μm and containing 10% by weight of eperisone hydrochloride. A tape preparation having an agent layer on one side of a support was prepared.

Comparative Example 2 The same operation as in Example 1 was carried out except that citric acid was not added in step 2) of Example 2, and the drug-containing group having a thickness of 50 μm and containing 10% by weight of eperisone hydrochloride. A tape preparation having an agent layer on one side of a support was prepared.

Comparative Example 3 The same procedure as in Example 1 was carried out except that maleic acid was not added in step 2) of Example 3, and a drug-containing group having a thickness of 50 μm and containing 10% by weight of eperisone hydrochloride. A tape preparation having an agent layer on one side of a support was prepared.

Comparative Example 4 The same operation as in Example 1 was performed except that 2 parts by weight of succinic acid was added instead of fumaric acid in step 2) of Example 1, and 10% by weight of eperisone hydrochloride and 5% by weight were used. % Of fumaric acid, and a tape preparation having a 50 μm thick drug-containing base layer on one side of the support was prepared.

Comparative Example 5 The same procedure as in Example 4 was carried out except that fumaric acid was not added in step 2) of Example 4, and the drug-containing group having a thickness of 50 μm and containing 10% by weight tolperisone hydrochloride. A tape preparation having an agent layer on one side of a support was prepared.

Example 5 1) Preparation of adhesive base 75.5% by weight of 2-ethylhexyl acrylate and N
-Vinyl-2-pyrrolidone (24.5% by weight) and hexamethylene glycol dimethacrylate (0.04 parts by weight per 100 parts by weight of the former two) were charged into a separable flask, and the monomer concentration at the initial stage of polymerization was 85% by weight. Ethyl acetate was added so that This solution is placed under a nitrogen atmosphere at 60
The mixture was heated to 0 ° C., lauroyl peroxide as a polymerization initiator and ethyl acetate were successively 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 concentration of 34% by weight.

2) Preparation of a coating liquid containing a patch formulation. To 100 parts by weight of the obtained base solution, 4 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) and polyplasdone INF-
10 parts (crospovidone, GAF) 2 parts by weight were added, and these were thoroughly stirred in a dissolver to uniformly disperse the fine crystals of eperisone hydrochloride and the fine particles of polyplasdone INF-10. A coating liquid was prepared.

3) Preparation of percutaneous absorption preparation The coating solution of step 2) was applied on a release paper made of a polyethylene terephthalate film having a thickness of 38 μm, and the temperature was 60 ° C.
30 minutes in a gear oven to form a drug-containing adhesive base layer.

Then, polyethylene terephthalate, which is a support of polyethylene terephthalate and ethylene-vinyl acetate copolymer laminated film and has a thickness of 30 μm, was brought into close contact with the base layer.

Thus containing 10% by weight of eperisone hydrochloride and 5% by weight of polyplasdone INF-10,
A tape preparation having a drug-containing base layer having a thickness of 50 μm on one side of a support was prepared. In this drug-containing base layer, fine crystals of eperisone hydrochloride and fine particles of polyplasdone INF-10 were well dispersed.

4) Dehumidification of percutaneous absorption preparation This tape preparation was measured in a size of 50 cm ² (7.1 cm × 7.1 c).
After punching into m, square with a radius of 5 mm at the corners, the obtained test piece was dried with a desiccant (granular silica gel approximately 2
It was packaged with g) in an aluminum packaging material, and the packaged product was stored at room temperature for 24 hours. Thus, a dehumidifying tape agent was obtained.

Example 6 1) Preparation of adhesive base 2-ethylhexyl methacrylate 78.3% by weight, 2-ethylhexyl acrylate 9.1% by weight, dodecyl methacrylate 12.6% by weight and the above three Hexamethylene glycol dimethacrylate (0.04 parts by weight) was added to a separable flask with respect to 100 parts by weight of the total amount of ethyl acetate, and ethyl acetate was added so that the monomer concentration at the initial stage of polymerization was 85% by weight. This solution was heated to 60 ° C. under a nitrogen atmosphere, lauroyl peroxide as a polymerization initiator and ethyl acetate were successively added little by little, and a polymerization reaction was carried out for 24 hours.
Ethyl acetate was added to the obtained polymer to dilute the reaction solution,
A base solution having a solid content concentration of 59.5% by weight was obtained.

