JP3466305B2 - Dissolving agent and external preparation containing the dissolving agent - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a solubilizer of an active ingredient and an external preparation containing the solubilizer. More specifically, it is used as a dissolving agent for medicinal components and fat-soluble powders in percutaneous absorption preparations such as poultices and plasters, and has excellent solubility of active ingredients, and safety, stability, and high compatibility, and The present invention relates to a solubilizer which is odorless and has a refreshing feeling, and an external preparation containing the solubilizer.

[0002]

2. Description of the Related Art Conventionally, various attempts have been made to obtain a desired therapeutic effect by transdermally absorbing a drug. In such a percutaneously absorbable preparation, how to efficiently release the drug (pharmacologically active ingredient) from the base, that is, to transfer the drug from the base to the skin is an important issue. In general,
When attempting formulation design using a certain drug, crystallization etc. may occur due to insufficient dissolution of the drug in the base, and a sufficient therapeutic effect may not be obtained due to a decrease in drug release. . Therefore, the selection of the most suitable drug-dissolving agent is an important factor in the formulation design, and depending on the selection of the drug-dissolving agent, the dissolution of the drug is insufficient. It decreases and cannot fully show the therapeutic effect.

At present, alcohols, glycols, some surfactants, essential oils such as peppermint oil, crotamiton, methyl salicylate, glycolic salicylate are used as drug solubilizers. , Fatty acid esters represented by isopropyl myristylate and the like. For example,
JP-A-56-154413 discloses an external anti-inflammatory analgesic agent comprising flurbiprofen dissolved in a terpene-based substance or a fatty acid ester and comprising this oil-in-water emulsion and an aqueous base, and JP-A-57-98209. Discloses an anti-inflammatory analgesic external preparation in which indomethacin is dissolved in a monohydric alcohol, a polyhydric alcohol or the like. However, these solubilizers have insufficient dissolving power and may cause crystal precipitation,
There is a problem in stability such as limited use due to odor, poor compatibility with the base, bleeding over time, and decomposition or coloration over time. There were many cases where satisfactory results could not be obtained, such as causing unwanted side effects due to skin irritation.

[0004]

The object of the present invention is to solve the above problems and to provide excellent dissolution of the active ingredient,
The present invention also provides a solubilizer having high safety, stability and compatibility, and an external preparation containing the solubilizer.

[0005]

The above object of the present invention is achieved by using 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol as a solubilizer for the active ingredient. That is, the present invention is 2- (2-
A solubilizer for an active ingredient consisting of methoxy-1-methylethyl) -5-methylcyclohexanol, and an external preparation containing the solubilizer and the active ingredient.

The active ingredient in the present invention refers to a medicinal ingredient used in a percutaneous absorption agent. 2- which is the dissolving agent of the present invention
(2-Methoxy-1-methylethyl) -5-methylcyclohexanol is a known substance, and is described as a substance having a cooling sensation in International Publication No. WO94 / 10117, for example. However, there is no example of dissolving an active ingredient such as a medicinal ingredient using this substance, let alone an attempt to transdermally absorb a medicinal ingredient dissolved with this substance, which the present inventors have been able to make for the first time. , A completely new finding.

The content of 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol in the external preparation of the present invention is 0.01 to 2 with respect to the total amount of the external preparation.
It is used in the range of 0% by weight, preferably in the range of 0.1 to 10% by weight, more preferably in the range of 0.5 to 10% by weight. If this amount is less than 0.01% by weight, the effect as a solubilizer is not sufficiently exhibited, and if it exceeds 20% by weight, it is difficult to obtain a stable formulation.

The medicinal component used in the percutaneous absorption preparation which is one of the external preparations of the present invention is not particularly limited, and any medicinal component known in the prior art can be selected and used. Such drug components include, for example, prednisolone, dexamethasone, hydrocortisone, fluocinolone acetonide, betamethasone valerate, betamethasone dipropionate, clobetasone butyrate, steroidal anti-inflammatory agents such as prednisolone succinate, indomethacin, diclofenac, ibuprofen, Ketoprofen, flufenamic acid, ketorolac, flurbiprofen, felbinac, suprofen, pranoprofen,
Tiaprofen, loxoprofen, tenidap, aspirin, actarit, mizoribine, oxaprozin,
Non-steroidal anti-inflammatory agents such as auranofin, indomethacin fanelsyl, oxaprozin, mofezolac, etodolac and their ester derivatives, tranilast,
Antiallergic agents such as azelastine, ketotifen, ibudilast, oxatomide, emedastine, epinastine, etc.
Drug, anti-histamines such as diphenhydramine, chlorpheniramine, promethazine, triperenamine, central nervous system drugs such as chlorpromazine, nitrazepam, diazepam, phenoparbital, reserpine, insulin,
Hormonal agents such as testosterone, norethisterone, methyltestosterone, progesterone, estradiol, clonidine, reserpine, guanethidine sulfate, antihypertensive agents such as efonidipine, cardiotonic agents such as digitoxin, digoxin, propranolol hydrochloride, procainamide hydrochloride, ajmaline , Pindolol, antiarrhythmic agents such as tulobuterol hydrochloride, coronary vasodilators such as nitroglycerin, isosorbide nitrate, papaverine hydrochloride, nifedipine,
Local anesthetics such as lidocaine, benzocaine, procaine hydrochloride and tetracaine, morphine, aspirin, codeine, acetanilide, analgesics such as aminopyrine, eperisone, tizanidine, tolperisone, skeletal muscle relaxants such as inaperisone, acetophenylamine, nitrofurazone,
Antimycotic agents such as pentamycin, naphthiomate, miconazole, omoconazol, clotrimazol, butenafine hydrochloride, bifonazole, antitumor agents such as 5-fluorouracil, busulfan, actinomycin, pleomycin, mitomycin, hydrochloric acid. Urinary disorders such as telolysin and oxybutynin hydrochloride, antiepileptics such as nitrazepam and meprobamate, antiparkinsonian agents such as chlorzoxazone and lepodopa, smoking cessation aids such as nicotine, vitamins, prostaglandins and their Examples thereof include medically acceptable inorganic salts and organic salts, but are not limited to these. The blending amount of these medicinal components is not particularly limited, but is preferably 0.001 to 20% by weight, more preferably 0.01 to 10% by weight, based on the total amount of the external preparation.

