JP2006176502A - External preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal preparation for external use, containing a refrigerant reduced in pungent odors such as a mint odor and exerting substantially no influence on the rate of percutaneous absorption of the medicinal ingredient. <P>SOLUTION: The medicinal preparation for external use comprises (1) a medicinal ingredient and (2) a refrigerant reduced in the mint odor and exerting substantially no influence on the rate of percutaneous absorption of the medicinal ingredient, such as 2-methyl-3-(1-menthyloxy)propane-1,2-diol or a derivative thereof. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an external preparation containing a medicinal component and a refreshing agent that does not substantially affect the transdermal absorption rate of the medicinal component.

  Conventionally, menthols such as l-menthol, mint oil, and the like are generally used as a refreshing agent blended in a preparation for external use. Menthols and mint oils are highly sublimable and have a mint odor, so they emit a strong odor especially when formulated in patches such as poultices and tapes. Therefore, topical preparations in the form of patches containing menthols and mint oil have problems such as stinking odors around them and adsorbing odors on clothes and hair, causing odor residues. ing. Because of this problem, there is a serious situation in which the patient restricts the use of the patch himself, or the patch is peeled off even though the treatment has not been completed, and compliance is reduced and sufficient treatment cannot be performed. Often it was.

  Also, the mint odor of l-menthol and other menthols has the effect of reducing appetite and suppressing gastric juice secretion, so it can be applied to patches, hair preparations and skin lotions. When menthols are blended in an external preparation, the user has an appetite due to a mint smell and sometimes has problems such as nausea and vomiting. Furthermore, since menthols such as l-menthol are solid at room temperature, when l-menthol is blended in a preparation for external use as a cooling agent, crystals form over time or a cooling agent is present uniformly in the preparation. There was a problem that it could not be done and sublimated over time and the refreshing feeling was not maintained. Mentha oil contains about 50% menthol, and when mint oil is used as a refreshing agent, problems similar to the above occur. Moreover, since mint oil is a natural product, its components are often non-uniform, and there is another problem that the stability of the product standard is lacking.

  Japanese Patent Publication No. 61-48813 discloses 3-l- (menthoxypropane-1,2-diol) as a refreshing agent that suppresses the strong volatility and mint smell of menthol, and Japanese Patent No. 2852816. Discloses an external preparation containing the above substance as a solubilizer for a specific drug. This external preparation has no mint smell such as mint oil or menthol, and can be used as an external preparation that solves the above problems. However, this substance has a problem that it affects the percutaneous absorption rate of a medicinal component (for example, an anti-inflammatory agent) in an external preparation. That is, menthols such as mint oil and l-menthol have the effect of promoting percutaneous absorption of drugs, but 3-l- (menthoxypropane-1,2-diol) is also mint oil and menthols. Similarly, it has the effect of promoting percutaneous absorption of medicinal components, and the cumulative permeation amount of medicinal components in percutaneous absorption shows a significant increase depending on the concentration of the substance. Therefore, in order to control the cumulative permeation amount of medicinal ingredients over a long period of time, the blending amount of 3-l- (menthoxypropane-1,2-diol) must be limited, thereby reducing the refreshing feeling. There were problems such as. For these reasons, it has been desired to provide an external preparation containing a refreshing agent that has suppressed volatility and mint and does not substantially affect the transdermal absorption rate of medicinal ingredients.

On the other hand, 2-methyl-3- (l-menthyloxy) propane-1,2-diol was developed for the purpose of suppressing the bitterness of the above-mentioned 3-l- (menthoxypropane-1,2-diol). It is a refreshing feeling improving agent and is disclosed in Japanese Patent No. 3219995. In this patent publication, a refreshing sensation improving agent comprising 2-methyl-3- (l-menthyloxy) propane-1,2-diol is disclosed, and the refreshing sensation is sustained by using in combination with l-menthol. The effect is described. Moreover, the said patent gazette has the suggestion about mix | blending the said substance with a poultice. However, the above patent publication does not suggest or teach whether this substance affects the percutaneous absorption rate of a medicinal component of an external preparation.
Japanese Patent Publication No. 61-48813 Japanese Patent No. 2852816 Japanese Patent No. 3219995

  An object of the present invention is to provide an external preparation that solves the above-mentioned problems, and more specifically, an irritating odor such as a peppermint odor is suppressed, and the percutaneous absorption rate of a medicinal ingredient is substantially reduced. An object of the present invention is to provide an external preparation containing a refreshing agent that does not affect the skin.