2) Preparation of a coating liquid containing a patch formulation: To 100 parts by weight of the obtained base solution, 7 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) and polyplasdone INF-
3.5 parts by weight of 10 were added and sufficiently stirred in a dissolver to prepare a coating solution in which fine crystals of eperisone hydrochloride and fine particles of polyplasdone INF-10 were uniformly dispersed in the solution. did.

3) Preparation of percutaneous absorption preparation Using the coating solution of step 2) and following the same procedure as step 3) of Example 5, 10% by weight of eperisone hydrochloride and 5% by weight of polyplasdone INF were prepared. -10 and containing, thickness 5
A tape preparation having a 0 μm drug-containing base layer on one side of a support was prepared. In this drug-containing base layer, fine crystals of eperisone hydrochloride and fine particles of polyplasdone INF-10 were well dispersed.

4) Dehumidification of percutaneous absorption preparation This tape was dehumidified by the same procedure as in step 4) of Example 5 to obtain a dehumidified tape.

Example 7 1) Preparation of adhesive base 100 parts by weight of styrene-isoprene-styrene block copolymer (QTC3420, manufactured by Nippon Zeon Co., Ltd.), 33 parts by weight of polybutene (HV-300F, manufactured by Nippon Petrochemical Co., Ltd.), 283 parts by weight of alicyclic saturated hydrocarbon resin (Arakawa Chemical Co., Alcon P-90), 250 parts by weight of liquid paraffin and 4 parts by weight of butylhydroxytoluene were added and mixed to cyclohexane to give a solid content concentration of 59% by weight. A base solution was obtained.

2) Preparation of a liquid containing a formulation for patching To 100 parts by weight of the obtained base solution, 7 parts by weight of eperisone hydrochloride and 3.5 parts by weight of polyplasdone INF-10 were added, and these were dissolved in a dissolver. The mixture was thoroughly stirred to prepare a coating solution in which fine crystals of eperisone hydrochloride and fine particles of polyplasdone INF-10 were uniformly dispersed in the solution.

3) Preparation of percutaneous absorption preparation By the same operation as in step 3) of Example 5 using the coating solution of step 2), 10% by weight of eperisone hydrochloride and 5% by weight of polyplasdone INF were prepared. -10 and containing, thickness 5
A tape preparation having a 0 μm drug-containing base layer on one side of a support was prepared. In this drug-containing base layer, fine crystals of eperisone hydrochloride and fine particles of polyplasdone INF-10 were well dispersed.

4) Dehumidification of percutaneous absorption preparation This tape was dehumidified by the same operation as in step 4) of Example 5 to obtain a dehumidified tape.

Example 8 A tape preparation obtained by the same procedure as steps 1) to 3) of Example 5 was used, and it had a size of 50 cm ² (7.1 cm × 7.1 cm, rounded corners with a radius of 5 mm). After punching into squares, the obtained test pieces were dried for 21 hours in a desiccator containing a desiccant (granular silica gel). Then, this tape agent was packaged in an aluminum packaging material containing no desiccant to obtain a dehumidifying tape agent.

Example 9 A dehumidifying tape was prepared in the same manner as in Example 5 except that 4 parts by weight of tolperisone hydrochloride (manufactured by Sigma) was added in place of eperisone hydrochloride in step 2) of Example 5. Obtained.

Comparative Example 6 In step 4) of Example 5, except that the test pieces of the preparation were packed in a desiccant-free aluminum wrapping material,
A tape preparation was obtained in the same manner as in Example 5.

Comparative Example 7 In step 4) of Example 6, except that the test pieces of the preparation were packaged in an aluminum packaging material containing no desiccant,
A tape preparation was obtained in the same manner as in Example 6.

Comparative Example 8 In step 4) of Example 7, except that the test pieces of the formulation were packaged in a desiccant-free aluminum wrapping material,
A tape preparation was obtained in the same manner as in Example 7.

Comparative Example 9 In step 4) of Example 9, except that the test pieces of the formulation were packaged in a desiccant-free aluminum wrapping material,
A tape preparation was obtained in the same manner as in Example 9.

Performance Test a) Each tape preparation obtained in Examples 1 to 4 and Comparative Examples 1 to 5 was measured to have a size of 50 cm ² (7.1 cm × 7.1 cm, square with a radius of 5 mm at the corners). ), The obtained test piece is packaged in an aluminum packaging material, and then the temperature is set to 60.
It was stored for 10 days in a constant temperature bath at ℃. After storage, the amounts of the drug and its decomposed products contained in the preparation were measured to determine the ratio of the decomposed products to the drug.

