JP2018188429A - External preparation for skin containing loxoprofen - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a component that suppresses a decreased viscosity, or the appearance of precipitated insoluble matter, in a loxoprofen-containing skin external preparation that comprises a high concentration of lower alcohol.SOLUTION: Diisopropanolamine is selected as a pH regulator.SELECTED DRAWING: None

Description

  The present invention relates to a skin external preparation containing loxoprofen having an excellent analgesic / anti-inflammatory action. More specifically, the present invention relates to a loxoprofen-containing external preparation for skin which increases the transparency of the preparation as seen from the appearance and suppresses a decrease in the viscosity of the preparation by containing a specific pharmaceutical additive in loxoprofen.

  Loxoprofen, which is a propionic non-steroidal antipyretic analgesic / anti-inflammatory agent (NSAID), has antipyretic / analgesic / anti-inflammatory effects based on the inhibitory action of prostaglandin biosynthesis, similar to other NSAIDs. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract and remains active in the body as an intact substance with weak gastric mucosal irritation after oral administration. However, it is also known (for example, refer nonpatent literature 1).

  In recent years, loxoprofen has been put into clinical use as a topical anti-inflammatory analgesic and is used clinically (see, for example, Non-Patent Document 2). Loxoprofen is known to be converted to a trans-OH form (active form) by ketone reductase in the skin (see, for example, Patent Document 1).

  So far, it has been disclosed that percutaneous absorption of loxoprofen is enhanced by blending a carboxyvinyl polymer in an external gel preparation containing loxoprofen and 10-30% by weight of lower alcohol (see Patent Document 2). Further, it is disclosed that skin permeability, stability, and aesthetics are improved when an organic amine is blended with a patch containing amphenac sodium (see Patent Document 3). These preparations are external preparations containing no lower alcohol or 30% by weight or less.

  However, it is necessary to increase the content of lower alcohol when adding oil-soluble ingredients such as cooling agents to improve the feeling of use, or when increasing the quick-drying property of the preparation to reduce adhesion to clothes, etc. There is. However, in the external preparation containing loxoprofen sodium, as the content of the lower alcohol is increased, it is difficult to increase the viscosity, and further, there is a problem in appearance such as precipitation or separation of the preparation. For this reason, the appearance of an external preparation containing loxoprofen that suppresses a decrease in the viscosity of the preparation and does not cause precipitation of insoluble matters is desired.

  So far, gel agents containing carboxyvinyl polymer and isopropanol and diisopropanolamine in indomethacin have been commercially available (see Non-Patent Document 3). Moreover, the gel agent which contains a carboxy vinyl polymer and ethanol and diisopropanolamine in felbinac is marketed (refer nonpatent literature 4). However, external preparations containing loxoprofen and carboxyvinyl polymer and diisopropanolamine and lower alcohol of 30.5% by weight or more are not known, and in such a case, how diisopropanolamine affects the formulation viscosity or appearance. Is not known at all.

JP 2008-074873 A Japanese Patent No. 4195178 Special republication 2010-103844

Pharmacology and treatment Vol.16 No.2 1988 p.611-619 JAPIC Ethical Drug Collection 2013 Maruzen 2012 Vantelin Kowagel LT package insert Fetus gel package insert

  As mentioned above, when adding oil-soluble ingredients such as refreshing agents to improve the feeling of use, or when increasing the quick-drying property of the preparation to reduce adhesion to clothes, etc., the inclusion of lower alcohol in the preparation The amount needs to be increased. However, the present inventors, for example, in a preparation containing loxoprofen sodium and carboxyvinyl polymer according to Patent Document 2, for example, when the content of lower alcohol is higher than 10 to 30% by weight described in Patent Document 2, it is remarkable. It has been found that at least one of viscosity reduction and insoluble matter precipitation occurs. Therefore, the subject of this invention is providing the formulation by which the viscosity fall was suppressed and insoluble matter precipitation was suppressed in the loxoprofen containing skin external preparation which mix | blends a high concentration lower alcohol.

  The present inventors include loxoprofen sodium by selecting diisopropanolamine as a pH regulator (carboxyvinyl polymer neutralizing agent) in a skin external preparation containing loxoprofen formulated with a high concentration of lower alcohol. The present invention has been completed by remarkably suppressing the decrease in viscosity and the precipitation of insoluble matter in the external preparation for skin.

That is, the present invention
(1) A skin external preparation containing loxoprofen, carboxyvinyl polymer, diisopropanolamine and lower alcohol,
(2) The skin external preparation according to (1), wherein the content of the lower alcohol is 30.5% by weight or more,
(3) The skin external preparation according to (1) or (2), further containing 0.1 to 5.0% by weight of a cellulose-based water-soluble polymer,
(4) The skin according to (3), 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 agent,
(5) The skin external preparation according to any one of (1) to (4), wherein the formulation pH is 6.0 to 7.5,
(6) The skin external preparation according to any one of (1) to (5), further comprising a polyhydric alcohol,
(7) The skin external preparation according to any one of (1) to (6), further containing l-menthol,
(8) The external preparation for skin according to any one of (1) to (7), which is used for analgesic / anti-inflammatory.
(9) The external preparation for skin according to any one of (1) to (8), 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), wherein the dosage form is a gel.
It is.