The dosage form of the percutaneous absorption preparation of the present invention is not particularly limited, and is a dosage form conventionally used as an external preparation, such as a poultice, a plaster, an ointment, a gel, a cream or a gel cream. Agent, lotion agent, reservoir type patch,
It can be used as a percutaneous absorption preparation of any dosage form such as a liniment agent and an aerosol agent.

Next, examples of the percutaneous absorption preparation of the present invention will be explained for poultices and tapes. For example, as a poultice, the base is a hydrophilic base containing a water-soluble polymer, a polyhydric alcohol and water in consideration of stability over time, releasability, transdermal absorbability, and skin safety. As the water-soluble polymer used for this hydrophilic base, gelatin, casein,
Pullulan, dextran, sodium alginate, soluble starch, carboxystarch, dextrin, carboxymethylcellulose, carboxymethylcellulose sodium, methylcellulose, ethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyethylene oxide, polyacrylic acid, polyacrylamide, sodium polyacrylate, polyvinylpyrrolidone, Carboxyvinyl polymer, polyvinyl ether,
One or more of methoxyethylene maleic anhydride copolymer, N-vinylacetamide, N-vinylacetamide and acrylic acid and / or acrylate copolymer are appropriately selected. In this case, the content of the water-soluble polymer is 1 to 30% by weight, preferably 1 to 2% by weight of the whole preparation.
It is 0% by weight, more preferably 1 to 15% by weight. If it is less than 1% by weight, the viscosity becomes low and the shape retention cannot be maintained.
If it exceeds 5% by weight, the viscosity becomes high and the workability at the time of kneading or coating decreases.

The polyhydric alcohol may be one or more of polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, isobutylene glycol, glycerin, diglycerin, sorbitol and the like. If necessary, two or more kinds are appropriately selected, and the compounding amount thereof is 10 to 90% by weight, preferably 1
It is 0 to 70%, more preferably 20 to 60% by weight.
If it is less than 10% by weight, the moisturizing effect is insufficient, and 90% by weight
A higher amount affects the solubility of the water-soluble polymer. The blending amount of water is 10 to 90% by weight, preferably 20 to 80% by weight, which dissolves a water-soluble polymer to increase viscosity, cohesiveness,
It is necessary to bring out the shape retention.

Further, in addition to the above essential components, if necessary,
A polyvalent metal compound as a cross-linking agent, specifically aluminum hydroxide, aluminum chloride, calcium hydroxide, calcium chloride, aluminum sulfate, ammonium aluminum sulfate, potassium aluminum sulfate, magnesium aluminometasilicate, dihydroxyaluminum aminoacetate, etc. Other examples of the cross-linking agent include compounds having at least two epoxy groups in the molecule, specifically, ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene glycol didiene. Glycidyl ether, polytetramethylene glycol diglycidyl ether, glycerol polyglycidyl ether, polyglycerol polyglycidyl ether, sorby Polyglycidyl ether, sorbitan polyglycidyl ether, pentaerythritol polyglycidyl ether, resorcin diglycidyl ether, neopentyl glycol diglycidyl ether, 1,6-hexanediol diglycidyl ether, etc. Alternatively, two or more kinds may be suitably mixed appropriately.

In addition, fillers such as kaolin, zinc oxide, titanium dioxide, talc, bentonite and synthetic aluminum silicate, preservatives such as thymol, methylparaben and ethylparaben, ascorbic acid, stearic acid ester, dibutylhydroxytoluene, Antioxidants such as butylhydroxyanisole, gallic acid ester, vitamin E, vitamin E acetate, disodium edetate, etc.,
UV absorbers such as 2-hydroxy-4-methoxybenzophenone, ethyl p-aminobenzoate, 2- (2-hydroxy-5-methylphenyl) benzotriazole, glycol salicylate, methyl salicylate, phenyl salicylate, sorbitan fatty acid ester, glycerin One or more components composed of emulsifiers such as fatty acid ester, decaglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester, and polyoxyethylene alkyl ether may be appropriately blended.

As a support for the poultice, it is important to select a material that does not affect the release of the medicinal component.
In other words, it is essential that the support has no interaction or adsorption with the medicinal component. For example, it is selected from a film or sheet of polyethylene, polypropylene, polyvinyl chloride, polyester, nylon, polyurethane, or the like, or a porous body, a foamed body, a cloth, a nonwoven fabric, or a laminate product thereof. Further, as the release coating, polyethylene, polypropylene, polyester, or those obtained by subjecting these to release treatment with silicone, release paper, and the like can be used.

Next, a method for producing the poultice will be described, which can be easily produced by a known production method. For example, (A) the medicinal ingredient is 2- (2-methoxy-1-methylethyl) -5-methylcyclohexano-
Dissolve using If necessary, stabilizers, antioxidants, ultraviolet absorbers, emulsifiers, preservatives, antibacterial agents and the like may be added. (B) The water-soluble polymer is mixed, dispersed and dissolved in a polyhydric alcohol and water to obtain a uniform kneaded product. Then add (A) to (B) and disperse it evenly and spread it directly on the support, or spread it on a paper or film that has been once subjected to a peeling treatment, and then press transfer it to the support to be used. It can also be manufactured. It should be noted that the order of mixing each base, medicinal component or other ingredient in the above-mentioned production method is only one example, and is not limited to this mixing order.