Both the drug and the degradation product were measured using a liquid chromatograph.

The measurement results are shown in Table 1.

[0105]

[Table 1] As is clear from Table 1, it is recognized that the tape preparations of Examples 1 to 4 have a low ratio of decomposed products after storage. That is, it is understood that the tape preparations of Examples 1 to 4 suppress the decomposition of eperisone hydrochloride and tolperisone hydrochloride.

B) The water content, the drug content and the amount of decomposed products in the tape preparations obtained in Examples 5 to 9 and Comparative Examples 6 to 9 were measured and used as initial values. The water content is measured by Karl Fischer's water content measurement method,
The drug content and the amount of degradation products were measured by liquid chromatography. A column packed with octadecylsilylated silica gel (ODS-silica gel) and a methanol / water eluent were used for measuring the drug content, and a column packed with silica gel and normal hexane / isopropanol were used for measuring the decomposition products. The eluent of the system was used.
The results of these measurements are shown in FIGS.

Each tape preparation obtained in Examples 5-9 and Comparative Examples 6-9 was stored in an aluminum packaging material for 13 days in a constant temperature bath at 60 ° C. After storage, the water content, drug content and amount of decomposed products in the preparation were measured. The results of these measurements are also shown in FIGS.

As apparent from FIGS. 1 to 5, Example 5
It is recognized that the dehumidifying tape preparations of Nos. 9 to 9 have a low ratio of decomposed products after storage. That is, it is understood that the dehumidifying tape preparations of Examples 5 to 9 suppress the decomposition of eperisone hydrochloride and tolperisone hydrochloride.

C) The tape preparations of Examples 5 to 7 were evaluated for the percutaneous absorbability of the drug by the following method. That is, the dehumidifying tape formulations (50 cm ² ) obtained in Examples 5 to 7 were attached to the back of Japanese white rabbits that had been hair-removed using an electric clipper or an electric shaver, and the drug in the plasma of rabbits was attached. The change in concentration with time was measured. In addition, for comparison, measurement was also performed in the case of oral administration. The measurement result is shown in FIG.

As is clear from FIG. 6, the dehumidifying tape preparations obtained in Examples 5 to 8 showed good transdermal absorbability,
It is recognized that it is useful as a percutaneous absorption preparation.

[0111]

INDUSTRIAL APPLICABILITY According to the present invention, pKa is contained in a base containing eperisone, tolperisone, or a salt thereof.
A dicarboxylic acid or tricarboxylic acid of 3.5 or less is contained, or a water content of a base containing eperisone, tolperisone, or a salt thereof and crospovidone is 0.2% by weight or less. Therefore, hydrolysis of eperisone, tolperisone, or salts thereof with water is effectively suppressed. As a result, an eperisone or tolperisone percutaneous absorption preparation having excellent storage stability can be provided.

[Brief description of drawings]

FIG. 1 is a graph showing the water content and the amount of decomposed products for the dehumidifying tape preparations of Example 5 and Comparative example 6.

FIG. 2 is a graph showing the moisture content and the amount of decomposed products for the dehumidifying tape preparations of Example 6 and Comparative example 7.

FIG. 3 is a graph showing the water content and the amount of decomposed products for the dehumidifying tape preparations of Example 7 and Comparative Example 8.

FIG. 4 is a graph showing the water content and the amount of decomposed products for the dehumidifying tape preparations of Example 8 and Comparative example 6.

FIG. 5 is a graph showing the moisture content and the amount of decomposed products for the dehumidifying tape preparations of Example 9 and Comparative example 9.

FIG. 6 is a graph showing the relationship between plasma eperisone concentration and time.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location A61K 31/445 ADA 47/32 E 7433-4C (72) Inventor Yasushi Arai Nishi, Honjo City, Saitama Prefecture 493 Tomita No. 2 (72) Inventor Jun Nonaka 1-15-4 Midori, Honjo City, Saitama Prefecture

Claims (2)

[Claims] 1. A percutaneous absorption preparation of eperisone or tolperisone, characterized in that a base material containing eperisone, tolperisone, or a salt thereof contains a dicarboxylic acid or tricarboxylic acid having a pKa of 3.5 or less. 2. A percutaneous absorption preparation of eperisone or tolperisone, characterized in that the water content of the base containing eperisone, tolperisone, or a salt thereof and crospovidone is 0.2% by weight or less. .