JP2014166979A - Loxoprofen-containing solid formulation for external application - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a loxoprofen-containing solid formulation for external application which maintains its shape even after long-term storage and has excellent shape retention performance, and also keeps its transparent or translucent appearance.SOLUTION: A solid formulation for external application comprises following components (A) and (B): (A) loxoprofen or salt thereof; and (B) glycerol.

Description

  The present invention relates to a solid preparation for external use containing loxoprofen or a salt thereof.

As a preparation to be applied to the skin, an external preparation for skin is known, which is roughly classified into an application agent and a patch.
Examples of the coating agent include an external solid agent (tick agent), an external liquid agent (liniment agent, lotion agent), an ointment, a cream agent, and a gel agent. Among these, the external solid agent is stored in an appropriate container. In this case, since the drug can be applied to the skin without staining hands and fingers, it is difficult to cause discomfort during use.
However, when formulating a solid preparation for external use using various drugs, problems often arise in the hardness and shape retention of the preparation. Although various studies have been made so far (Patent Documents 1 to 6), none of them is necessarily satisfactory in terms of hardness, shape retention, appearance transparency, and the like of the preparation.

  By the way, loxoprofen is a kind of phenylpropionic acid type non-steroidal anti-inflammatory analgesic (NSAID). As an external preparation for skin using this, it contains loxoprofen sodium hydrate, and it is a poultice and tape that has osteoarthritis, myalgia, swelling / pain after trauma, and anti-inflammatory / analgesic effects. Although an agent and a gel agent are known (patent documents 7 to 9 and non-patent document 1), an external solid preparation containing loxoprofen has not been known yet.

Japanese Patent Laid-Open No. 55-2645 JP-A-56-79619 JP-A-57-42613 JP-T 6-505245 JP 2003-176209 A JP 2004-161714 A JP 2002-128701 A JP 2004-43512 A International Publication No. 2006/048939

The 16th revision Japanese Pharmacopoeia Manual Sasakawa Shoten Co., Ltd. C-5359-5364

  An object of the present invention is to provide a loxoprofen-containing external solid preparation that retains its shape and is excellent in shape retention even after long-term storage and maintains a transparent or translucent appearance.

  As a result of intensive studies, the present inventor has used loxoprofen or a salt thereof in combination with glycerin to maintain the shape and maintain a transparent or translucent appearance even after long-term storage and maintain a transparent or translucent appearance. The present invention was completed by finding that a solid preparation for external use was obtained.

That is, the present invention provides a solid preparation for external use containing the following components (A) and (B).
(A) Loxoprofen or a salt thereof (B) Glycerin The present invention also provides a shape-retaining agent for loxoprofen or a salt-containing external solid preparation containing glycerin.
Furthermore, the present invention provides a clearing agent for loxoprofen or a salt-containing external solid preparation containing glycerin.

The solid preparation for external use of the present invention has a high commercial value because it maintains a transparent or translucent appearance even after long-term storage or high-temperature storage, and is excellent in shape retention even after long-term storage.
Moreover, the shape retention agent of this invention is excellent in the shape retention ability of the external solid agent.
Moreover, the transparency imparting agent of the present invention is excellent in the transparency control ability of the external solid preparation.

<Component (A)>
The loxoprofen or a salt thereof contained in the external solid preparation of the present invention includes loxoprofen itself, a pharmaceutically acceptable salt of loxoprofen, and a solvate of these with water, alcohol and the like. In the present invention, loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate) is preferable.
Loxoprofen or a salt thereof is a known compound, and can be produced by a known method, or a commercially available product can be used.

  The content of loxoprofen or a salt thereof (in terms of loxoprofen sodium anhydrate) may be appropriately determined according to the desired anti-inflammatory analgesic effect, and is preferably 0.01 to 10 parts by mass in 100 parts by mass of the external solid preparation. 0.1-5 mass parts is more preferable, and 0.5-3 mass parts is still more preferable.

