JP2022176349A - Loxoprofen-containing skin care preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a component that suppresses reduction of viscosity of a skin care preparation containing loxoprofen in which high-concentration lower alcohol is compounded, and precipitation of insoluble substance seen in an external appearance.

SOLUTION: Diisopropanolamine is selected as a pH regulator.

SELECTED DRAWING: None

COPYRIGHT: (C)2023,JPO&INPIT

Description

TECHNICAL FIELD The present invention relates to an external preparation for skin containing loxoprofen having an excellent analgesic and anti-inflammatory effect. More specifically, it relates to a loxoprofen-containing topical preparation for skin, in which loxoprofen contains specific pharmaceutical additives to improve the transparency of the formulation as seen from its appearance and to suppress the decrease in the viscosity of the formulation.

Loxoprofen, which is a propionate non-steroidal antipyretic, analgesic, anti-inflammatory drug (NSAID), has antipyretic, analgesic, and antiphlogistic effects based on the inhibition of prostaglandin biosynthesis, like other NSAIDs. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract as an unchanged form with a weak gastric mucosa-irritating effect after oral administration and becomes an active form in the body. It is also known (for example, see Non-Patent Document 1).

In recent years, loxoprofen has been marketed as an external anti-inflammatory analgesic in poultices, tapes and gels, and has been clinically used (see, for example, Non-Patent Document 2). It is known that loxoprofen is converted to a trans-OH form (active form) by ketone reductase even in the skin (see, for example, Patent Document 1).

So far, it has been disclosed that percutaneous absorption of loxoprofen was enhanced by blending a carboxyvinyl polymer in an external gel preparation containing loxoprofen and 10 to 30% by weight of a lower alcohol (see Patent Document 2). Further, it is disclosed that skin permeability, stability and aesthetic appearance are improved when an organic amine is added to a patch containing amfenac sodium (see Patent Document 3). These formulations do not contain lower alcohol, or if they do contain lower alcohol, they are external preparations containing 30% by weight or less.

However, when adding an oil-soluble component such as a cooling agent to improve the feeling of use, or when increasing the quick-drying properties of the formulation to reduce adhesion to clothes, etc., it is necessary to increase the lower alcohol content. There is However, external preparations containing loxoprofen sodium have difficulty in thickening as the content of lower alcohol is increased, and also have problems in appearance such as deposits or separation of the formulation. Therefore, there is a strong demand for a loxoprofen-containing external preparation that suppresses the decrease in viscosity of the preparation and does not cause precipitation of insoluble matter.

So far, gel agents containing carboxyvinyl polymer, isopropanol and diisopropanolamine in indomethacin have been marketed (see Non-Patent Document 3). In addition, a gel agent containing carboxyvinyl polymer, ethanol and diisopropanolamine in felbinac is commercially available (see Non-Patent Document 4). However, topical preparations containing loxoprofen and carboxyvinyl polymer and diisopropanolamine and 30.5% by weight or more of lower alcohols are not known, and how diisopropanolamine affects formulation viscosity or appearance in such cases. Nothing is known about.

Japanese Patent Application Laid-Open No. 2008-074873 Japanese Patent No. 4195178 Special republication 2010-103844

Pharmacology and Treatment Vol.16 No.2 1988 p.611-619 JAPIC Prescription Drugs 2013 Maruzen 2012 Vantelin Kowa Gel LT package insert Fatus Gel package insert

As mentioned above, when adding oil-soluble ingredients such as cooling agents to improve the feeling of use, or when improving the quick-drying properties of the formulation to reduce adhesion to clothes, etc., the inclusion of lower alcohols in the formulation need to increase the quantity. However, the present inventors have found that, for example, in a formulation containing loxoprofen sodium and a carboxyvinyl polymer according to Patent Document 2, if the lower alcohol content is higher than 10 to 30% by weight described in Patent Document 2, there is a significant It was found that at least one of viscosity reduction and insoluble matter precipitation occurred. Accordingly, an object of the present invention is to provide a loxoprofen-containing topical skin preparation formulated with a high concentration of a lower alcohol in which viscosity reduction is suppressed and insoluble matter precipitation is suppressed.