As the adhesive base, the adhesive base can be appropriately selected from the known bases in consideration of skin safety, release of medicinal components, adhesion to the skin and the like. 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 copolymer of an alkyl (meth) acrylic acid alkyl ester having 4 to 18 carbon atoms,
Alternatively, a copolymer of the above-mentioned (meth) acrylic acid alkyl ester and another functional monomer is preferably used. Examples of the (meth) acrylic acid ester include butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate, and acrylic. Stearyl acid, methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate, stearyl methacrylate, etc. are exemplified. .

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 copolymerization 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-butoxymethyl acrylamide, N
-N-alkoxymethyl (meth) acrylamides such as ethoxymethylacrylamide, diacetone acrylamide, etc. are exemplified. 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 the rubber-based adhesive, natural rubber, synthetic isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polyisoprene, polybutadiene,
Examples thereof include a styrene-butadiene copolymer, a styrene-isoprene copolymer, a styrene-isoprene-styrene block copolymer and the like. As the silicone-based pressure-sensitive adhesive, those containing polyorganosiloxane or polydimethylsiloxane as a main component are used. As the tackifier, rosin-based rosin and hydrogenation, disproportionation,
Polymerized and esterified rosin derivative: α-pinene, β
-Terpene resin such as pinene: terpene-phenol resin: aliphatic, aromatic, alicyclic, copolymer petroleum resin, and alkyl-phenyl resin: xylene resin. The emollient is one that plasticizes and softens the base polymer to maintain appropriate adhesion to the skin. Examples of the softening agent include polybutene, liquid paraffin, higher fatty acid esters such as isopropyl myristate, silicone oil, almond oil, olive oil, camellia oil,
Vegetable oils such as Persic oil and peanut oil are exemplified.
As the support of the tape agent, a support that does not affect the release of the medicinal component is desirable, and a stretchable or non-stretchable support is used. For example, as a synthetic resin film, a film or sheet of polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane or the like, or a laminate of these, a porous film, a foam, paper, cloth and It is selected from non-woven fabrics and the like.

This tape agent can be easily produced by a conventionally known production method. For example, in the case of a synthetic rubber tape, a mixer such as a kneader or a mixer is used,
The adhesive base, the softening agent and the tackifier are heated and mixed at 120 to 160 ° C., and then the medicinal component and 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol are added and mixed directly. It may be spread on a polypropylene or polyester film, or once spread on a release-treated paper or film and then covered with a desired support and pressure-transferred. In the case of acrylic tape, an adhesive base, a drug and an absorption promoter, and if necessary, a compounding agent are dissolved or dispersed in an appropriate solvent, and the resulting solution or dispersion is directly applied to the surface of the support and dried. Then, a sticking layer having a thickness of 30 to 200 um is formed. Further, this solution or dispersion may be coated on a protective release paper, and the adhesive layer obtained after drying may be brought into close contact with the support. The solvent used in this production method is not particularly limited as long as it is an organic solvent that is compatible with all of the compounding components such as the adhesive base and the drug, but for example, aromatic hydrocarbons such as toluene, benzene, and xylene. , Esters such as ethyl acetate, and halogenated hydrocarbons such as carbon tetrachloride, chloroform and methylene chloride.

Next, an ointment which is another percutaneous absorption agent,
The formulation of gels, creams, gel creams, lotions, reservoir patches, liniments, and aerosols will be briefly described. Ointments include, in addition to the medicinal component and 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol, higher fatty acids or their esters such as myristic acid, waxes such as spermaceti, and polyoxy. At least a surfactant such as ethylene and a hydrocarbon such as hydrophilic petrolatum are blended. The formulation of this ointment is, for example, 5 to higher fatty acid or its ester.
15% by weight, 1 to 10% by weight of surfactant, 0.
5 to 10 wt%, 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol 0.5 to 10 wt% are mixed at room temperature or under heating, and waxes are added to 4 to 10 wt%. After adding 50 to 90% by weight of hydrocarbon, heating or melting by heating and maintaining at 50 to 100 ° C., all components become a transparent solution, and then uniformly mixed with a homomixer. Then, the mixture is cooled to room temperature with stirring to give an ointment.

The gel agent is, in addition to the medicinal component and 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol, gels lower alcohols such as ethanol, water, carboxyvinyl polymer and the like. Agent, and at least a neutralizing agent such as triethanolamine. The pharmaceutical formulation of this gel agent is, for example, 55% by weight or less and 0.5 to 5% by weight of a gelling agent is added to expand. On the other hand, 0.5 to 10% by weight of the medicinal component is added to 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol 0.5 to 10% by weight.
It is dissolved in a mixture of 40% by weight or less of glycols and 60% by weight or less of lower alcohol. Mix both of these and add a neutralizing agent to adjust the pH to 4
The gelling agent is obtained by adjusting so as to be ~ 7.

In addition to the medicinally active ingredient and 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol, creams include higher fatty acid esters such as myristic acid ester, carbonized water and liquid paraffin. At least an emulsifier such as hydrogen or polyoxyethylene alkyl ether is blended. The formulation of this cream is as follows: 2- (2-methoxy-1-methylethyl)-
5-methylcyclohexanol, higher fatty acid ester,
It can be obtained by adding appropriate amounts of water, hydrocarbons and an emulsifier, mixing and stirring.

The gel-like cream agent has a property intermediate between that of the gel agent and the cream agent, and in addition to the above-mentioned components of the cream agent, a gelling agent such as carboxyvinyl polymer and diisopropanolamine. PH of 4 with a neutralizing agent
It is obtained by adjusting to -8, preferably 5-6.5. The formulation of the gel cream is, for example, 0.5 to 10% by weight of the medicinal component of 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol 0.5 to 10.
It is dissolved in 10% by weight, further dissolved in a mixture of 25% by weight or less of a higher fatty acid ester and 40% by weight or less of a lower alcohol, and 5% by weight or less of an emulsifier is further added. on the other hand,
Swell by adding 0.5 to 5% by weight of a gelling agent to water. Next, both are mixed and uniformly emulsified with a homomixer, and after the emulsification, a neutralizing agent is added to adjust the pH to 4-8.