<Component (B)>
Glycerin contained in the external solid preparation of the present invention is a known compound having a chemical name of 1,2,3-propanetriol.
The content of glycerin may be appropriately determined according to the shape retention ability and transparency control ability of the desired external solid agent, and is preferably 1 to 60 parts by mass, and 3 to 50 masses in 100 parts by mass of the external solid agent. Part is more preferable, and 5 to 40 parts by mass is further preferable.
Moreover, as mass ratio [(B) / (A)] of content of (A) loxoprofen or a salt thereof (in terms of loxoprofen sodium anhydrate) and (B) glycerin, imparting appropriate hardness and appearance From a viewpoint, 1-60 are preferable, 3-50 are more preferable, and 5-40 are more preferable.

  In addition, glycerin can be produced by a known method, or a commercially available product can be used. For example, “glycerin” or “concentrated glycerin” described in the 16th revised Japanese Pharmacopoeia manual may be used.

  The external solid preparation of the present invention is based on the publicly known methods described in the 16th revised Japanese Pharmacopoeia General Rules for Preparation, etc., and the components (A) and (B) are added to the commonly used external solid preparation base as necessary. It can be produced by mixing with an agent or other preparation additives, dissolving or dispersing, and then solidifying. In the present invention, a soap gel base is preferable as the base of the external solid agent in consideration of stickiness and spreadability during application / coating of the external solid agent.

<Ingredient (C)>
As the base for the external solid preparation of the present invention, those containing a saturated higher fatty acid salt (hereinafter sometimes referred to as component (C)) are preferred.
The saturated higher fatty acid salt is preferably one having 12 to 22 carbon atoms. Examples include laurate, myristate, pentadecanoate, palmitate, margarate, stearate, isostearate, arachidate, behenate, etc., and these may be used alone Two or more kinds may be used in combination. Among these, those having 14 to 22 carbon atoms are more preferable, specifically, palmitate, myristate, stearate and isostearate are preferable, and stearate and isostearate are more preferable. It is done.
Moreover, as such a salt, inorganic salts, such as aluminum salt, potassium salt, sodium salt, magnesium salt, are preferable, and sodium salt is especially preferable.
Specific examples of the saturated higher fatty acid salt include sodium myristate, potassium myristate, sodium palmitate, aluminum stearate, potassium stearate, sodium stearate, magnesium stearate, sodium isostearate and the like. More preferred is sodium stearate.

  In addition, when a saturated higher fatty acid salt is contained in a solid preparation for external use, a saturated higher fatty acid, preferably a compound having 12 to 22 carbon atoms, and a compound that dissociates a cation that forms a salt with the saturated higher fatty acid (potassium hydroxide, sodium hydroxide, etc.) May be added to form a saturated higher fatty acid salt. A soap base or a medicinal soap containing a saturated higher fatty acid salt (such as a sodium salt of a saturated higher fatty acid) may also be used.

As content of saturated higher fatty acid salt, 0.1-30 mass parts is preferable in 100 mass parts of external solid preparations, 0.5-20 mass parts is more preferable, 1-15 mass parts is further more preferable, 5- 10 parts by mass is particularly preferred.
In addition, the mass ratio [(C) / (A)] of the content of (A) loxoprofen or a salt thereof (in terms of loxoprofen sodium anhydride) and (C) a saturated higher fatty acid salt is appropriate for a solid preparation for external use. From the viewpoint of imparting hardness, 1 to 25 is preferable, 3 to 15 is more preferable, and 5 to 10 is more preferable.

<Component (D)>
As the base of the external solid preparation of the present invention, those containing alcohol (hereinafter also referred to as component (D)) in addition to component (C) are preferable. Such an alcohol functions as a base for an external solid preparation.
Moreover, the alcohol of the said component (D) means alcohol except the thing which has alcoholic hydroxyl group among the glycerol of a component (B) and component (E) terpenes.
As said alcohol, it divides roughly into monohydric alcohol and a polyhydric alcohol, 1 type may be used independently and may be used in combination of 2 or more type.
Examples of the monohydric alcohol include methanol, ethanol, methanol-modified alcohol, propanol, isopropanol, butanol, isobutanol, octaacetyl sucrose-modified alcohol, phenylethyl alcohol, and phenylethyl alcohol-modified alcohol. Among these, ethanol, methanol-modified alcohol, isopropanol, octaacetyl sucrose-modified alcohol, phenylethyl alcohol, phenylethyl alcohol-modified alcohol and the like are preferable.