The present inventors selected diisopropanolamine as a pH adjusting agent (neutralizing agent for carboxyvinyl polymer) in an external skin preparation containing loxoprofen containing a high concentration of a lower alcohol to contain loxoprofen sodium. The present inventors have found that the reduction in viscosity and the precipitation of insoluble matter in external preparations for skin can be significantly suppressed, and the present invention has been completed.

That is, the present invention
(1) A skin external preparation containing loxoprofen, a carboxyvinyl polymer, diisopropanolamine and a lower alcohol,
(2) The topical skin preparation according to (1) above, wherein the lower alcohol content is 30.5% by weight or more;
(3) The external preparation for skin according to (1) or (2), which further contains 0.1 to 5.0% by weight of a cellulose-based water-soluble polymer.
(4) The skin according to (3) above, wherein the cellulose-based water-soluble polymer is one or more selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, hydrophobized hydroxypropylmethylcellulose, hypromellose and methylcellulose. topical agents,
(5) The external preparation for skin according to any one of (1) to (4) above, wherein the formulation pH is 6.0 to 7.5;
(6) The external preparation for skin according to any one of (1) to (5) above, which further contains a polyhydric alcohol;
(7) The external preparation for skin according to any one of (1) to (6) above, which further contains l-menthol;
(8) The skin external preparation according to any one of (1) to (7) above, which is for analgesic and antiphlogistic use;
(9) The external preparation for skin according to any one of (1) to (8) above, wherein the dosage form is a gel, cream, liquid, or aerosol;
or
(10) The external preparation for skin according to any one of (1) to (8) above, which is in the form of a gel.

The topical skin preparation containing loxoprofen, carboxyvinyl polymer, diisopropanolamine and a lower alcohol of the present invention, especially the topical skin preparation containing 30.5% or more of the lower alcohol, is excellent in feeling when used and has a high lower alcohol content. It remarkably suppresses viscosity reduction and/or precipitation of insoluble matter that occurs in , and is clinically extremely useful.

In the present invention, "loxoprofen" is loxoprofen or a salt thereof (including a hydrate salt), preferably loxoprofen sodium or loxoprofen sodium dihydrate, more preferably loxoprofen sodium dihydrate. It is Japanese.

Loxoprofen of the present invention is listed in the Japanese Pharmacopoeia 17th Edition as loxoprofen sodium hydrate.

Carboxyvinyl polymer (also called carboxypolymethylene) is a pharmaceutical excipient used for external preparations for purposes such as thickening agents, adhesives, dispersing agents, stabilizers, and bases. Co., 2016).

Diisopropanolamine is a pharmaceutical additive used in external preparations for applications such as stabilizers, bases, pH adjusters, solvents, and dissolution aids, and is listed in Dictionary of Pharmaceutical Excipients 2016.

Lower alcohols are aliphatic alcohols having 1 to 4 carbon atoms that are used in external agents such as solubilizers, bases, preservatives, solvents, solubilizers, etc. Examples include methanol, ethanol (ethyl one or more selected from the group consisting of alcohol), propanol, isopropanol (also referred to as isopropyl alcohol), and butyl alcohol, preferably one or two selected from the group consisting of ethanol and isopropanol is. Those with an ethanol content of 99.5% by volume or more are also called anhydrous ethanol.

l-Menthol is a pharmaceutical additive used in external preparations for applications such as cooling agents, fragrances, and stabilizers, and is listed in Dictionary of Pharmaceutical Additives 2016.

A cellulose-based water-soluble polymer is made water-soluble by modifying the hydroxyl groups of water-insoluble cellulose with methyl chloride, propylene oxide, ethylene oxide, or the like. . The cellulosic water-soluble polymer is, for example, one or more selected from the group consisting of ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydrophobized hydroxypropylmethylcellulose, hypromellose and methylcellulose, Preferably, one or more selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, hydrophobized hydroxypropylmethylcellulose, hypromellose and methylcellulose.