The lotion agent contains, in addition to the medicinal component and 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol, at least a lower alcohol such as ethanol, water and / or glycols. . The formulation of this lotion is based on the above-mentioned medicinal ingredients, 2-
It is obtained by adding (2-methoxy-1-methylethyl) -5-methylcyclohexanol, a lower alcohol, water and / or glycols in an appropriate amount, mixing and stirring.

The reservoir patch comprises at least (1) backing material layer, (2) drug storage layer, (3) drug release layer, and (4) pressure-sensitive adhesive layer, and (2) drug storage layer is effective. Ingredient, 2- (2-methoxy-1-methylethyl)-
In addition to 5-methylcyclohexanol, (a) at least glycols, lower alcohols, water, water-soluble polymers, (b) at least aliphatic alcohols and polyhydric alcohols (c) at least paraffins, silicones, It is composed of a base material containing either one. The liniment agent is, in addition to the medicinal component, 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol, alcohols such as ethanol and polyethylene glycol, water, fatty acid esters such as adipic acid and sebacic acid. Is mixed at least.

The formulation of the liniment agent is 0.
5-10% by weight was dissolved in 0.5-10% by weight of 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol, which was further mixed with 10-70% by weight of alcohol and 55% by weight of water. % Or less, and 60% by weight or less of a fatty acid ester are mixed and stirred.

The aerosol agent contains at least a lower alcohol, water, dimethyl ether and / or liquefied petroleum gas in addition to the medicinal component 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol. If desired, a medicinal agent such as camphor, α-tocophenol, menthol, etc. may be added. The specific formulation of the aerosol is as follows: 0.5 to 10% by weight of the medicinal component is dissolved in 0.5 to 10% by weight of 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol. Further, it can be obtained by blending lower alcohol and water, filling an aerosol container, and pressurizing dimethyl ether and / or liquefied petroleum gas as a propellant. These percutaneous absorption preparations of the present invention, to the extent that the object of the present invention is not impaired,
Various pharmacologically acceptable additives such as stabilizers, antioxidants, fragrances, fillers, ultraviolet absorbers, antihistamines, preservatives, antibacterial agents, and transdermal absorption enhancers can be added.

[0028]

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. Example 1 Pap agent (A) 2- (2-methoxy-1-methylethyl) -5-1.0% by weight Methylcyclohexanol diclofenac 0.5% by weight (B) Purified water 48.5% by weight Gelatin 8.0% by weight Kaolin 1.0% by weight Glycerin 35.0% by weight Sodium polyacrylate 2.0% by weight Polyvinyl alcohol 3.0% by weight Aluminum hydroxide 1.0% by weight Dissolve and stir the above components to homogeneity. I got a kneaded product. This is spread on polypropylene non-woven fabric using a spreading machine to a thickness of about 1 mm.
And then covered with a polypropylene film and cut into a predetermined size to give a preparation.

Example 2 Pap agent (A) 2- (2-methoxy-1-methylethyl) -5-2.0% by weight Methylcyclohexanol Loxoprofen 1.0% by weight Thymol 0.1% by weight (B ) Purified water 62.4% by weight Gelatin 3.0% by weight Titanium oxide 1.0% by weight Glycerin 25.0% by weight Sodium polyacrylate 3.0% by weight Carboxymethyl cellulose 1.0% by weight Ethylene glycol diglycidyl ether 1. 0 wt% sorbitan fatty acid ester 0.5 wt% The above components were dissolved and stirred to obtain a uniform kneaded product. This is spread on a polyester non-woven fabric using a spreading machine to a thickness of about 0.5 m.
m, and then covered with a polyethylene film and cut into a predetermined size to give a preparation.

Example 3 Poultice (A) 2- (2-methoxy-1-methylethyl) -5-3.0% by weight Methylcyclohexanol ibuprofen 0.5% by weight Ethylparaben 0.2% by weight ( B) Purified water 42.3% by weight Methoxyethylene maleic anhydride copolymer 5.0% by weight Synthetic aluminum silicate 3.0% by weight Glycerin 40.0% by weight Polyacrylic acid 2.0% by weight Polyvinyl alcohol 2.5 % By weight Calcium hydroxide 1.5% by weight The above components were dissolved and stirred to obtain a uniform kneaded product. This is spread on a polyurethane film with a spreading machine to a thickness of about 1 mm.
Then, it was covered with a polyester film and cut into a predetermined size to give a preparation.

Example 4 Pap agent (A) 2- (2-methoxy-1-methylethyl) -5-2.0 wt% methylcyclohexanol-ketoprofen 0.5 wt% (B) Purified water 36.0 Weight% N-vinylacetamide 5.0 weight% Glycerin 50.0 weight% Polyacrylic acid 3.0 weight% Carboxymethyl cellulose 1.0 weight% Magnesium aluminometasilicate 1.5 weight% Glycerin fatty acid ester 1.0 weight% The above components were dissolved and stirred to obtain a uniform kneaded product. Approximately 1 mm thick on a polyester non-woven fabric using a spreading machine
Then, it was covered with a polyester film and cut into a predetermined size to give a preparation.

Comparative Example 1 Pap agent (A) Crotamiton 1.0 wt% Suprofen 0.8 wt% (B) Purified water 54.2 wt% Gelatin 6.0 wt% Bentonite 5.0 wt% Glycerin 25.0 wt % Sodium alginate 2.0% by weight Polyethylene oxide 4.0% by weight Aluminum sulfate 1.5% by weight Polyethylene glycol fatty acid ester 0.5% by weight The above components were dissolved and stirred to obtain a uniform kneaded product. This was spread on a polyvinyl chloride film using a spreading machine to a thickness of about 0.
It was applied to 3 mm, then covered with a polypropylene film and cut into a predetermined size to give a preparation.