  The present inventors have intensively searched for a refreshing agent that suppresses mint smell and does not substantially affect the percutaneous absorption rate of a medicinal component contained in an external preparation. As a result, 2-methyl-3- It has been found that a group of refreshing agents represented by (l-menthyloxy) propane-1,2-diol or derivatives thereof has the above desirable properties. Conventionally, the existence of a cooling agent that achieves both of the above two properties is not known at all. In addition, by blending an appropriate amount of 2-methyl-3- (l-menthyloxy) propane-1,2-diol in a preparation for external use as a cooling agent, the transdermal absorption rate of the medicinal component is not substantially affected. Furthermore, the present inventors have found that an external preparation having a very high refreshing feeling and no irritating odor such as mint smell can be provided. The present invention has been completed based on the above findings.

That is, according to the present invention, a refreshing agent which is an external preparation, wherein (1) medicinal ingredients and (2) mint smell are suppressed and does not substantially affect the transdermal absorption rate of the medicinal ingredients. A preparation for external use is provided.
According to a preferred embodiment of the present invention, the above external preparation wherein the refreshing agent is 2-methyl-3- (1-menthyloxy) propane-1,2-diol or a derivative thereof; The above-mentioned external preparation which is methyl-3- (1-menthyloxy) propane-1,2-diol; the amount of the refreshing agent is 0.0001 to 20% by weight based on the total weight of the composition of the external preparation The above external preparation, wherein the medicinal ingredient is one or more medicinal ingredients selected from the group consisting of non-steroidal anti-inflammatory agents, skeletal muscle relaxants, and vasodilators; Tapes, patches, or patches such as reservoir-type patches, solid preparations such as sticks, semi-solid preparations such as gel ointments, ointments, or creams, lotions, or liniments Solutions, or the external application preparations in the form of sprays, such as aerosols or non-gas spraying agent.

  The refreshing agent contained in the external preparation of the present invention has excellent properties that it does not substantially affect the percutaneous absorption rate of the medicinal component of the external preparation in addition to the suppression of mint smell. ing. Therefore, in the external preparation of the present invention, the blending ratio of the above-mentioned refreshing agent with respect to the medicinal component can be significantly increased as compared with the conventional external preparation, and thus it can be used as an external preparation with a very excellent refreshing feeling. it can. Moreover, since the percutaneous absorption rate of the medicinal component is not affected, the formulation design becomes easy. Moreover, the preparation for external use of the present invention containing a large amount of the above-mentioned refreshing agent has almost no irritating odor such as a mint odor, and does not make the patient feel uncomfortable.

  The preparation for external use of the present invention comprises (1) a medicinal component, and (2) a refreshing agent that suppresses mint smell and does not substantially affect the transdermal absorption rate of the medicinal component. It is said. The kind of the medicinal component in the external preparation of the present invention is not particularly limited, but for example, steroidal anti-inflammatory agents such as hydrocortisone, prednisolone, dexamethasone, triamcinolone, betamethasone, salicylate glycol, indomethacin, ketoprofen, flurbiprofen, felbinac, piroxicam , Meloxicam, diclofenac and its salts, loxoprofen and its salts, non-steroidal anti-inflammatory agents such as suprofen, zaltoprofen, thiaprofen, tenidap and derivatives thereof, antiallergic agents such as tranist, ketotifen, azelastine, ibudilast, eperisone hydrochloride, tolperisone, Skeletal muscle relaxants such as tizanidine and pridinol, antihistamines such as diphenhydramine and chlorpheniramine, nitroglycerin, glass Vasodilators such as isosorbide, carpronium chloride, minoxidil, local anesthetics such as lidocaine, procaine hydrochloride, benzocaine, antifungal agents such as miconazole, clotrimazole, butenafine hydrochloride, bifonazole, oxybutynin hydrochloride, tamsulosin hydrochloride, ritodrine hydrochloride, etc. Antiepileptic agents such as dysuria, nitrazepam, diazepam and the like. Two or more of these medicinal ingredients may be used in combination. Of these, one or more medicinal ingredients selected from the group consisting of non-steroidal anti-inflammatory agents and derivatives thereof, skeletal muscle relaxants, and vasodilators are preferred.

