JPH07267860A - Eperisone or tolperisone transdermal preparation - Google Patents

Abstract

PURPOSE:To obtain a transdermal preparation which is particularly useful in summer because it develops at first analgesic effect and cool feeling due to menthol and shows excellent quick-acting properties against a variety of symptoms caused by spastic paralysis, low back pain and humeral articulation periarthritis. CONSTITUTION:The transdermal preparation is prepared by adding eperisone, tolperisone or one of their salts such as chloride, phosphate or methanesulfonate salt and 1-menthol to the base. The contents of the active ingredients are preferably 0.05 to 30wt.%, particularly 0.1 to 20wt.%. The preparation is applied in the form of tape, patch, cataplasm, ointment or cream.

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 rapid-acting eperisone, tolperisone or a salt thereof. It relates to a transdermal preparation.

[0002]

2. Description of the Related Art Eperisone, tolperisone or salts thereof (hereinafter, these are collectively referred to as "the compound according to the present invention").
Is a central nervous system skeletal muscle relaxant that is effective as a remedy for various conditions based on spastic paralysis; or as a remedy for muscle tone due to diseases such as cervical-shoulder-arm syndrome, periarthritis of the shoulder, and low back pain. .

The compounds according to the invention are usually administered orally. 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 (physiologically active substance) 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.

1-Menthol has been conventionally used as a poultice and the like, and, for example, JP-A-60-15241.
No. 3, discloses a composition for promoting percutaneous absorption of a drug by incorporating 1-menthol.

Further, it is known that the compound according to the present invention is a drug which is percutaneously absorbed. As a percutaneous absorption preparation containing this drug, JP-A-64-52716 discloses a fatty acid monoglyceride having 8 to 12 carbon atoms and / or 12 to 1 carbon atoms as a transdermal absorption promoter in a base.
No. 8 describes the percutaneous absorption preparation in which the percutaneous absorption of the compound according to the present invention is remarkably improved by containing the lactic acid ester of fatty acid alcohol. In addition, JP-A-4-
217979 describes a transdermal preparation capable of effectively transdermally absorbing the compound of the present invention by including a water-swellable crosslinked polyvinylpyrrolidone (crospovidone) in a base.

[0007]

However, since the compound according to the present invention is a central drug, it is suitable for patients suffering from pain such as low back pain and periarthritis of the shoulder due to the existence of absorption lag time. The treatment was not fast enough.

The present invention has been made in view of the above points, and an object thereof is to provide a percutaneous absorption preparation having excellent rapid-acting properties, which is a preparation containing eperisone, tolperisone or a salt thereof. It is in.

[0009]

A percutaneous absorption preparation according to the present invention is characterized by containing eperisone, tolperisone which is a compound according to the present invention or a salt thereof and l-menthol as a base. is there.

The form of the transdermal preparation according to the present invention is a tape preparation, a patch, a poultice, a plaster, an ointment,
It may be a cream formulation or the like. Tape formulation, patch,
Patches such as plasters and poultices have a drug-containing layer provided on an appropriate support. These patches can be preferably used in order to accurately adjust the dose per administration. Further, in consideration of the ease of use, tape preparations, plaster preparations and patch preparations are preferable.

A compound according to the invention contained in a base,
-The content of menthol and absorption promoter corresponds to the content of the formulation itself in ointments and creams, and in patches such as tape formulations, plasters and poultices, the support and release paper are excluded from the formulation. It corresponds to the content in the other part, that is, the part of the drug-containing layer (paste layer), and in the patch, it corresponds to the content in 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, which is a compound according to the present invention, 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.

The compound according to the present invention is dissolved in a base material described later, 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 the compound according to the present invention is preferably 0.05 to 30% by weight, more preferably 0.1 to 20% by weight. When the content of the compound according to the present invention is less than 0.05% by weight, the percutaneous absorption effect per unit area of administration of the drug is insufficient and the percutaneous absorption preparation has a practical administration area (150 cm ² or less). In some cases, 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, 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) 1-Menthol is a main component of peppermint oil and widely exists in nature, and not only gives a refreshing refreshing feeling, but also has awakening action and local irritation action. This is preferably 0.5 to 20% by weight in the formulation, more preferably 1 to
It is blended so as to have a ratio of 10% by weight. By blending 1-menthol, the analgesic effect of 1-menthol is obtained during the lag time from the absorption of the compound according to the present invention, which is a central nervous system muscle relaxant, to the exertion of the drug effect. As a whole, the analgesic effect is exerted quickly.
Furthermore, the combination of 1-menthol gives a refreshing refreshing feeling, and this formulation is particularly suitable for use in summer.
If the content of 1-menthol is too small, the rapid effect on stiff shoulders, low back pain, etc. is not good, and if it is too large, the menthol odor is too strong.