The polyhydric alcohol has a plurality of alcoholic hydroxyl groups, specifically, dihydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, polypropylene glycol, and polyoxyethylene polyoxypropylene glycol. Trivalent alcohol; sugar alcohols such as erythritol, sorbitol, mannitol and the like. Among these, propylene glycol, 1,3-butylene glycol, and polyethylene glycol are preferable.
In addition, when using a polyhydric alcohol as alcohol, it is preferable to use combining 1, 3- butylene glycol from a viewpoint of appearance change suppression.

As content of alcohol, it is 10-90 mass parts normally in 100 mass parts of external preparation solids, 15-85 mass parts is preferable, and 20-80 mass parts is more preferable.
In addition, (A) Loxoprofen or a salt thereof (in terms of loxoprofen sodium anhydrate) and (D) the mass ratio of the content of alcohol [(D) / (A)] From a viewpoint to provide, 10-90 are preferable, 15-85 are more preferable, and 20-80 are more preferable.
As content of monohydric alcohol, 5-70 mass parts is preferable in 100 mass parts of external solid preparations, 7-60 mass parts is more preferable, and 10-50 mass parts is further more preferable.
Moreover, as content of polyhydric alcohol (except glycerol of a component (B)), 5-80 mass parts is preferable in 100 mass parts of external preparations, 10-70 mass parts is more preferable, and 20-60 masses is preferable. Part is more preferred.

  As described above, the solid preparation for external use of the present invention is based on known methods described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations, etc. It can be produced by mixing, dissolving or dispersing, and then solidifying.

  Examples of the other preparation additives include oils such as diisopropyl adipate, crotamiton, squalane, squalene, diethyl sebacate, castor oil, isopropyl palmitate, isopropyl myristate, cetyl myristate, myristyl myristate; sucrose fatty acid ester , Surfactants such as sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyglycerin fatty acid ester, sodium lauryl sulfate, lauromacrogol, polyoxyethylene cetyl ether; oleyl alcohol, lauryl alcohol, etc. Higher alcohol; hydrochloric acid, sodium acetate hydrate, tartaric acid, sodium tartrate, sodium hydroxide, sodium carbonate hydrate, sodium lactate, sodium malate pH adjusting agents and the like; antioxidants, and the like. These may be used alone or in combination of two or more.

Examples of the antioxidant include sodium nitrite, ascorbic acid, L-ascorbic acid stearate, sodium hydrogen sulfite, alpha thioglycerin, sodium edetate, erythorbic acid, cysteine hydrochloride, dry sodium sulfite, and citric acid hydrate. , Potassium dichloroisocyanurate, dibutylhydroxytoluene, sodium thioglycolate, sodium thiomalate, natural vitamin E, tocopherol, d-δ-tocopherol, tocopherol acetate, concentrated mixed tocopherol, ascorbic acid palmitate, sodium pyrosulfite Butylhydroxyanisole, 1,3-butylene glycol, benzotriazole, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyl Yl) propionate], propyl gallate, 2-mercaptobenzimidazole, and malic acid. Among them, sodium nitrite, sodium hydrogen sulfite, dibutylhydroxytoluene, natural vitamin E, tocopherol, d-δ-tocopherol, tocopherol acetate, sodium pyrosulfite, butylhydroxyanisole, 1,3-butylene glycol, sodium pyrosulfite, etc. preferable.
When the antioxidant is added to the external solid preparation of the present invention, the content may be appropriately determined according to the type of the antioxidant, etc., but in an amount of 0.01 to 50 mass in 100 mass parts of the external solid preparation. Part is preferable, 0.02 to 10 parts by mass is more preferable, and 0.03 to 2 parts by mass is further preferable.

  Further, when malic acid and / or citric acid hydrate is used as an antioxidant, it is preferably used in combination with higher fatty acids such as myristic acid, palmitic acid, stearic acid, and isostearic acid. The content of malic acid and / or citric acid hydrate in the case of containing an antioxidant is preferably 0.1 to 3 parts by mass in 100 parts by mass of the external solid preparation, while the content of higher fatty acids is as follows. 0.1 to 5 parts by mass is preferable.