  As a refreshing agent in which the mint smell is suppressed and does not substantially affect the transdermal absorption rate of the medicinal component, for example, 2-methyl-3- (l-menthyloxy) propane-1,2- A diol or a derivative thereof can be preferably used, but is not limited to these specific substances. Any refreshing agent may be used as long as the mint smell is suppressed and it has a property that does not substantially affect the transdermal absorption rate of the medicinal component. Examples of the derivative of 2-methyl-3- (l-menthyloxy) propane-1,2-diol include ester derivatives, alkyl derivatives, halogen derivatives, and the like, but the type is not particularly limited. Particularly preferred is 2-methyl-3- (l-menthyloxy) propane-1,2-diol.

  Although it does not specifically limit about the refreshing effect of the refreshing agent used for the external preparation of this invention, For example, menthol, mint oil, 3-l- (menthoxypropane-1,2-diol), or 2-methyl- It is desirable that the cooling effect is almost the same as that of a conventionally known cooling agent such as 3- (1-menthyloxy) propane-1,2-diol. The cooling effect can be easily measured by those skilled in the art according to methods well known in the art. The fact that the mint odor of the refreshing agent used in the external preparation of the present invention is suppressed is, for example, tested using 2-methyl-3- (1-menthyloxy) propane-1,2-diol as a comparative control. What is necessary is just to confirm that the mint odor of a refreshing agent is the mint odor equivalent to or less than the said substance. Such confirmation can be performed by, for example, a sensory test.

It can be easily confirmed by those skilled in the art that the refreshing agent used in the external preparation of the present invention does not substantially affect the transdermal absorption rate of the medicinal component by the method specifically described in the examples of the present specification. . Although the percutaneous absorption profile differs depending on the type and dosage form of the medicinal ingredient, it cannot be generally stated. Less than 250 percent, preferably less than 200 percent, more preferably less than 100 percent, particularly preferably less than 50 percent, and most preferably less than 30 percent compared to the absence of a cooling agent. In this specification, the percutaneous absorption rate of a medicinal component is the amount of medicinal component contained in the formulation for permeation per unit time when the formulation for external application is applied to the skin, mucous membrane, or scalp. Indicated by. Usually, the unit is μg / cm ² / hr and is evaluated as a permeation rate.

  The amount of the refreshing agent blended in the external preparation of the present invention is not particularly limited, but the refreshing agent used in the external preparation of the present invention has a property that it does not substantially affect the percutaneous absorption rate of the medicinal component. Therefore, compared with the conventional external preparation, the blending ratio of the refreshing agent to the medicinal component can be increased, thereby providing the external preparation of the present invention as an external preparation having a high refreshing feeling. It becomes possible. In general, the blending amount of the refreshing agent can be selected from the viewpoint of the refreshing feeling perceived by humans and the durability thereof, for example, 0.0001 to 20% by weight based on the total weight of the composition of the external preparation It is preferably about 0.01 to 10% by weight, and most preferably about 0.1 to 5% by weight.

  The form of the external preparation of the present invention is not particularly limited, and is a preparation form conventionally used as an external preparation, such as a patch, a tape, a patch, a patch such as a reservoir type patch, a stick, etc. Provided as external preparations in the form of solid preparations, gel ointments, ointments, semi-solid preparations such as creams, liquids such as lotions or liniments, or sprays such as aerosols or non-gas sprays it can.