In addition, the polyhydric alcohol in the present invention is an alcohol having two or more hydroxyl groups in the molecule, which is used in external preparations such as solubilizers, bases, wetting agents, thickeners, solvents, and dissolution aids. , for example, propylene glycol, 1,3-butylene glycol, concentrated glycerin, macrogol 200, macrogol 300, macrogol 400, D-sorbitol, etc., listed in the dictionary of pharmaceutical excipients 2016.

The content of loxoprofen contained in the external preparation of the present invention is not particularly limited, but is preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight. Apply this once to several times a day.

In addition, the upper limit of the amount of lower alcohol added (the total amount of each alcohol added when two or more alcohols are included) is not particularly limited, but is preferably 30.5 to 65.0% by weight, and more preferably. is 30.5 to 55.0%.

The amount of carboxyvinyl polymer added is not particularly limited, but is preferably 0.1 to 5.0%, more preferably 0.7 to 3.0%.

Further, the amount of diisopropanolamine added is preferably 0.08 to 7.5%, more preferably 0.6 to 4.5%, and the amount of l-menthol added is not particularly limited. , preferably 0.01 to 10%, more preferably 0.1 to 7.5%.

The compounding ratio of the carboxyvinyl polymer and diisopropanolamine contained in the external preparation for skin of the present invention is preferably 0.75 parts by weight or more of diisopropanolamine per 1 part by weight of the carboxyvinyl polymer. It is more preferably 8 parts by weight or more. If the content of diisopropanolamine is less than 0.75 parts by weight per 1 part by weight of the carboxyvinyl polymer, problems such as precipitation may occur.

The amount of the cellulose-based water-soluble polymer added is not particularly limited, but is preferably 0.1 to 3%, more preferably 0.5 to 2.5%.

Furthermore, the amount of the polyhydric alcohol to be added is not particularly limited, but it is preferably 0.5 to 20%, more preferably 1.0 to 15%. Also, the pH range of the formulation is preferably 5.5 to 7.5, more preferably 6.0 to 7.4.

In addition, when the external skin preparation of the present invention is dispensed into a transparent glass bottle with a barrel diameter of 35 mm and the viscosity is measured using a B-type viscometer (spindle M4) manufactured by Toki Sangyo Co., Ltd., the viscosity is measured at 25 ° C., 12 rpm, 120 seconds. The subsequent viscosity values are usually from 5000 to 100000 mPa·s, preferably from 10000 to 70000 mPa·s. In particular, when the external preparation for skin of the present invention is in the form of a gel, it preferably has a viscosity of 10,000 to 70,000 mPa·s. If the viscosity is less than 10,000 mPa·s, it becomes difficult to adjust the discharge rate with tube-type containers used for commercial gel formulations, and dripping is likely to occur during application, resulting in poor usability. Conversely, if the viscosity is higher than 70,000 mPa·s, it becomes difficult to discharge from the tube-shaped container, and spreadability during application is poor, and stickiness after application is also aggravated. Therefore, it is preferable that the viscosity of the preparation (preferably gel) is within a certain lower and upper limit range. By blending the specific diisopropanolamine into the formulation according to the present invention, the viscosity value can be adjusted to 10,000 to 70,000 mPa·s, and a formulation with excellent usability and handling can be obtained.

In the topical preparation of the present invention, drugs and pharmaceutical additives that are usually used in analgesic and anti-inflammatory skin topical preparations other than the above ingredients can be added.

Such drugs include, for example, anti-inflammatory agents such as glycyrrhizic acid and glycyrrhetinic acid, antihistamines such as diphenhydramine and chlorpheniramine maleate, blood circulation improving ingredients such as tocopherol acetate and benzyl nicotinate, l-menthol, and nonylic acid. Locally stimulating ingredients such as vanillylamide and capsicum extract, crude drug ingredients such as arnica tincture, and the like can be mentioned, and these drugs can be blended within a range that does not impair the effects of the present invention.

Pharmaceutical additives other than the above ingredients are added as necessary for the purpose of, for example, further improving the stability of the content over time and the feeling of use. and cooling agents.

As such a wetting agent, for example, sodium dl-pyrrolidonecarboxylate solution, polysorbate 80, macrogol 200 and the like can be added.

Examples of pH adjusters that can be used include hydrochloric acid, sodium hydroxide, potassium hydroxide, phosphoric acid, lactic acid, organic amines, and the like.