Comparative Example 2 Pap agent (A) Glycol salicylate 2.0% by weight Ketoprofen 0.5% by weight (B) Purified water 36.0% by weight N-vinylacetamide 5.0% by weight Glycerin fatty acid ester 1.0% by weight % Glycerin 50.0% by weight Polyacrylic acid 3.0% by weight Carboxymethyl cellulose 1.0% by weight Magnesium aluminate metasilicate 1.5% by weight The above components were dissolved and stirred to obtain a uniform kneaded product. This was applied to a polyester non-woven fabric to a thickness of about 1 mm using a spreading machine, then covered with a polyester film and cut into a predetermined size to give a preparation.

Comparative Example 3 Pap agent (A) Butylene glycol 4.0 wt% Mint oil 1.0 wt% Loxoprofen 0.5 wt% (B) Purified water 47.5 wt% Gelatin 3.0 wt% Kaolin 1. 0% by weight glycerin 35.0% by weight sodium polyacrylate 3.0% by weight carboxyvinyl polymer 2.5% by weight dextrin 2.0% by weight sorbitan polyglycidyl ether 0.5% by weight Dissolve and stir the above ingredients I got a kneaded product. Using a spreading machine, make this a polypropylene non-woven fabric with a thickness of about 1 mm.
Then, it was covered with a polyester film and cut into a predetermined size to give a preparation.

Example 5 Plaster Styrene-isoprene-styrene block copolymer 22.5% by weight Polyisobutylene 5.0% by weight Tackifier (rosin ester) 15.0% by weight Liquid paraffin 56.0% by weight 2- (2-Methoxy-1-methylethyl) -5-1.0% by weight Methylcyclohexanol ketotifen 0.5% by weight The above components were heated and stirred and spread on a support to give a ketotifen-containing tape. Was prepared.

Example 6 Plaster Acrylic resin solvent-based pressure-sensitive adhesive 77.0% by weight (trade name: NISSETSU PE-300) (solid content conversion) 2- (2-methoxy-1-methylethyl) -5 -15.0 wt% Methylcyclohexanol Isosorbide dinitrate 8.0 wt% A mixture of the above components was spread on a support and the solvent was evaporated to prepare a tape containing isosorbide dinitrate.

Example 7 Plaster Silicone adhesive 89.0% by weight (Brand name: BIO-PSA X7-2920) (as solid content) 2- (2-methoxy-1-methylethyl) -5-7 0.0% by weight Methylcyclohexanol Clonidine 4.0% by weight A mixture obtained by stirring and mixing the above components was spread on a support,
The solvent was evaporated and a tape containing clonidine was prepared.

Comparative Example 4 Plaster Silicone adhesive 96.0% by weight (Brand name: BIO-PSA X7-2920) (as solid content) Clonidine 4.0% by weight A mixture of the above components with stirring, Spread on the support,
The solvent was evaporated and a tape containing clonidine was prepared. It should be noted that this comparative example 4 is the same as that of the dissolving agent in Example 7
It is a formulation excluding (2-methoxy-1-methylethyl) -5-methylcyclohexanol.

Comparative Example 5 Plaster Silicone adhesive 89.0% by weight (Brand name: BIO-PSA X7-2920) (as solid content) Isopropyl myristate 7.0% by weight Clonidine 4.0% by weight Spread the mixture of the components with stirring on a support,
The solvent was evaporated and a tape containing clonidine was prepared. It should be noted that this comparative example 5 is the same as the solubilizer 2-
This is a formulation using isopropyl myristate instead of (2-methoxy-1-methylethyl) -5-methylcyclohexanol.

Example 8 Plaster Styrene-isoprene-styrene block copolymer 25.0% by weight (trade name: Califlex TR-1107) Liquid paraffin 59.0% by weight Rosin ester derivative 5.0% by weight (trade name) : Ester gum AA-G) 2- (2-Methoxy-1-methylethyl) -5-10.0% by weight Methylcyclohexanol diclofenac 1.0% by weight After mixing the above formulation with a kneader, a direct PBT woven fabric It was spread over and covered with a liner from the top to give a plaster.

Example 9 Plaster Styrene-isoprene-styrene block copolymer 20.0% by weight (trade name: Califlex TR-1107) Liquid paraffin 43.5% by weight Polyisobutylene (trade name: Vistanex) 10. 0% by weight Rosin ester derivative (trade name: KE-311) 21.5% by weight 2- (2-methoxy-1-methylethyl) -5-4.0% by weight Methylcyclohexanol diclofenac 1.0% by weight The above formulations were mixed by a mixer, spread on a plastic film which had been previously subjected to a peeling treatment, covered with a PET woven cloth from above and pressure-transferred to obtain a plaster.

[0042]   Example 10 Plaster   Styrene-isoprene-styrene block copolymer 25.0% by weight   (Product name: Califlex TR-1107)   Liquid paraffin 68.0% by weight   Rosin ester derivative 5.0% by weight   (Product name: Ester gum AA-G)   2- (2-methoxy-1-methylethyl) -5-1.5% by weight                       Methyl cyclohexanol   Ketoprofen 0.5% by weight A plaster was prepared according to Example 9.

[0043]   Example 11 Plaster   Styrene-isoprene-styrene block copolymer 21.0% by weight   (Product name: Califlex TR-1107)   Liquid paraffin 66.8% by weight   Rosin ester derivative (trade name: KE-311) 7.2% by weight   2- (2-methoxy-1-methylethyl) -5-4.0% by weight                       Methyl cyclohexanol   Flurbiprofen 1.0% by weight A plaster was prepared according to Example 9.