  Further, the solid preparation for external use of the present invention includes drugs other than loxoprofen or a salt thereof, for example, local irritation component, analgesic component, anti-inflammatory component, bactericidal / disinfecting component, astringent / protective component, blood circulation promoting component, antihistamine component, Herbal medicines etc. are mentioned, and these may contain 1 type, or 2 or more types.

Examples of the local stimulation component include capsaicin, terpenes, nonanoic acid vanillylamide, and the like.
Examples of the analgesic component include salicylic acid, glycol salicylate, and methyl salicylate.
Examples of the anti-inflammatory component include glycyrrhizic acid, glycyrrhetinic acid, dipotassium glycyrrhizinate and the like.
Examples of the sterilizing / disinfecting component include thymol. Examples of the astringent / protective component include zinc oxide.
Examples of the blood circulation promoting component include benzyl nicotinate, heparin-like substances, sodium polyethylene sulfonate, and the like.

Antihistamine components include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastine fumarate, carbinoxamine diphenyl disulfonate, carbinoxamine maleate, Clemastine fumarate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, ketotifen fumarate, difeterol hydrochloride, difeterol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theocrate , Diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolysine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, mequitazi , Methdilazine hydrochloride, main blanking hydro Linna Paji sills salts include emetine Das Chin fumarate salt.
Examples of herbal medicines include arnica, gold, yellow cocoon, yellow ream, dry cinnamon cinnamon, safflower, mountain lion, horse chestnut, salmon, wood tempura, salmon plum, and extracts thereof (extract, tincture, etc.). It is done.

<Ingredient (E)>
As described above, the solid preparation for external use of the present invention can contain various drugs. Among them, terpenes (hereinafter referred to as components (E) from the viewpoint of local stimulating action and shape retention based on analgesic and antipruritic action. )).) Is preferably included. Terpenes are not particularly limited, and examples include monoterpenes and sesquiterpenes.
Examples of such terpenes include, for example, isoborneol, iron, osimene, carbeol, carbotanaseton, carbomenton, carvone, caren, caron, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, Citronellol, Cineol, Cymen, Silvestrene, Isotjojol, Tujon, Terpineol, Terpinene, Terpinolene, Tricyclene, Nerol, Pinene, Pinoccampheol, Pinol, Piperithenone, Ferrandral, Ferrandrene, Fentchen, Fentyl alcohol, Perillyl alcohol , Perylaldehyde, borneol, myrcene, menthol, menthone, yonor, yonon, linalool, limonene, etc. It may be used in combination thereof alone or. Among these, from the viewpoint of shape retention, camphor, geraniol, citronellal, terpineol, borneol, menthol, limonene and the like are preferable, camphor and menthol are more preferable, and dl-camphor, l-menthol and dl-menthol are particularly preferable.

In addition, when the above-mentioned terpenes are contained in an external solid preparation, an essential oil containing the terpenes as described above may be used.
Such essential oils include, for example, anise oil, ylang ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayap oil, caraway oil, kubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil Oil, salamander, perilla oil, citriodora oil, citronella oil, ginger oil, gingergrass oil, gingergrass oil, spearmint oil, mint oil, geranium oil, geranium oil, clove oil, turpentine oil, spruce oil , Neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgren oil, bay oil, peniroyal oil, henoposi oil, bergamot oil, bored rose oil, pepper oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil, lime Oil, lavender oil, linaloe oil, lemon , Lemongrass oil, rose oil, rosemary oil, Roman chamomile oil, and the like, may be used in combination thereof alone or.
Among these, ylang ylang oil, fennel oil, orange oil, chamomile oil, cinnamon oil, perilla oil, citronella oil, ginger oil, camphor oil, mint oil, geranium oil, clove oil, turpentine oil, spruce oil, neroli oil Mint oil, palmarosa oil, bergamot oil, eucalyptus oil, lavender oil, linaloe oil, lemon oil, rose oil, rosemary oil, roman chamomile oil, etc., camphor oil, mint oil, mint oil are more preferable, mint Oil is particularly preferred.