  The manufacturing method of the external preparation of this invention is not specifically limited, According to the form of external preparation, a well-known and usual manufacturing method can be employ | adopted by those skilled in the art. In the production of the external preparation of the present invention, one or two or more kinds of preparation additives can be used, and those needs and types can be appropriately selected by those skilled in the art depending on the form of the preparation. Is possible. For example, aqueous bases such as macrogol; oily bases such as petrolatum, liquid paraffin; gum arabic, gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyacrylic acid and salts thereof, polyvinyl alcohol, Water-soluble polymers such as polyvinylpyrrolidone; antioxidants such as erythorbic acid, sodium erythorbate, hydroxyanisole, and anhydrous sodium sulfite; preservatives; coloring agents; pH adjusters, etc. can be used as pharmaceutical additives. It is not limited to these.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
[Example 1] Tape agent
(weight%)
Styrene-isoprene-styrene block copolymer 21.5
Hydrogenated rosin glycerin ester 22.5
Liquid paraffin 39.5
Dibutylhydroxytoluene 1.0
Macrogol 10.0
Felbinac 2.5
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 3.0
The above components were mixed with a kneader, spread on a polyester film subjected to a release treatment, covered with a polyester woven cloth, and transferred by pressure bonding to obtain a tape agent.

[Example 2] Tape agent
(weight%)
Styrene-isoprene-styrene block copolymer 21.0
Hydrogenated rosin glycerin ester 22.0
Liquid paraffin 38.5
Dibutylhydroxytoluene 1.0
Macrogol 10.0
Diclofenac sodium 2.5
2-Methyl-3- (l-menthyloxy) propane-1,2-diol 5.0
The above components were mixed with a kneader, spread on a polyester film subjected to a release treatment, covered with a polyester woven cloth, and transferred by pressure bonding to obtain a tape agent.

[Example 3] Tape agent
(weight%)
Styrene-isoprene-styrene block copolymer 22.0
Hydrogenated rosin glycerin ester 24.0
Liquid paraffin 39.5
Dibutylhydroxytoluene 1.0
Macrogol 10.0
Eperisone hydrochloride 0.5
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 3.0
The above components were mixed with a kneader, spread on a polyester film subjected to a release treatment, covered with a polyester woven cloth, and transferred by pressure bonding to obtain a tape agent.

[Example 4] A poultice
(weight%)
Glycosalicylate 1.0
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 0.3
Sodium polyacrylate 5.0
Carboxyvinyl polymer 1.0
Carmellose sodium 1.5
Light anhydrous silicic acid 2.0
Sorbitan sesquioleate 0.5
Dry aluminum hydroxide gel 0.1
Lactic acid 1.0
Concentrated glycerin 30.0
Remaining amount of purified water The above components were mixed with a kneader, spread uniformly on a nonwoven fabric, and pressure-bonded with a polyester film as a release liner to obtain a poultice.

[Example 5] Gel ointment
(weight%)
Carboxyvinyl polymer 1.5
Triethanolamine 2.0
Ethanol 40.0
Ketoprofen 3.0
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 0.5
Purified water remaining amount The above ingredients were mixed in a mixer to obtain a gel ointment.

[Example 6] Gel ointment
(weight%)
Carboxyvinyl polymer 1.5
Triethanolamine 2.0
Ethanol 40.0
Ketoprofen 3.0
2-Methyl-3- (l-menthyloxy) propane-1,2-diol 1.0
Purified water remaining amount The above ingredients were mixed in a mixer to obtain a gel ointment.

[Example 7] Gel ointment
(weight%)
Carboxyvinyl polymer 1.5
Triethanolamine 2.0
Ethanol 40.0
Ketoprofen 3.0
2-Methyl-3- (l-menthyloxy) propane-1,2-diol 2.0
Purified water remaining amount The above ingredients were mixed in a mixer to obtain a gel ointment.

[Example 8] Gel ointment
(weight%)
Carboxyvinyl polymer 1.5
Triethanolamine 2.0
Ethanol 40.0
Indomethacin 1.0
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 0.5
Purified water remaining amount The above ingredients were mixed in a mixer to obtain a gel ointment.

[Example 9] Gel ointment
(weight%)
Carboxyvinyl polymer 1.5
Triethanolamine 2.0
Ethanol 40.0
Indomethacin 1.0
2-Methyl-3- (l-menthyloxy) propane-1,2-diol 1.0
Purified water remaining amount The above ingredients were mixed in a mixer to obtain a gel ointment.

[Example 10] Gel ointment
(weight%)
Carboxyvinyl polymer 1.5
Triethanolamine 2.0
Ethanol 40.0
Indomethacin 1.0
2-Methyl-3- (l-menthyloxy) propane-1,2-diol 2.0
Purified water remaining amount The above ingredients were mixed in a mixer to obtain a gel ointment.