[0044]   Example 12 Plaster   Styrene-isoprene-styrene block copolymer 15.0% by weight   (Product name: Califlex TR-1111)   Polyisobutylene (Brand name: Vistanex) 14.0% by weight   Liquid paraffin 38.0% by weight   Rosin ester derivative (trade name: KE-311) 26.0% by weight   2- (2-methoxy-1-methylethyl) -5-5.0% by weight                       Methyl cyclohexanol   Felbinac 2.0% by weight A plaster was prepared according to Example 12.

[0045]   Example 13 Plaster   Styrene-isoprene-styrene block copolymer 20.0% by weight   (Product name: Califlex TR-1107)   Polyisobutylene (Brand name: Vistanex) 5.0% by weight   Liquid paraffin 45.0% by weight   Rosin ester derivative (trade name: KE-311) 20.0% by weight   2- (2-methoxy-1-methylethyl) -5-9.0 wt%                       Methyl cyclohexanol   Estradiol 1.0% by weight A plaster was prepared according to Example 8.

[0046]   Example 14 Plaster   Styrene-isoprene-styrene block copolymer 22.0% by weight   (Product name: Califlex TR-1111)   Polyisobutylene (Brand name: Vistanex) 6.0% by weight   Liquid paraffin 45.0% by weight   Rosin ester derivative 23.0% by weight   (Product name: Foral 105)   2- (2-methoxy-1-methylethyl) -5-3.0% by weight                       Methyl cyclohexanol   Progesterone 1.0% by weight A plaster was prepared according to Example 10.

[0047]   Example 15 Plaster   Styrene-isoprene-styrene block copolymer 20.0% by weight   (Product name: Califlex TR-1111)   Polyisobutylene (Brand name: Vistanex) 5.0% by weight   Liquid paraffin 47.0% by weight   Rosin ester derivative (trade name: KE-311) 17.0% by weight   2- (2-methoxy-1-methylethyl) -5-10.0% by weight                       Methyl cyclohexanol   Norethisterone 1.0% by weight A plaster was prepared according to Example 12.

[0048]   Example 16 Plaster   Styrene-isoprene-styrene block copolymer 20.0% by weight   (Product name: Califlex TR-1112)   Polyisobutylene (Brand name: Vistanex) 12.0% by weight   Liquid paraffin 30.0% by weight   Rosin ester derivative 30.0% by weight   (Product name: Foral 105)   2- (2-methoxy-1-methylethyl) -5-7.0% by weight                       Methyl cyclohexanol   Test Stron 1.0% by weight A plaster was prepared according to Example 9.

Comparative Example 6 Plaster Styrene-isoprene-styrene block copolymer 20.0% by weight (trade name: Califlex TR-1107) Liquid paraffin 43.5% by weight Polyisobutylene (trade name Vistanex) 10.0 % By weight Rosin ester derivative (trade name: KE-311) 25.5% by weight Diclofenac 1.0% by weight The above formulation is mixed with a mixer and spread on a plastic film which has been previously subjected to a peeling treatment, and a polyester cloth is applied from above. Cover and pressure transfer was performed to obtain a plaster. The formulation excluding the solubilizer 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol in Example 9 was Comparative Example 6.

Comparative Example 7 Plaster Styrene-isoprene-styrene block copolymer 20.0% by weight (trade name: Califlex TR-1111) Polyisobutylene (trade name: Vistanex) 5.0% by weight Liquid paraffin 47. 0 wt% rosin ester derivative (trade name: KE-311) 17.0 wt% propylene glycol 10.0 wt% norethisterone 1.0 wt% Produced according to Example 12 to give a plaster. In addition, a formulation in which 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol as a dissolving agent in Example 15 was replaced with propylene glycol was set as Comparative Example 7.

Example 17 Ointment White petrolatum 76.0% by weight Glycerin monostearate 10.0% by weight Beef tallow 10.0% by weight Silicone oil 1.0% by weight 2- (2-methoxy-1-methylethyl) -5-2.0% by weight Methylcyclohexanol Flurbiprofen 1.0% by weight The above components were mixed by stirring to prepare a flurbiprofen-containing ointment.

Example 18 Ointment White petrolatum 82.95% by weight Isopropyl myristate 8.0% by weight Whale wax 3.0% by weight Sodium polyoxyethylene lauryl ether phosphate 2.0% by weight Butyl paraoxybenzoate 0.05 Weight% 2- (2-methoxy-1-methylethyl) -5-3.0 weight% Methylcyclohexanol indomethacin 1.0 weight% The above components were stirred and mixed to prepare an indomethacin-containing ointment.

Example 19 Gel agent Carboxyl vinyl polymer 1.5% by weight Hydroxylpropylcellulose 2.0% by weight Ethanol 17.0% by weight Purified water 35.3% by weight Propylene glycol 30.0% by weight Propylene carbonate 10. 0 wt% triethanolamine 0.2 wt% 2- (2-methoxy-1-methylethyl) -5-3.0 wt% methylcyclohexanol indomethacin 1.0 wt% The above components are stirred and mixed, A gelling agent containing indomethacin was prepared.

Example 20 Cream Agent Carboxyvinyl Polymer 1.0 wt% Glycerin 10.0 wt% Ethanol 5.0 wt% Diisopropanolamine 0.4 wt% Medium Chain Fatty Acid Triglyceride 3.0 wt% Flurbipro Phen 1.0 wt% 2- (2-Methoxy-1-methylethyl) -5-5.0 wt% Methylcyclohexanol Purified water 74.6 wt% The above components are stirred and mixed to give flurbiprofen. A containing cream was prepared.

Example 21 Gel cream Cream carboxyvinyl polymer 1.0% by weight Isopropyl palmitate 9.0% by weight Diethyl sebacate 9.0% by weight Polyoxyethylene cetyl ether 2.0% by weight Propylene carbonate 7.0% by weight % Methyl paraoxybenzoate 0.2% by weight Sodium hydroxide 0.1% by weight Indomethacin 1.0% by weight 2- (2-Methoxy-1-methylethyl) -5-5.0% by weight Methylcyclohexanol Purification Water 65.7% by weight The above components were mixed by stirring to prepare an indomethacin-containing gel cream.