Examples of antioxidants that can be used include tocopherol, tocopherol acetate, and the like.

Cooling agents include, for example, camphor, dl-camphor, peppermint oil, l-menthol, eucalyptus oil and the like.

Specific dosage forms of the external preparation for skin of the present invention include, for example, liquids, creams, ointments, gels, and aerosols. It can be produced according to the usual method described in the Japanese Pharmacopoeia and the like.

The topical skin preparation of the present invention is used as an analgesic and anti-inflammatory agent for patients suffering from pain and inflammation, such as low back pain, bruises, sprains, shoulder pain associated with stiff shoulders, tendonitis, elbow pain, and arthralgia. can be done.

EXAMPLES The present invention will be described more specifically below with reference to examples.

(Formulation example)
(Table 1)
Amount per 100 g of gel formulation (g) Formulation 1 Formulation 2 Formulation 3 Formulation 4 Formulation 5 Formulation 6 Formulation 7
――――――――――――――――――――――――――――――――――――――――
Loxoprofen 1.134 1.134 1.134 1.134 1.134 1.134 1.134
Sodium dihydrate*
Ethanol 45.0 47.5 50.0 50.0 45.0 47.5 50.0
Propylene glycol 3.0 5.0 5.0 3.0 3.0 5.0 3.0
1,3-butylene 2.0 - - - - - -
Glycol Concentrated Glycerin － － － 1.0 － － －
Macrogol 200 － － － － 1.0 － －
dl-pyrrolidone - - - - - 1.0 -
Sodium carboxylate solution Glycyrrhetinic acid 0.1 － 0.05 － － － 0.1
dl-camphor 3.0 － － － － － 3.0
Diphenhydramine 0.5 － － － － － 0.5
Capsicum extract 0.1 － － － － － 0.1
Peppermint oil － － － 0.3 － － －
Capsicum tincture － － － － 0.2 － －
Polyoxyethylene 1.2 － 1.2 1.2 － － 1.2
Hydrogenated castor oil 40
Tocopherol 0.1 － 0.5 0.1 － － 0.5
Acetate l-menthol 3.0 3.0 3.0 3.0 3.0 3.0 3.0
Carboxyvinyl 0.80 1.35 1.0 1.5 1.10 2.50 1.35
Polymer hypromellose 1.2 0.8 1.0 － 0.8 0.4 －
Hydroxypropyl － － － 0.5 － － 0.9
Cellulose xanthan gum － － － － 0.2 － －
Diisopropa 0.64 1.32 0.9 2.1 1.43 2.75 1.98
Nolamine Hydrochloric Acid※※ Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Phosphoric Acid※※ Appropriate Appropriate Appropriate Appropriate Appropriate Lactic Acid※※ Appropriate Appropriate Appropriate Appropriate Appropriate Purified Water Remainder Remainder Remainder Remainder Remainder Remainder Remainder ――――――――― ――――――――――――――――――――――――――――――
* Equivalent to 1 g of loxoprofen sodium (converted to anhydrous) ** Select one or more arbitrarily and add an appropriate amount

(Table 2)
(Gel agent)
Amount per 100 g of formulation (g) Formulation 8 Formulation 9 Formulation 10 Formulation 11 Formulation 12 Formulation 13
―――――――――――――――――――――――――――――――――――――――
Loxoprofen 1.134 1.134 1.134 1.134 1.134 1.134
Sodium dihydrate*
Ethanol 50.0 45.0 45.0 50.0 45.0 45.0
Propylene glycol 5.0 5.0 5.0 3.0 5.0 5.0
Nonanoic acid vanillylamide 0.012 － 0.015 0.025 0.012 0.1
Chlorpheniramine 0.1 0.1 0.1 - - -
Maleate Glycyrrhetinic acid － － 0.05 0.2 － －
Nicotinic acid － － 0.02 － 0.01 －
benzyl ester dl-camphor - - - - - -
Capsicum extract 0.1 － － － － －
Eucalyptus oil 0.5 － － － － －
Thymol 1.0 － － － － －
Polyoxyethylene － 1.6 － 1.6 － －
Hardened castor oil 60
Tocopherol Acetate － 0.1 － 0.5 － －
l-Menthol 3.0 3.0 3.0 3.0 3.0 6.0
Carboxyvinyl polymer 0.9 1.70 1.2 2.0 2.20 2.70
Hypromellose 1.0 0.8 － 0.9 － 0.2
Hydroxy － － 1.0 － 0.5 －
Propyl cellulose xanthan gum － － － － － 0.2
Diisopropanolamine 1.08 1.87 1.8 2.0 1.98 2.65
Hydrochloric acid※※ Appropriate Appropriate Appropriate Appropriate Phosphoric acid※※ Appropriate Appropriate Appropriate Appropriate Appropriate Lactic acid※※ Appropriate Appropriate Appropriate Appropriate Purified water Remainder Remainder Remainder Remainder Remainder Remainder ――――――――――――― ―――――――――――――――――――――――――
* Equivalent to 1 g of loxoprofen sodium (converted to anhydrous) ** Select one or more arbitrarily and add an appropriate amount