  The skin external preparation containing loxoprofen, carboxyvinyl polymer, diisopropanolamine and lower alcohol of the present invention, in particular, the skin external preparation containing 30.5% or more of lower alcohol is excellent in use feeling and has a high content of lower alcohol. Is remarkably suppressed in the decrease in viscosity and / or insoluble precipitates generated in the process.

  In the present invention, “loxoprofen” is loxoprofen or a salt thereof (including a hydrous salt), preferably loxoprofen sodium or loxoprofen sodium dihydrate, and more preferably loxoprofen sodium dihydrate. It is a Japanese product.

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

  Carboxyvinyl polymer (also referred to as carboxypolymethylene) is a pharmaceutical additive used as an external preparation in applications such as thickeners, adhesives, dispersants, stabilizers, and bases. 2016).

  Diisopropanolamine is a pharmaceutical additive used as an external preparation in applications such as a stabilizer, a base, a pH adjuster, a solvent and a solubilizing agent, and is listed in the Pharmaceutical Additives Dictionary 2016.

  The lower alcohol is an aliphatic alcohol having 1 to 4 carbon atoms used as an external preparation in applications such as a solubilizer, a base, a preservative, a solvent, and a solubilizing agent. For example, methanol, ethanol (ethyl) 1 type or 2 types selected from the group consisting of propanol, isopropanol (also called isopropyl alcohol), butyl alcohol and the like, preferably 1 type or 2 types selected from the group consisting of ethanol and isopropanol It is. Those having an ethanol content of 99.5% by volume or more are also called absolute ethanol.

  l-Menthol is a pharmaceutical additive used as an external preparation in applications such as a refreshing agent, a fragrance, and a stabilizer, and is listed in the Pharmaceutical Additives Dictionary 2016.

  Cellulose-based water-soluble polymers are those in which water-insoluble cellulose hydroxyl groups are made water-soluble by modification with methyl chloride, propylene oxide, ethylene oxide, and the like. For example, they are listed in the Pharmaceutical Additives Dictionary 2016. . The cellulose water-soluble polymer is, for example, one or more selected from the group consisting of ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydrophobized hydroxypropyl methyl cellulose, hypromellose, and methyl cellulose. Preferably, it is 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 as an external preparation in applications such as a solubilizer, base, wetting agent, thickener, solvent, and solubilizing agent. For example, propylene glycol, 1,3-butylene glycol, concentrated glycerin, macrogol 200, macrogol 300, macrogol 400, D-sorbitol, and the like are listed in the Pharmaceutical Additives Dictionary 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, and more preferably 0.5 to 5% by weight. This is applied one to several times a day.

  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, more preferably Is 30.5 to 55.0%.

  Moreover, although the addition amount of a carboxy vinyl polymer is not specifically limited, Preferably it is 0.1 to 5.0%, More preferably, it is 0.7 to 3.0%.

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

  The blending 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 with respect to 1 part by weight of the carboxyvinyl polymer. More preferably 8 parts by weight or more. When the amount is less than 0.75 part by weight of diisopropanolamine with respect to 1 part by weight of the carboxyvinyl polymer, problems in appearance such as precipitation may occur.

  Moreover, although the addition amount of a cellulose water-soluble polymer is not specifically limited, Preferably it is 0.1 to 3%, More preferably, it is 0.5 to 2.5%.

  Furthermore, although the addition amount of a polyhydric alcohol is not specifically limited, All are 0.5 to 20% preferably, More preferably, it is 1.0 to 15%. Moreover, the range of formulation pH becomes like this. Preferably it is 5.5-7.5, More preferably, it is 6.0-7.4.

  In addition, when the external preparation for skin of the present invention is dispensed into a transparent glass bottle with a body diameter of 35 mm and measured for viscosity using a B-type viscometer (spindle M4) manufactured by Toki Sangyo Co., Ltd., 12 rpm at 25 ° C. for 120 seconds. The later viscosity value is usually 5000 to 100,000 mPa · s, preferably 10,000 to 70000 mPa · s. In particular, when the dosage form of the external preparation for skin of the present invention is a gel, the viscosity value is preferably 10,000 to 70000 mPa · s. When the viscosity is less than 10,000 mPa · s, it is difficult to adjust the discharge amount in a tube-type container used in a commercially available gel agent, and it is easy to cause dripping at the time of application, and the usability deteriorates. On the other hand, when the viscosity is higher than 70000 mPa · s, it is difficult to discharge from the tube-type container, the elongation at the time of coating is poor, and the stickiness after coating is also worsened. For this reason, it is preferable that a viscosity exists in the range of a fixed lower limit and an upper limit as a characteristic of a formulation (preferably gel agent). By blending a specific diisopropanolamine in the preparation according to the present invention, the viscosity value can be set to 10,000 to 70000 mPa · s, and a preparation excellent in feeling and handling can be obtained.