Example 22 Lotion Agent Ethanol 38.0% by weight Purified water 50.0% by weight Propylene glycol 6.0% by weight 2- (2-methoxy-1-methylethyl) -5-5 0.0 wt% Methylcyclohexanol Indomethacin 1.0 wt% The above components were mixed by stirring to prepare a lotion agent containing indomethacin.

Example 23 Reservoir type patch (1) Backing material layer Polyester film (2) Drug storage layer 4 g of the gel composition shown below was enclosed. Ketorolac 5.0% by weight 2- (2-methoxy-1-methylethyl) -5-3.0% by weight Methylcyclohexanol Carboxyvinyl polymer 2.0% by weight Propylene glycol 30.0% by weight Triethyl citrate 19 0.0 wt% Purified water 39.4 wt% 2-Hydroxy-4-methoxybenzophenone 0.5 wt% Diisopropanolamine 1.1 wt% (3) Drug release layer Duraguard (4) Pressure-sensitive adhesive layer Silicon type Adhesive The above-mentioned (1) to (4) constituted this reservoir type patch, and a release liner was applied to the pressure-sensitive adhesive surface to form a laminate.

Example 24 Reservoir type patch (1) Lining material layer Aluminum laminated polyester film (2) Drug storage tank layer 4 g of the gel composition shown below was enclosed. Tulobuterol hydrochloride 5.0 wt% 2- (2-methoxy-1-methylethyl) -5-5.0 wt% methylcyclohexanol stearyl alcohol 10.0 wt% cetyl alcohol 10.0 wt% behenyl alcohol 10.0 % By weight Propylene glycol 20.0% by weight 1,3-butylene glycol 35.0% by weight Lauryl alcohol 5.0% by weight (3) Drug release layer Coatlan (4) Pressure sensitive adhesive layer Silicon adhesive (support Peripheral part) In (1) to (4) above, this reservoir type patch was constructed, and a release liner was applied to the pressure sensitive adhesive surface to form a laminate.

Example 25 Liniment Agent Polyethylene glycol monolaurate 15.0% by weight 2,2-dihydroxy-4-methoxybenzophenone 0.7% by weight Diisopropyl adipate 4.0% by weight α-tocopherol 1.0% by weight 3- Acetylated sucrose denatured alcohol 49.6% by weight ketorolac 3.0% by weight 2- (2-methoxy-1-methylethyl) -5-5.0% by weight methylcyclohexanol purified water 21.7% by weight Above The ingredients were stirred and mixed to prepare a ketorolac-containing liniment agent.

Example 26 4.5% by weight of camphor relative to the total amount of the aerosol agent, 2- (2-methoxy-1-methylethyl) -5-methylcyclohexano-
4.0 wt.%, Ketoprofen 3.0 wt.%, 2-hydroxy-4-methoxybenzophenone 1.0 wt.% Were dissolved in ethanol 32.5 wt.
To prepare an undiluted solution containing 4.0% by weight of talc, which is added with 1% by weight of talc and 13.0% by weight of dimethyl ether as a propellant and 1 part of liquefied petroleum gas.
A mixture with 2.0% by weight was injected under pressure to obtain an anti-inflammatory analgesic aerosol.

Test Example 1 Dissolution test A sample was prepared by changing the dissolution conditions (ratio of dissolution agent to drug) and heated at 120 ° C. to gradually dissolve it. Taking into consideration the stability of the drug, the heating was performed for up to 2 hours. (2
Those that were insoluble after heating for an hour were considered to have no dissolving power. ) After dissolution, the mixture was allowed to stand at room temperature for 2 weeks or more, and the state of crystal precipitation was observed. In addition, when the crystal precipitation was not clear, the sample was left standing at 5 ° C. The results of dissolution tests for ketoprofen, indomethacin and clotrimazol are shown in Table 1 (comparison of solubility of ketoprofen with various solubilizers), Table 2 (comparison of solubility of indomethacin with various solubilizers), Table 3 (for various solubilizers). Comparative solubility of clotrimazole). In the table, MMMC is 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol (solvent of the present invention), EtOH is ethanol, and PEG (400).
Means polyethylene glycol 400, PG means propylene glycol, and IPM means isopropyl myristate.

[0062]

[Table 1] Note) × → precipitation in less than 1 week, △ → precipitation in 1-2 weeks, ○ → no precipitation after 2 weeks

[0063]

[Table 2] Note) × → precipitation in less than 1 week, △ → precipitation in 1-2 weeks, ○ → no precipitation after 2 weeks

[0064]

[Table 3] Note) × → precipitation in less than 1 week, △ → precipitation in 1 to 2 weeks, ○ → no precipitation after 2 weeks From the results in Tables 1 to 3, 2- (2-methoxy-1-methylethyl) -5- Methylcyclohexanol showed an overall better solubility than the currently widely used solubilizers.

Test Example 2 Formulation Stability Test The plasters of Examples 7 and 9 and the plasters of Comparative Examples 4 to 6 were stored at 5 ° C. for 2 weeks, and the crystallization of the medicinal component was observed with time. The results are shown in Table 4.

[Table 4] O: No crystallization is observed. X: Crystallization is observed. As is clear from the above results, in Comparative Examples 4 and 6 in which no solubilizer is added, and in Comparative Example 5 using isopropyl myristate, clonidine or Whereas diclofenac crystallizes over time, 2- (2-methoxy-
In Examples 7 and 9 using 1-methylethyl) -5-methylcyclohexanol, the drug was still dissolved in the base even after 2 weeks. That is, it supports the usefulness of 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol as a dissolving agent.