Further, the content of terpenes may be appropriately determined according to the local stimulating action based on the desired analgesic and antipruritic action in the external solid preparation, and is preferably 0.01 to 15 parts by mass in 100 parts by mass of the external solid preparation. 0.1-10 mass parts is more preferable, and 0.5-7 mass parts is still more preferable.
Moreover, as a mass ratio [(E) / (A)] of content of (A) loxoprofen or a salt thereof (in terms of loxoprofen sodium anhydrate) and (E) terpenes, 0.01 to 15 is preferable, 0.1-10 are more preferable and 0.5-7 are still more preferable.

  When terpenes have a hydroxyl group, from the viewpoint of suppressing ester formation between the hydroxyl group and the carboxy group of loxoprofen, metal carbonates such as urea, calcium carbonate and magnesium carbonate, sodium hydrogen sulfite, 2-mercaptobenzimidazole Etc. may be further contained. The content of these components in the case of containing these may be appropriately examined, but it is preferable to contain 0.5 to 3 parts by mass of urea in 100 parts by mass of the external solid preparation. In this case, in particular, 0.01 to 3 parts by mass of metal carbonate is preferably contained, 0.01 to 2 parts by mass of sodium bisulfite is preferably contained, and 0.01 to 2 parts by mass of 2-mercaptobenzimidazole. It is preferable to contain a part.

  The external solid preparation of the present invention is housed in a container, and it is preferable to use a sealed container as the container. As the sealed container, an extrusion type or dial type lifting and lowering type container is preferable from the viewpoint of use and storage of the external solid agent.

As described in Examples below, the external solid preparation of the present invention is excellent in shape retention and has a transparent appearance, and therefore has a high commercial value.
Moreover, since loxoprofen or a salt thereof exhibits an anti-inflammatory analgesic effect as a phenylpropionic acid-based nonsteroidal anti-inflammatory analgesic, the external solid preparation of the present invention can be used as a medical drug or an OTC drug, and transdermally absorbed. It is extremely useful as a type of analgesic / anti-inflammatory agent. Applicable symptoms and diseases include osteoarthritis, shoulder periarthritis, tendon / tendonitis, peritonitis, humerus condyleitis, muscle pain, swelling / pain after trauma, shoulder stiffness, shoulder stiffness Pain, low back pain, joint pain, tendonitis, elbow pain, bruise, sprain, fracture pain, muscle fatigue and the like.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.

Test example 1
Loxoprofen sodium hydrate, l-menthol, sodium stearate, propylene glycol, Japanese Pharmacopoeia Concentrated Glycerin, Macrogol 400, ethanol and water are mixed and dissolved so that the concentrations shown in Table 1 are obtained. A working solution was obtained. 50 mL of the obtained external solid preparation liquid was filled into a transparent 10K glass bottle and solidified at room temperature to obtain an external solid preparation filled in the glass bottle.
The appearance (transparency) of the obtained external solid preparation was confirmed with the naked eye, and then stored at 40 ° C. and 75% relative humidity, and the decrease rate before and after storage in the external solid preparation after 1 week was measured. The reduction rate was determined by measuring the volume of the external solid preparation before and after storage. The results are shown in Table 1.

From the comparison between the reference examples and the examples, it can be seen that glycerin makes the appearance of the solid preparation for external use transparent and enhances the shape retention.
Therefore, it was found that glycerin has an effect as a clarifying agent or a shape-retaining agent for loxoprofen or a salt-containing external solid preparation.

Test example 2
A mixture of Briton-Robinson broad-area buffer (pH 7) and absolute ethanol was prepared at a ratio of 1: 1, and loxoprofen sodium hydrate, sodium stearate and Japanese Pharmacopoeia concentrated glycerin were mixed to the concentrations shown in Table 2. Was dissolved in the above mixed solution, and the pH was adjusted to 8 to obtain a liquid for external solid preparation.
10 mL of the obtained liquid for external solid preparation was filled in a transparent 10K glass bottle and solidified at room temperature to obtain an external solid preparation filled in the glass bottle.
The obtained solid preparation for external use is stored at room temperature, and the appearance (transparency) of the solid preparation for external use at the start of storage and after 3 days is confirmed with the naked eye, and further, the rate of decrease of the solid preparation for external use after 3 days storage is tested. Calculation was performed in the same manner as in Example 1. The results are shown in Table 2.