C) Next, the base will be explained for each formulation.

As a base for tapes, plasters, poultices, etc., the compound of the present invention, l-menthol,
An adhesive having excellent compatibility with an absorption enhancer and the like and having an adhesive force capable of fixing the preparation on the skin surface at room temperature for a long time is used. Examples of such an adhesive include an acrylic adhesive, a rubber adhesive, a silicone adhesive, and the like. Considering the adhesive properties and cost, acrylic adhesives and rubber adhesives are preferred.

As the acrylic pressure-sensitive adhesive, in particular, a homopolymer or copolymer of an alkyl group-containing (meth) acrylic acid alkyl ester having 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 alkyl ester include butyl acrylate, isobutyl acrylate,
Hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, 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.

Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group,
Examples thereof include a monomer having an amide group and a monomer having a pyrrolidone ring. Examples of the monomer having a hydroxyl group include hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate. Examples of the monomer having a carboxyl group include α, β-unsaturated carboxylic acids such as acrylic acid and methacrylic acid; maleic acid monoalkyl esters 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 monomer having an amide group include alkyl (meth) acrylamides such as acrylamide, dimethyl acrylamide and diethyl acrylamide; N-alkoxymethyl (meth) acrylamides such as N-butoxymethyl acrylamide and N-ethoxymethyl acrylamide; diacetone acrylamide and the like. It is illustrated. Examples of the monomer having a pyrrolidone ring include N-vinyl-2-pyrrolidone.

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

In order to produce a (meth) acrylic acid alkyl ester copolymer, 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.

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,
A styrene-butadiene copolymer, a styrene-isoprene copolymer, a styrene-isoprene-styrene block copolymer, etc. are used.

Silicone rubber such as polyorganosiloxane is used as the silicone adhesive.

If desired, various compounding agents may be added to the above-mentioned pressure-sensitive adhesive base. Such compounding agents include, for example, tackifiers such as rosin-based resins, polyterpene resins, chroman-indene resins, petroleum-based resins, and terpene phenol resins; liquid polybutene, mineral oil, lanolin, liquid isobutylene, liquid polyacrylates, etc. Examples include plasticizers, fillers, antiaging agents, and the like.

When the preparation of the present invention is a poultice,
As its base, sodium alginate, gelatin,
Natural polymers such as corn starch and tragacanth gum;
Cellulosic polymers such as methyl cellulose, hydroxyethyl cellulose, 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 are used. These bases include, if necessary, purified water; a moisturizer made of a polyhydric alcohol such as glycerin and propylene glycol; an inorganic filler such as kaolin, pentonite, zinc white, and titanium dioxide; a viscosity modifier; crosslinking. Agents; anti-aging agents and the like may be added.

When the preparation of the present invention is used as an ointment or cream preparation, the base is beeswax, oil or fat,
Lanolin, white petrolatum, paraffin, hydrocarbon gel (Plastibase ^R , manufactured by Bristol-Myers Squibb), higher fatty acid, higher alcohol, emulsifier,
Macrogol, carboxyvinyl polymer, etc. are used. These bases include, as necessary, fat-soluble solubilizers such as crotamiton, liquid paraffin, isopropyl myristate, and diethyl sebacate; ethanol; polyhydric alcohols such as glycerin as water-soluble solubilizers;
An H regulator and the like may be added.

D) 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 promoter, 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, crospovidone, lecithin, glycyrrhetin, urea, salicylic acid, calcium thioglycolate, lactic acid, lactate ester, olive oil, squalene, Lanolin, liquid paraffin, glycerin, etc. are used.

Crospovidone is the Pharmacopeia NF of the United States.
11. As described in XVII (official compendial), a crosslinked homopolymer of N-vinyl-2-pyrrolidone,
It is a substance containing nitrogen atoms in the range of 0 to 12.8% by weight (in anhydrous state). Suitable examples of commercially available crospovidone include Kollidon CL (registered trademark), Kollidon CL-M (registered trademark) manufactured by BASF, Polyplasdone XL (registered trademark) manufactured by IPS, and ISP. Polyplusdon INF-10 (registered trademark) and the like are available.