Test Example 3 Compatibility Test With respect to the plaster of Example 15 and the plaster of Comparative Example 7, the compatibility between the base and the dissolving agent, that is, the dissolving agent's blood was observed. The results are shown in Table 5.

[Table 5] ◯: no bleed x: bleed As is clear from the above results, in Comparative Example 7 in which propylene glycol was used as the solubilizer, while bleeding was observed from the beginning, 2- In Example 15 using (2-methoxy-1-methylethyl) -5-methylcyclohexanol, no bleed was observed due to its excellent compatibility with the base material. That is, 2- (2-methoxy-
This proves the usefulness of 1-methylethyl) -5-methylcyclohexanol as a solubilizer.

Test Example 4 Adhesion Test Regarding the poultices of Examples 1 to 4 and Comparative Examples 1 to 3,
The adhesive strength and the change with time of the adhesive strength were examined. The test method is N
It carried out according to the ichiban Rolling Ball method. In this method, the ball is rolled while drawing a sine curve at an angle of 30 degrees from a predetermined height, and the distance traveled from the sample arrival point is measured. That is, the shorter the distance is, or the larger the ball is, the better the tackiness is. In this test, the sample was
Cut it to 0 mm and attach it so that the adhesive side is on the front side.
Stainless steel balls (20/32 inch: J
IS standard) was rolled and the distance traveled was measured. The results are shown in Table 6.

[0068]

[Table 6] As described above, the poultices of Examples 1 to 4 had good adhesiveness and did not change with time, and were good.

Test Example 5 Skin Safety Test For the poultices of Examples 1 to 4 and Comparative Examples 1 to 3,
A skin safety test was conducted. The test is a closed patch test of 25 healthy men and women for 48 hours.
The degree of skin change after lapse of time and 24 hours was observed, and the degree of skin irritation was evaluated according to the following criteria. The results are shown in Tables 7-8. -: No change was observed on the skin +: Clear redness on the skin ±: Slight redness on the skin ++: Serious feel on the skin

[0070]

[Table 7]

[0071]

[Table 8] As described above, the skin safety of the poultices of Examples 1 to 4 was extremely high.

Test Example 6 Transdermal Absorption Experiment by Humans The samples of Example 9 and Comparative Example 6 punched out by 3 × 3 cm ² were attached to the upper backs of 6 healthy volunteers, and after 8 hours, they were recovered and diclofenac remained. The amount was quantified by HPLC. The calculation of the human absorption rate, the quantitative method, and the HPLC conditions were performed as follows. (1) Human absorption rate = (1-remaining amount / initial content) x 100 (2) Quantitative method: The collected sample was ultrasonically extracted with 30 ml of tetrahydrofuran for 2 hours, and after extraction, the amount of tetrahydrofuran was changed to 50 ml by HPLC. Was used as a sample. (3) HPLC conditions: mobile phase; 0.2% aqueous acetic acid solution: acetonitrile = 1: 1 detection wavelength; 275 nm column; TSKgel ODS-80TM flow rate; 1.0 / min The results are shown in FIG. As shown in FIG. 1, Example 9 showed significantly higher absorption than Comparative Example 6. That is, in Example 9, 2
Due to the dissolving action of-(2-methoxy-1-methylethyl) -5-methylcyclohexanol, diclofenac was present in a dissolved state, so that the release was good.

[0073]

INDUSTRIAL APPLICABILITY The present invention is known as 2- (2) which is known as a cooling sensation agent.
By adding -methoxy-1-methylethyl) -5-methylcyclohexanol as a solubilizer of the active ingredient, the action of dissolving the active ingredient is excellent, and the safety and stability are improved.
High compatibility. Therefore, when the preparation for percutaneous absorption is a preparation for external use, the release of medicinal components and the percutaneous absorption are improved. In addition, side effects such as skin irritation caused by repeated application of the external preparation are reduced, and there is no skin irritation, and the safety is high. Moreover, this external preparation is odorless and has a pleasant refreshing feeling. Therefore, the external preparation of the present invention is suitable as a percutaneous absorption preparation in medicine and has high industrial applicability.

[0074]

─────────────────────────────────────────────────── --- Continuation of the front page (56) References JP-A-3-68513 (JP, A) JP-A-3-68512 (JP, A) JP-A-63-88125 (JP, A) International Publication 94/010117 (WO, A1) International Publication 93/004677 (WO, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 47/10 A61K 9/06 A61K 9/12 A61K 9/70 CA (STN ) REGISTRY (STN) Medline (STN) BIOSIS (STN) EMBASE (STN)

Claims (5)

(57) [Claims] 1. A solubilizer for a medicinal component , which comprises 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol. 2. A medicinal component and 2 as a dissolving agent for the medicinal component.
Percutaneous inhalation characterized by containing-(2-methoxy-1-methylethyl) -5-methylcyclohexanol
Collected formulation . 3. A medicinal component is a steroidal anti-inflammatory drug or non-medicine.
Steroidal anti-inflammatory drugs and their ester derivatives,
Allergic agents, antihistamines, central nervous system agents, formo
Drug, antihypertensive drug, antiarrhythmic drug, coronary vasodilator, local
Local anesthetics, analgesics, skeletal muscle relaxants, antifungal agents, anti-malignant tumors
Ulcer, dysuria, antiepileptic, antiparkinsonian
Agents, smoking cessation aids, vitamins, prostaglandins
And any of their medically acceptable inorganic or organic salts
The transdermal preparation according to claim 2, which is 4. 2- (2-methoxy-1-methylethyl) -5-methylcyclohexanol 0.01 to 20
The percutaneous absorption preparation according to claim 2 or 3, which is contained in a weight percentage. 5. The dosage form is a poultice, plaster, ointment, gel, cream, gel cream, lotion,
5. The transdermal absorption product according to any one of claims 2 to 4, which is one of a reservoir type patch, a liniment agent and an aerosol agent .
Agent .