As shown in Table 2, the external solid preparation containing no glycerin and containing loxoprofen sodium hydrate (Reference Example 3) is opaque (white turbid) before and after storage, and after 3 days storage As a result, the volume of the solid preparation for external use was significantly reduced as compared with that at the start of storage.
On the other hand, the external solid preparation (Example 3) containing glycerin was transparent in appearance before and after storage. Moreover, the volume reduction of the external preparation solid was hardly recognized compared with the time of storage start.
From this result, it can be seen that glycerin has a function of making the appearance of the external solid preparation transparent, enhances the shape retention of the external solid preparation, and acts as a shape retention agent for the external solid preparation.
Therefore, it was found that glycerin has an effect as a clarifying agent or a shape-retaining agent for loxoprofen or a salt-containing solid preparation for external use.

Test example 3
Loxoprofen sodium hydrate, Japanese pharmacopoeia concentrated glycerin, sodium stearate, propylene glycol, 1,3-butylene glycol, macrogol 400 and ethanol are mixed in water to a concentration shown in Table 3, and the pH is adjusted to 8 To obtain a solid preparation liquid for external use.
10 mL of the obtained liquid for external solid preparation was filled in a transparent 10K glass bottle and solidified at room temperature to obtain an external solid preparation filled in the glass bottle.
The obtained external solid preparation was stored at 80 ° C., and the appearance (clarity) of the external solid preparation at the start of storage and after 5, 6 and 7 days was visually confirmed. The results are shown in Table 3.

As shown in Table 3, the external solid preparations of Examples 4 to 7 maintained a clear appearance even under severe storage after high temperature.
From this result, it was found that glycerin has a function of clarifying the appearance of the external solid preparation.

Test example 4
Each component shown in Tables 4 to 7 was heated and dissolved as desired, filled in a container and then cooled to room temperature, to produce a solid preparation for external use of formulations 1 to 20.

Claims (10)

An external solid preparation containing the following components (A) and (B).
(A) Loxoprofen or a salt thereof (B) Glycerin   The external solid preparation according to claim 1, further comprising (C) a saturated higher fatty acid salt.   Furthermore, the solid preparation for external use of Claim 1 or 2 containing (E) terpenes.   The external solid preparation according to any one of claims 1 to 3, wherein the component (A) is loxoprofen sodium hydrate.   The external solid agent according to any one of claims 2 to 4, wherein the component (C) is a saturated higher fatty acid salt having 12 to 22 carbon atoms.   Ingredient (E) is isoborneol, iron, osimene, carveol, carbotanaceton, carbomenton, carvone, caren, caron, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellal acid, citronellol, cineol, Cymene, Silvestrene, Isotjojol, Tujon, Terpineol, Terpinene, Terpinolene, Tricyclene, Nellore, Pinene, Pinoccampheol, Pinol, Piperithenone, Ferrandral, Ferrandrene, Fentchen, Fentyl Alcohol, Perillyl Alcohol, Perillyl Aldehyde , Borneol, Myrcene, Menthol, Mentone, Yonor, Yonon, Linalool and Limonene External solid agent according to any one of claims 3-5 is species or more.   Content of a component (A) is 0.01-10 mass parts in 100 mass parts of external solid preparations in conversion of loxoprofen sodium anhydride, The external solid preparation of any one of Claims 1-6.   Content of a component (B) is 1-60 mass parts in 100 mass parts of external solid preparations, The external solid preparation of any one of Claims 1-7.   Content of a component (C) is 0.1-30 mass parts in 100 mass parts of external solid preparations, The external solid preparation of any one of Claims 2-8.   Content of a component (E) is 0.01-15 mass parts in 100 mass parts of external solid preparations, The external solid preparation of any one of Claims 3-9.