Example 11 Ointment
(weight%)
Polyethylene glycol 400 45.5
Polyethylene glycol 4000 45.5
Isopropyl myristate 5.0
Piroxicam 1.0
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 3.0
The above ingredients were mixed with a mixer to obtain an ointment.

[Example 12] Ointment
(weight%)
Polyethylene glycol 400 45.5
Polyethylene glycol 4000 45.5
Isopropyl myristate 5.0
Meloxicam 1.0
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 3.0
The above ingredients were mixed with a mixer to obtain an ointment.

[Example 13] Cream
(weight%)
Decaglyceryl pentasulfonate 1.0
Stearic acid 3.5
Behenyl alcohol 2.5
Cetyl palmitate 3.0
Squalane 8.0
Glyceryl tri-2-ethylhexanoate 8.0
1,3-butylene glycol 3.0
Glycerin 3.0
Flurbiprofen 1.0
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 3.0
Purified water remaining amount The above ingredients were mixed in a mixer to obtain a cream.

[Example 14] Cream
(weight%)
White petrolatum 25.0
Stearyl alcohol 22.0
Propylene glycol 12.0
Sodium lauryl sulfate 1.5
Flurbiprofen 1.0
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 3.0
Purified water remaining amount The above ingredients were mixed in a mixer to obtain a cream.

[Example 15] Lotion
(weight%)
Ethanol 50.0
1,3-butylene glycol 5.0
Carpronium chloride 1.0
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 0.1
Purified water remaining amount The above ingredients were mixed in a mixer to obtain a lotion agent.

[Example 16] Lotion
(weight%)
Ethanol 50.0
Propylene glycol 5.0
Minoxidil 1.0
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 0.3
Purified water remaining amount The above ingredients were mixed in a mixer to obtain a lotion agent.

Example 17 Liniment Agent
(weight%)
Ethanol 45.0
Concentrated glycerin 2.5
Felbinac 3.0
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 0.3
Purified water remaining amount The above ingredients were mixed in a mixer to obtain a liniment. Further, the same operation was performed, and the container for spraying was filled to obtain a non-gas spray agent.

[Example 18] Aerosol
(weight%)
Ethanol 55.0
Crotamiton 5.0
Indomethacin 1.0
2-Methyl-3- (1-menthyloxy) propane-1,2-diol 0.3
Purified water remaining amount The above components were mixed in a mixer, put in a pressure vessel, filled with dimethyl ether, and used as an aerosol agent.

Example 19 Stick agent
(weight%)
Sodium stearate 7.0
Isopropanol 5.0
1,3-butylene glycol 65.0
Ferpinac 1.0
Polyoxyethylene hydrogenated castor oil 1.0
2-Methyl-3- (l-menthyloxy) propane-1,2-diol 7.0
Purified water remaining amount The above components were mixed while heating with a mixer to obtain a uniform solution, which was cooled and solidified to obtain a stick agent.

[Comparative Example 1] Gel ointment A gel ointment was prepared by exactly the same formulation and production method as Example 5, except that 2-methyl-3- (l-menthyloxy) propane-1,2-diol was not blended. did.
[Comparative Example 2] Gel ointment The same formulation and production method as in Example 5 except that l-menthol was blended in place of 2-methyl-3- (l-menthyloxy) propane-1,2-diol A gel ointment was prepared.
[Comparative Example 3] Gel ointment The same formulation and production method as in Example 6 except that l-menthol was blended instead of 2-methyl-3- (l-menthyloxy) propane-1,2-diol. A gel ointment was prepared.

[Comparative Example 4] Gel ointment The same formulation and production method as in Example 7 except that l-menthol was blended instead of 2-methyl-3- (l-menthyloxy) propane-1,2-diol. A gel ointment was prepared.
[Comparative Example 5] Gel ointment A gel ointment was prepared in exactly the same manner as in Example 8 except that 2-methyl-3- (l-menthyloxy) propane-1,2-diol was not blended. did.
[Comparative Example 6] Gel ointment The same formulation and production method as in Example 8 except that l-menthol was blended instead of 2-methyl-3- (l-menthyloxy) propane-1,2-diol. A gel ointment was prepared.