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

  Examples of such drugs include anti-inflammatory agents such as glycyrrhizic acid and glycyrrhetinic acid, antihistamines such as diphenhydramine and chlorpheniramine maleate, blood circulation improving components such as tocopherol acetate and benzyl nicotinate, l-menthol and nonylic acid Examples include local stimulating components such as crocodile amide and pepper extract, and herbal medicine components such as arnica tincture. These drugs can be blended within a range not impairing the effects of the present invention.

  Pharmaceutical additives other than the above components are added as necessary for the purpose of, for example, further improving the content stability over time and the feeling of use. For example, wetting agents, pH adjusting agents, antioxidants, etc. And a refreshing agent.

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

  As the pH adjuster, for example, hydrochloric acid, sodium hydroxide, potassium hydroxide, phosphoric acid, lactic acid, organic amine and the like can be used.

  As the antioxidant, for example, tocopherol, tocopherol acetate and the like can be used.

  Examples of the refreshing agent include camphor, dl-camphor, peppermint oil, l-menthol, and eucalyptus oil.

  Specific dosage forms of the external preparation for skin of the present invention include, for example, liquids, creams, ointments, gels, aerosols, etc. Additives and bases suitable for each dosage form are appropriately used. It can be used and manufactured according to the usual methods described in the Japanese Pharmacopoeia.

  The external preparation for skin of the present invention is used for pain and inflammation, for example, patients with back pain, bruise, sprain, shoulder pain associated with stiff shoulder, tendonitis, elbow pain, joint pain, etc. Can do.

  Hereinafter, the present invention will be described more specifically with reference to examples.

(Formulation example)
(Table 1)
Formulation in 100g of gel preparation (g) Formula 1 Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 Formula 7 Formula 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-rich 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
Pepper extract 0.1 − − − − − 0.1
Mentha oil---0.3---
Pepper tincture − − − − 0.2 − −
Polyoxyethylene 1.2 − 1.2 1.2 − − 1.2
Hardened 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--
Diisoprop 0.64 1.32 0.9 2.1 1.43 2.75 1.98
Noramine Hydrochloric acid ** Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water ――――――――――――――――――――――――――――――
* Equivalent to 1 g of loxoprofen sodium (anhydrous equivalent)
* * Select one or more types and add appropriate amount.

(Table 2)
(Gel agent)
Formulation amount in 100 g of preparation (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------
Pepper 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-
Propylcellulose xanthan gum-----0.2
Diisopropanolamine 1.08 1.87 1.8 2.0 1.98 2.65
Hydrochloric acid ※※ Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Purified Water Remaining Residual ―――――――――――――――――――――――――
* Equivalent to 1 g of loxoprofen sodium (anhydrous equivalent) * * Select one or more types and add appropriate amount

(Table 3)
(Solid preparation for external use)
Formulation amount in 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 *
Absolute 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
Hardened castor oil 40
Tocopherol acetate-----0.5
Isopropyl myristate − − 1 1 − −
Sodium hydroxide Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Purified Water Remaining Remaining Remaining Remaining Remaining Remaining Remaining Remaining ――――――――――――――――――――――――――――――――― ――――――
* Equivalent to 1 g of loxoprofen sodium (anhydrous equivalent)

(Table 4)
(Liquid)
Formulation amount in 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 − −
Maleate
Glycyrrhetinic acid 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
Propylmethylcellulose diisopropanolamine 0.2 0.46 0.45 1.05 0.96 0.99
Sodium hydroxide ※※ Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate Purified ――――――――――――――――――――――――――――――――――――
* Equivalent to 1 g of loxoprofen sodium (anhydrous equivalent) * * Select one or more types and add appropriate amount

  The amounts of the components listed in Tables 1 to 4 above are taken and manufactured according to the sections of the Japanese Pharmacopoeia General Rules for “Pharmaceutics”, “Solid for External Use”, and “Liquid for External Use” to obtain Prescription Examples 1 to 25.