(Table 3)
(Solid formulation for external use)
Amount per 100 g of formulation (g) Formulation 14 Formulation 15 Formulation 16 Formulation 17 Formulation 18 Formulation 19
―――――――――――――――――――――――――――――――――――――――
Loxoprofen 1.134 1.134 1.134 1.134 1.134 1.134
Sodium dihydrate*
Anhydrous ethanol 20 15 25 － 30 15
Isopropanol － － － 15 － －
Concentrated glycerin 30 10 30 30 － －
Propylene glycol － 30 10 10 － －
1,3-butylene glycol 10 - - - 35 40
Sodium Stearate 7 8 9 8 7 9
l-Menthol 3 3 3 3 6 3
Sodium Lauryl Sulfate 1 － 1 1 － －
Polyoxyethylene － 1 － － － 2
Hydrogenated castor oil 40
Tocopherol Acetate － － － － － 0.5
Isopropyl myristate - - 1 1 - -
Sodium hydroxide Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Balance Balance Balance Balance Balance ―――――――――――――――――――――――――――――――――― ――――――
* Equivalent to 1 g of loxoprofen sodium (converted to anhydrous)

(Table 4)
(liquid)
Amount per 100 g of formulation (g) Formulation 20 Formulation 21 Formulation 22 Formulation 23 Formulation 24 Formulation 25
―――――――――――――――――――――――――――――――――――――――
Loxoprofen 1.134 1.134 1.134 1.134 1.134 1.134
Sodium dihydrate*
Ethanol 50.0 50.0 45.0 47.5 45.0 45.0
Propylene glycol 5.0 5.0 5.0 3.0 5.0 5.0
Nonanoic Acid Vanillylamide 0.025 0.025 － 0.012 － －
Chlorpheniramine 0.1 0.1 0.1 0.1 - -
Glycyrrhetinic acid maleate 0.2 0.2 － － － －
Nicotinic acid 0.02 － － 0.01 － －
Benzyl ester polyoxyethylene － 1.6 － － － －
Hardened castor oil 60
Tocopherol Acetate － 0.5 － － － －
l-Menthol 3.0 3.0 3.0 3.0 3.0 6.0
Carboxyvinyl polymer 0.2 0.35 0.50 0.70 0.80 0.90
Hypromellose 0.2 0.1 － 0.3 － －
Hydrophobized hydroxy － － － － 0.1 0.1
Propyl methylcellulose diisopropanolamine 0.2 0.46 0.45 1.05 0.96 0.99
Sodium hydroxide※※ Appropriate amount Appropriate amount Appropriate amount Appropriate amount Hydrochloric acid※※ Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Phosphoric acid※※ Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Lactic acid※※ Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Remainder Remainder Remainder Remainder Remainder Remainder ――― ――――――――――――――――――――――――――――――――――――
* Equivalent to 1 g of loxoprofen sodium (converted to anhydrous) ** Select one or more arbitrarily and add an appropriate amount

Take the amounts of the ingredients described in Tables 1 to 4 above, and manufacture according to the Japanese Pharmacopoeia General Rules for Preparations "Gels", "Solid Formulations for External Use", and "Liquid Formulations for External Use" to obtain Formulation Examples 1 to 25.