[Comparative Example 7] Gel ointment The same formulation and production method as in Example 9 except that l-menthol was blended instead of 2-methyl-3- (l-menthyloxy) propane-1,2-diol A gel ointment was prepared.
[Comparative Example 8] Gel ointment The same formulation and production method as in Example 10 except that l-menthol was blended instead of 2-methyl-3- (l-menthyloxy) propane-1,2-diol. A gel ointment was prepared.
[Comparative Example 9] Cathartic agent The same formulation and production method as in Example 4 except that l-menthol was blended instead of 2-methyl-3- (l-menthyloxy) propane-1,2-diol. A poultice was prepared.

[Test Example 1]
A hairless mouse skin permeation test was performed on the gel ointment of Examples 5 to 10 and the gel ointment of Comparative Examples 1 to 8. In the test method, hairless mouse-extracted skin was attached to a Franz-type cell, 0.5 mL of the preparation was applied to the donor cell, and 4 mL of phosphate buffered saline was applied to the receiver cell. The experiment was performed at 32 ° C. A portion of the receiver solution was collected at regular time intervals, and the amount of drug that permeated the receiver side was quantified by HPLC. Table 1 shows the permeation rate and lag time of ketoprofen, and Table 2 shows the permeation rate and lag time of indomethacin.

When the medicinal component is ketoprofen, the permeation rate is 114.8 (μg / cm ² / hr) of Comparative Example 1 in which no refreshing agent is blended, and 2-methyl-3- (l- Menthyloxy) propane-1,2-diol was blended in an amount of 0.5% by weight, 1.0% by weight, and 2.0% by weight, respectively. %, 51%, and 84%, which hardly affected the transdermal absorption rate.
On the other hand, the increase rate of the permeation rate in Comparative Example 2, Comparative Example 3 and Comparative Example 4 in which l-menthol was similarly blended with the refreshing agent was 70%, 284%, and 373%, which greatly affected the transdermal absorption rate. did.

When the medicinal component is indomethacin, the permeation rate of 16.5 (μg / cm ² / hr) of Comparative Example 5 in which no refreshing agent is blended, the 2-methyl-3- (l- Menthyloxy) propane-1,2-diol was blended in an amount of 0.5% by weight, 1.0% by weight, and 2.0% by weight, respectively. %, 61% and 220%, which hardly affected the transdermal absorption rate.
On the other hand, the increase rate of the permeation rate in Comparative Example 6, Comparative Example 7, and Comparative Example 8 in which l-menthol was similarly blended with the refreshing agent was 212%, 900%, and 985%, which greatly affected the transdermal absorption rate. did.

[Test Example 2]
A sensory evaluation test was performed on the cataplasm of Example 4 and the cataplasm of Comparative Example 9. As a test method, a poultice was applied to the shoulder, and its physiological cooling effect and odor were compared and examined. The test was performed using the judgment items shown in Table 3. Table 4 shows the sensory evaluation results indicating the average value by summing up the scores that the test subjects answered.

  As is clear from the above results, the external preparation of Example 4 in which 2-methyl-3- (l-menthyloxy) propane-1,2-diol was blended as a refreshing agent was compared with l-menthol. Compared to Example 9, while maintaining the same refreshing strength, the odor strength was about 1/6.

Claims (6)

A preparation for external use,
(1) An external preparation containing a medicinal component, and (2) a refreshing agent that suppresses mint smell and does not substantially affect the transdermal absorption rate of the medicinal component. The external preparation according to claim 1, wherein the refreshing agent is 2-methyl-3- (l-menthyloxy) propane-1,2-diol or a derivative thereof. The external preparation according to claim 1, wherein the refreshing agent is 2-methyl-3- (l-menthyloxy) propane-1,2-diol. The external preparation according to any one of claims 1 to 3, wherein the amount of the refreshing agent is 0.0001 to 20% by weight based on the total composition weight of the external preparation. The medicinal component is one or more medicinal components selected from the group consisting of non-steroidal anti-inflammatory agents and derivatives thereof, skeletal muscle relaxants, and vasodilators. Topical formulation. The external preparation according to any one of claims 1 to 5, which is in the form of a patch, a solid preparation, a semi-solid preparation, a solution, or a spray.