(Test example) Appearance preservation stability test of loxoprofen-containing external skin preparation (1) Test materials Loxoprofen sodium dihydrate is from Daiichi Sankyo Chemical Pharma Co., Ltd., diclofenac sodium and indomethacin are from Tokyo Chemical Industry The carboxyvinyl polymer is manufactured by Sumitomo Seika Co., Ltd. (product name: AQUPEC HV-501E or AQUPEC HV-505E (Examples 4-5, Comparative Examples 4-5)). Hypromellose is manufactured by Ashland, anhydrous ethanol is manufactured by Imazu Pharmaceutical Co., Ltd., isopropanol is manufactured by Kominato Pharmaceutical Co., Ltd., diisopropanolamine and triethanolamine are manufactured by Wako Pure Chemical Industries, Ltd. L-menthol is manufactured by Suzuki Hikaru Co., Ltd., and propylene glycol is manufactured by Maruishi Pharmaceutical Co., Ltd. I used it. As the transparent glass vial, a Mighty vial (transparent, No. 7) manufactured by Marumu Co., Ltd. was used.

(2) Preparation of specimens After mixing and dissolving the components described in Tables 5 to 7 below, gel agents of Examples 1 to 6 and Comparative Examples 1 to 10 were obtained.

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

(Table 5)
Formulation amount in 100 g of preparation (g) 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
Absolute 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
Carboxyvinyl 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 ―――――――――――――――――――――――――――――――――――――――
After storage at 25 ° C for 1 week Appearance × ○ ○ ○ ○ ○
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 (anhydrous equivalent)
○: No insoluble precipitate
×: Insoluble matter precipitated

(Table 6)
Formulation amount in 100 g of preparation (g) 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 *
Absolute 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 ―――――――――――――――――――――――――――――――――――――――
After storage at 25 ° C for one week
Appearance × ○ × ○ × ○
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 (anhydrous equivalent)
○: No insoluble precipitates ×: Insoluble precipitates present

(Table 7)
Formulation amount in 100 g of preparation (g) Comparative Example 9 Example 5 Comparative Example 10 Example 6
―――――――――――――――――――――――――――――――――――
Loxoprofen 1.134 1.134 1.134 1.134
Sodium dihydrate *
Absolute 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 Remaining Remaining Remaining Remaining Remaining Remaining ―――――――――――――――――――――――――――――――――――
After storage at 25 ° C for one week
Appearance × ○ × ○
Viscosity (mPa · s) 2100 13500 2500 16500
pH 7.04 7.10 6.70 6.74
―――――――――――――――――――――――――――――――――――
* Equivalent to 1 g of loxoprofen sodium (anhydrous equivalent)
○: No insoluble precipitate
×: Insoluble matter precipitated

(4) Test results Appearance confirmation results are shown in Tables 5-7. From Comparative Examples 1, 6, 7, 8, 9 and 10, it was found that in the loxoprofen-containing preparation, 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 addition, according to Comparative Examples 2 to 5, this decrease in viscosity and precipitation of insoluble matter may be a phenomenon peculiar to a loxoprofen-containing preparation that does not occur in other NSAID-containing preparations (preparations other than NSAID have the same composition). Indicated. From the results of Example 1, it was found that only a specific diisopropanolamine was used instead of triethanolamine as a pH regulator, and the viscosity reduction and insoluble matter precipitation were remarkably suppressed.
Furthermore, from the results of Examples 1 to 6, when either ethanol or isopropanol is used as the lower alcohol, diisopropanolamine should be used in the loxoprofen-containing preparation in the presence of a high concentration of lower alcohol of 30.5% or more. As a result, it was found that the decrease in viscosity and precipitation of insoluble matter as seen from the appearance are remarkably suppressed.

  The topical skin preparation containing loxoprofen, carboxyvinyl polymer, diisopropanolamine and lower alcohol according to the present invention is excellent in use feeling, and remarkably suppresses a decrease in viscosity and / or precipitation of insoluble matter, particularly under a high content of lower alcohol. It is extremely useful clinically.

Claims (10)

  A skin external preparation containing loxoprofen, carboxyvinyl polymer, diisopropanolamine and lower alcohol.   The skin external preparation according to claim 1, wherein the content of the lower alcohol is 30.5% by weight or more.   Furthermore, the skin external preparation of Claim 1 or Claim 2 containing 0.1-5.0 weight% of a cellulose water-soluble polymer.   The skin external preparation according to claim 3, wherein the cellulose-based water-soluble polymer is one or more selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, hydrophobized hydroxypropylmethylcellulose, hypromellose and methylcellulose.   Furthermore, the skin external preparation of any one of Claims 1-4 whose formulation pH is 6.0-7.5.   Furthermore, the skin external preparation of any one of Claims 1-5 containing a polyhydric alcohol.   Furthermore, the skin external preparation of any one of Claims 1-6 containing 1-menthol.   The external preparation for skin according to any one of claims 1 to 7, which is used for analgesic / anti-inflammatory.   The skin external preparation according to any one of claims 1 to 8, wherein the dosage form is a gel, cream, liquid, or aerosol.   The skin external preparation of any one of Claims 1-8 whose dosage form is a gel.