(Test example) Appearance storage stability test of loxoprofen-containing topical skin preparation (1) Test materials Loxoprofen sodium dihydrate manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd. Diclofenac sodium and indomethacin were manufactured by Tokyo Chemical Industry Co., Ltd. Co., Ltd., and the carboxyvinyl polymer is manufactured by Sumitomo Seika Co., Ltd. (product name: AQUPEC HV-501E or AQUPEC HV-505E (Examples 4 to 5, Comparative Examples 4 to 5)). , Hypromellose from Ashland, absolute ethanol from Imazu Pharmaceutical Co., Ltd., isopropanol from Kosakai Pharmaceutical Co., Ltd., diisopropanolamine and triethanolamine from Wako Pure Chemical Industries, Ltd. The l-menthol used was from Suzuki Minka Co., Ltd., and the propylene glycol was from Maruishi Seiyaku Co., Ltd., respectively. As a transparent glass vial, Mighty Vial (transparent, No. 7) manufactured by Maruem Co., Ltd. was used.

(2) Preparation of Samples After mixing and dissolving the components shown in Tables 5 to 7 below, gels of Examples 1 to 6 and Comparative Examples 1 to 10 were obtained.

(3) Test method Each preparation obtained was dispensed into a transparent glass vial with a barrel diameter of 35 mm and sealed. Each was stored at 25° C. and 60% relative humidity, and one week later, the pH of the formulation, visual confirmation of appearance, and viscosity of the formulation were measured. The formulation viscosity is the viscosity value after 120 seconds at 25° C., 12 rpm, measured using a B-type viscometer (spindle M4) manufactured by Toki Sangyo Co., Ltd.

(Table 5)
Amount (g) per 100 g of formulation Comparative Example 1 Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5
――――――――――――――――――――――――――――――――――――――――
Loxoprofen 1.134 1.134 － － － －
Sodium dihydrate*
Diclofenac sodium - - 1.0 1.0 - -
Indomethacin － － － － 1.0 1.0
Anhydrous ethanol 45.0 45.0 45.0 45.0 45.0 45.0
Propylene glycol 5.0 5.0 5.0 5.0 5.0 5.0
Hypromellose 0.6 0.6 0.6 0.6 0.6 0.6
Carboxy vinyl polymer 1.2 1.2 1.2 1.2 1.2 1.2
Triethanolamine 1.3 － 1.3 － 1.3 －
Diisopropanolamine - 1.2 - 1.2 - 1.2
l-Menthol 3.0 3.0 3.0 3.0 3.0 3.0
Purified water Remainder Remainder Remainder Remainder Remainder Remainder――――――――――――――――――――――――――――――――――――――――
Appearance after 1 week storage at 25°C × ○ ○ ○ ○ ○
Viscosity (mPa・s) 2000 18800 15000 26500 26000 36900
pH 7.12 7.16 6.82 6.69 6.44 6.44
―――――――――――――――――――――――――――――――――――――――
* Equivalent to 1 g of loxoprofen sodium (converted to anhydrous) ○: No precipitation of insoluble matter ×: Precipitation of insoluble matter

(Table 6)
Amount (g) per 100 g of formulation Comparative Example 6 Example 2 Comparative Example 7 Example 3 Comparative Example 8 Example 4
―――――――――――――――――――――――――――――――――――――――
Loxoprofen 1.134 1.134 1.134 1.134 1.134 1.134
Sodium dihydrate*
Anhydrous ethanol 30.5 30.5 － － － －
Isopropanol － － 30.5 30.5 40.0 40.0
Propylene glycol 10.0 10.0 10.0 10.0 5.0 5.0
Hypromellose 0.5 0.5 0.5 0.5 0.6 0.6
Carboxyvinyl polymer 0.7 0.7 0.8 0.8 1.2 1.2
Triethanolamine 0.8 － 0.9 － 1.3 －
Diisopropanolamine － 0.7 － 0.8 － 1.2
l-Menthol － － － － 3.0 3.0
Purified water Remainder Remainder Remainder Remainder Remainder Remainder――――――――――――――――――――――――――――――――――――――――
Appearance after 1 week storage at 25°C × ○ × ○ × ○
Viscosity (mPa・s) 15700 21700 3100 19300 2300 16400
pH 6.66 6.67 6.69 6.80 6.66 6.56
―――――――――――――――――――――――――――――――――――――――
* Equivalent to 1 g of loxoprofen sodium (converted to anhydrous) ○: No precipitation of insoluble matter ×: Precipitation of insoluble matter