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 20% by weight or less, preferably 0.1 to 10% by weight. When the content of the absorption enhancer exceeds 20% by weight, the resulting preparation has a high skin irritation, and when administered to the skin, redness and itching occur.

E) Next, a method for preparing the percutaneous absorption preparation of the present invention will be described.

When the percutaneous absorption preparation of the present invention is an ointment or cream preparation, it is prepared by adding the compound of the present invention, 1-menthol and, if necessary, an absorption enhancer into a base and mixing them. To be done.

When the percutaneous absorption preparation of the present invention is a patch preparation such as a tape preparation, a patch, a plaster preparation and a poultice preparation, the percutaneous absorption preparation of the present invention can be applied to the surface of an appropriate support. It is prepared by laminating a drug-containing layer containing the compound according to the present invention, 1-menthol, a base, and optionally an absorption enhancer. As a method for forming the drug-containing layer on the surface of the support, various known coating methods such as a solution coating method, a hot melt coating method and an electron beam curing emulsion coating method can be applied. In particular, the solvent coating method can be preferably used. In the solvent coating method, first, the above base is diluted with an appropriate solvent,
To this, a compound according to the present invention, 1-menthol, and, if necessary, an absorption promoter and various compounding agents are added. The target dispersion is formed by applying the obtained dispersion on the surface of a support and drying it to remove the solvent. Further, the above-mentioned dispersion may be applied to a release paper and dried, and then the obtained drug-containing layer may be brought into close contact with the support.
The thickness of the drug-containing layer thus formed on the support varies depending on the purpose of use, but is preferably about 30 μm to
It is in the range of about 200 μm. A release paper may be attached on the drug-containing layer until the time of use for the purpose of protecting this layer.

As the support used for these patches, any of the supports usually used for patches can be used. Examples of the material of the support include cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, ethylene-methyl acrylate copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized poly Examples include vinyl chloride, polyurethane, polyvinylidene chloride, and aluminum. These materials can be used as a single-layer sheet or a laminate of two or more sheets. Alternatively, materials other than aluminum can be used as woven or non-woven fabrics.

The patch thus prepared is used by being stuck to the affected area.

[0041]

The percutaneous absorption preparation according to the present invention is a percutaneous absorption preparation containing the compound according to the present invention and a base, in which l-menthol is added. Until the compound according to the present invention exerts an effect on such pain, the analgesic effect of l-menthol is rapidly exhibited, and a transdermal preparation having excellent rapid-acting properties as a whole is provided.

[0042]

EXAMPLES Examples of the present invention will be described below. Example 1 1) Preparation of adhesive base 2-ethylhexyl acrylate 75.5 wt% 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 was heated to a temperature of 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 32 hours. Ethyl acetate was added to the produced polymer to obtain a base solution having a solid content concentration of 43%.

2) Preparation of a liquid containing a compound for patching To 200 parts by weight of the obtained base solution, 10 parts by weight of eperisone hydrochloride (manufactured by Eisai Chemical Co., Ltd.) and polyplasdone INF were added.
-10 (crospovidone, ISP) 2 parts by weight;
6 parts by weight of menthol (manufactured by Takasago International Co., Ltd.) and sufficiently stirred in a dissolver, fine crystals of eperisone hydrochloride and fine particles of polyplasdone INF-10 were uniformly dispersed in the solution. A coating liquid was prepared.

3) Preparation of percutaneous absorption preparation This coating solution was applied on a polyethylene terephthalate release paper having a thickness of 38 μm and dried in a gear oven at a temperature of 60 ° C. for 30 minutes to form a drug-containing layer. did. This drug-containing layer was brought into close contact with a polyethylene terephthalate and ethylene-vinyl acetate copolymer laminated film (manufactured by Nippon Matai Co., Ltd.) having a thickness of 30 μm to obtain 10 wt% of eperisone hydrochloride and 2 wt% of polyplasdone INF-10. A tape preparation was obtained in which a drug-containing layer having a thickness of 50 μm was laminated. The l-menthol content was 2% by weight as a result of volatilization during the preparation process.

Example 2 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 45% by weight. A base solution was obtained.

2) Preparation of a liquid containing a formulation for patching To 200 parts by weight of the obtained base solution, 5 parts by weight of eperisone hydrochloride and 15 parts by weight of l-menthol were added and thoroughly stirred in a dissolver to obtain eperisone hydrochloride. To prepare a coating liquid in which the fine crystals of were uniformly dispersed in the solution.