(Table 7)
Amount (g) per 100 g of formulation Comparative Example 9 Example 5 Comparative Example 10 Example 6
―――――――――――――――――――――――――――――――――――
Loxoprofen 1.134 1.134 1.134 1.134
Sodium dihydrate*
Anhydrous ethanol 55.0 55.0 － －
Isopropanol － － 47.0 47.0
Propylene glycol 4.0 4.0 3.0 3.0
Hypromellose 1.0 1.0 1.0 1.0
Carboxyvinyl polymer 1.2 1.2 1.4 1.4
Triethanolamine 1.3 － 1.6 －
Diisopropanolamine - 1.2 - 1.4
l-Menthol 3.0 3.0 3.0 3.0
Purified water Remainder Remainder Remainder Remainder――――――――――――――――――――――――――――――――――――
Appearance after 1 week storage at 25°C × ○ × ○
Viscosity (mPa・s) 2100 13500 2500 16500
pH 7.04 7.10 6.70 6.74
―――――――――――――――――――――――――――――――――――
* Equivalent to 1 g of loxoprofen sodium (converted to anhydrous) ○: No precipitation of insoluble matter ×: Precipitation of insoluble matter

(4) Test Results The results of appearance confirmation are shown in Tables 5-7. Comparative Examples 1, 6, 7, 8, 9 and 10 showed that at least one of viscosity reduction and insoluble matter precipitation occurred in the presence of a high concentration of lower alcohol of 30.5% or more in loxoprofen-containing preparations. In addition, according to Comparative Examples 2 to 5, this viscosity decrease and insoluble matter precipitation are phenomena peculiar to loxoprofen-containing formulations that do not occur in other NSAID-containing formulations (components other than NSAID have the same composition). shown. Further, from the results of Example 1, it was found that only by using a specific diisopropanolamine instead of triethanolamine as a pH adjuster, the decrease in viscosity and the deposition of insoluble matter were significantly suppressed.
Furthermore, from the results of Examples 1 to 6, even when either ethanol or isopropanol is used as the lower alcohol, diisopropanolamine can be used in loxoprofen-containing preparations in the presence of a high concentration of lower alcohol of 30.5% or more. It was found that the viscosity reduction and precipitation of insoluble matter, which can be seen from the appearance, can be significantly suppressed.

The external preparation for skin containing loxoprofen, carboxyvinyl polymer, diisopropanolamine and lower alcohol according to the present invention has an excellent feel when used, and significantly suppresses viscosity reduction and/or precipitation of insoluble matter, especially when the lower alcohol content is high. It is clinically very useful.

Claims (9)

An external skin preparation containing loxoprofen, carboxyvinyl polymer, diisopropanolamine, isopropanol and l-menthol, wherein the l-menthol content is 3% by weight or more. 2. The skin external preparation according to claim 1, wherein the content of isopropanol is 30.5% by weight or more. 3. The external preparation for skin according to claim 1, further comprising 0.1 to 5.0% by weight of a cellulose-based water-soluble polymer. 4. The external preparation for skin according to claim 3, wherein the water-soluble cellulose polymer is one selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, hydrophobized hydroxypropylmethylcellulose, hypromellose and methylcellulose. 5. The external preparation for skin according to any one of claims 1 to 4, further having a formulation pH of 6.0 to 7.5. The external preparation for skin according to any one of claims 1 to 5, further comprising a polyhydric alcohol. 7. The external preparation for skin according to any one of claims 1 to 6, which is for analgesic and antiphlogistic use. The skin external preparation according to any one of claims 1 to 7, wherein the dosage form is gel, cream, liquid, or aerosol. The skin external preparation according to any one of claims 1 to 8, wherein the dosage form is a gel.