3) Preparation of percutaneous absorption preparation A tape preparation was prepared in the same manner as in Example 1 using this coating solution. The drug-containing layer of this tape preparation contained 5% by weight of eperisone hydrochloride, and the content of 1-menthol was 5% by weight.

Example 3 1) Base solution 20 obtained in step 1) of Example 1
To 0 parts by weight, 17.4 parts by weight of tolperisone hydrochloride (manufactured by Sigma), 5.8 parts by weight of cetyl lactate (manufactured by VAN DYK), and 17.4 parts by weight of 1-menthol were added and sufficiently stirred in a dissolver. A coating solution in which fine crystals of tolperisone hydrochloride were uniformly dispersed in the solution was prepared.

2) Preparation of transdermal preparation A transdermal preparation was prepared in the same manner as in Example 1 using this coating solution. The drug-containing layer of this tape preparation contains 15
It contained 5% by weight tolperisone hydrochloride and 5% by weight cetyl lactate and a 1-menthol content of 5% by weight.

Comparative Example 1 A transdermal preparation was prepared in the same manner as in Example 1 except that l-menthol was not added in step 2) of Example 1.

Comparative Example 2 1) Preparation of a patch-containing liquid containing patch To 200 parts by weight of the base solution obtained in step 1) of Example 2, 4.7 parts by weight of eperisone hydrochloride were added, and the mixture was thoroughly dissolved in a dissolver. The mixture was stirred to prepare a coating liquid in which fine crystals of eperisone hydrochloride were uniformly dispersed in the solution.

2) Preparation of percutaneous absorption preparation Using this coating solution, a percutaneous absorption preparation was prepared in the same manner as in Example 1. The drug-containing layer of this tape preparation contained 5% by weight of eperisone hydrochloride.

Comparative Example 3 1) Preparation of Adhesive Blend-Containing Liquid 200 parts by weight of the base solution obtained in step 1) of Example 1 was added to 16.2 parts by weight of tolperisone hydrochloride and cetyl lactate (manufactured by VAN DYK). 5.4 parts by weight was added and sufficiently stirred in a dissolver to prepare a coating solution in which tolperisone hydrochloride microcrystals were uniformly dispersed in the solution.

2) Preparation of transdermal preparation A transdermal preparation was prepared in the same manner as in Example 1 using this coating solution. The drug-containing layer of this tape preparation contains 15
It contained wt% tolperisone hydrochloride and 5 wt% cetyl lactate.

Performance Test For the transdermal absorption preparations of Examples 1 to 3 and Comparative Examples 1 to 3, the transdermal absorbability of the drug and the transfer rate of 1-menthol were evaluated by the following methods.

<Transdermal Absorption of Drug> Each of the transdermal absorption preparations of Examples 1 to 3 and Comparative Examples 1 to 3 was punched out into a size of 100 cm ² to obtain a test piece. The test piece was attached to the back of a Japanese white rabbit that had been hair-removed using an electric clipper or an electric shaver, and the time-dependent change in the drug concentration in plasma was measured by liquid chromatography.

<Transfer of l-menthol> Examples 1 to 3
Each of the transdermal preparations of Comparative Examples 1 to 3 was punched out to a size of 100 cm ² , and a test piece was obtained. The above test piece was attached to the back of a Japanese white rabbit that had been hair-removed using an electric hair clipper or electric shaver, and the amount of 1-menthol remaining in the tape after 3 hours was measured by liquid chromatography, and transferred according to the following formula. I asked for the rate.

[0058]

The results are summarized in Table 1.

[0060]

[Table 1]

[0061]

EFFECTS OF THE INVENTION According to the transdermal preparation of the present invention, l-menthol is analgesic until the compound of the present invention exerts its effect on pain such as low back pain and shoulder periarthritis after administration. It is possible to provide a percutaneous absorption preparation which exhibits the effect rapidly and is excellent in the immediate effect as a whole.

Further, this preparation gives a refreshing sensation by containing 1-menthol, and is particularly suitable for use in summer.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Toshiyuki Ashizawa 3-6-3 Ginza, Honjo City, Saitama Prefecture

Claims (1)

[Claims] 1. A percutaneously absorbable preparation characterized by containing eperisone, tolperisone or a salt thereof and l-menthol as a base.