JP6224578B2 - Loxoprofen-containing solid preparation for external use - Google Patents

Description

  The present invention relates to a solid preparation for external use containing loxoprofen or a salt thereof, a shape retention agent for a solid preparation for external use, and a hardness enhancer.

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 into a solid preparation for external use using various drugs, problems often occur in the hardness and shape retention of the preparation, and various studies have been made so far (Patent Documents 1 to 6), None of the preparations were satisfactory in terms of hardness and shape retention.

  By the way, loxoprofen is a kind of phenylpropionic acid type non-steroidal anti-inflammatory analgesic (NSAID). This medicine contains loxoprofen sodium hydrate, and it is used to treat osteoarthritis, myalgia and swelling / pain after trauma, as well as antiphlogistic / analgesic, poultice, tape, gel Although the agent is known (Patent Documents 7 to 9 and Non-Patent Document 1), a solid preparation for external use containing loxoprofen is not yet known.

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

  This invention makes it a subject to provide the external shape solid agent which is excellent in shape retention property, and has moderate hardness, the shape retention agent of an external solid agent, and a hardness enhancer.

  As a result of intensive studies, the present inventors have found that by using a combination of loxoprofen or a salt thereof, a saturated higher fatty acid salt, and terpenes, an external solid preparation having excellent shape retention and appropriate hardness can be obtained. The headline and the present invention were completed.

That is, this invention provides the external solid agent containing the following components (A), (B), and (C).
(A) Loxoprofen or its salt (B) Saturated higher fatty acid salt (C) Terpenes Moreover, this invention provides the shape retention agent of the external solid agent containing terpenes.
Furthermore, the present invention provides a hardness enhancer capable of adjusting the hardness of an external solid preparation containing loxoprofen or a salt thereof.

Since the external solid preparation of the present invention is excellent in shape retention and has an appropriate hardness that is easy to apply, the commercial value is high.
Moreover, the shape retention agent of this invention is excellent in the shape retention ability of the external solid agent.
Moreover, the hardness enhancer of this invention is excellent in the hardness adjustment capability of the solid agent for external use.

<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.

  Further, 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, but from the viewpoint of imparting appropriate hardness to the external solid preparation, In 100 parts by mass of the agent, 0.01 to 15 parts by mass is preferable, 0.01 to 10 parts by mass is more preferable, 0.1 to 5 parts by mass is further preferable, and 0.5 to 3 parts by mass is particularly preferable.

<Component (B)>
The saturated higher fatty acid salt contained in the external preparation for external use of the present invention functions as a soap gel base.
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 mentioned.
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 included in a solid preparation for external use, a saturated higher fatty acid salt is formed by blending a saturated higher fatty acid and a compound that forms a salt with the saturated higher fatty acid (potassium hydroxide, sodium hydroxide, etc.). You may let them. 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.

Moreover, as content of saturated higher fatty acid salt, 0.1-30 mass parts is preferable in 100 mass parts of external preparations, 0.5-20 mass parts is more preferable, 1-15 mass parts is more preferable, 5 to 10 parts by mass is particularly preferable.
In addition, (A) Loxoprofen or a salt thereof (in terms of loxoprofen sodium anhydrate) and (B) a mass ratio of content of saturated higher fatty acid salt [(B) / (A)] gives moderate hardness. 1 to 25 is preferable, 3 to 15 is more preferable, and 5 to 10 is more preferable.

<Ingredient (C)>
The terpenes contained in the external solid preparation of the present invention are not particularly limited, and examples thereof 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, Isotujol, Tujon, Terpineol, Terpinene, Terpinolene, Tricyclene, Nerol, Pinene, Pinoccamphorol, 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 the terpenes may be appropriately determined according to the desired hardness and the local stimulating action based on the analgesic and analgesic action in the external solid preparation, but from the viewpoint of shape retention, in 100 parts by mass of the external solid preparation, 0.01-15 mass parts is preferable, 0.1-10 mass parts is more preferable, and 0.5-7 mass parts is further more preferable.
In addition, the mass ratio [(C) / (A)] of (A) loxoprofen or a salt thereof (in terms of loxoprofen sodium anhydrate) and (C) terpenes is 0 from the viewpoint of shape retention. 0.01-15 is preferable, 0.1-10 is more preferable, and 0.5-7 is still more preferable.

Moreover, as an external preparation for external use of this invention, what contains the component (D) other alcohol other than the said component (A)-(C) is preferable.
Other alcohols may be used as long as they function as a base for external solid preparations, and examples thereof include monohydric alcohols and polyhydric alcohols. One type may be used alone, or two or more types may be used in combination. May be. However, terpenes having an alcoholic hydroxyl group are excluded from other alcohols.
Examples of the monohydric alcohol include methanol, ethanol, geraniol-modified alcohol, methanol-modified alcohol, propanol, isopropanol, butanol, isobutanol, octaacetyl sucrose-modified alcohol, phenylethyl alcohol, phenylethyl alcohol-modified alcohol, and the like. Among these, ethanol, geraniol-modified alcohol, methanol-modified alcohol, isopropanol, octaacetyl sucrose-modified alcohol, phenylethyl alcohol, phenylethyl alcohol-modified alcohol and the like are preferable.

The polyhydric alcohol means one having a plurality of alcoholic hydroxyl groups. For example, dihydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, polypropylene glycol, polyoxyethylene polyoxypropylene glycol; trihydric alcohols such as glycerin and concentrated glycerin; erythritol, sorbitol, mannitol, etc. Sugar alcohol and the like. Among these, propylene glycol, 1,3-butylene glycol, polyethylene glycol, glycerin and concentrated glycerin are preferable.
In addition, when using glycerin and / or concentrated glycerin as other alcohol, it is preferable to further use 1,3-butylene glycol in combination from the viewpoint of suppressing change in appearance.

Moreover, as content of other alcohol, it is 10-90 mass parts normally in 100 mass parts of external preparations, 15-85 mass parts is preferable, and 20-80 mass parts is 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 a polyhydric alcohol, 5-80 mass parts is preferable in 100 mass parts of external solid preparations, 10-70 mass parts is more preferable, and 20-60 mass parts is further more preferable.

The solid preparation for external use of the present invention can be prepared by adding components (A) to (C) to the above-mentioned other alcohols (component (D) as necessary. ) And other preparation additives, dissolved or dispersed, and then solidified.
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.

The said antioxidant is mentioned as a formulation additive which enhances the skin permeability of loxoprofen. 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-hydroxypheny ) Propionate], propyl gallate, 2-mercaptobenzimidazole, and malic acid.
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.

  When malic acid and / or citric acid hydrate is used as an antioxidant, it is used in combination with higher fatty acids such as myristic acid, palmitic acid, stearic acid and isostearic acid from the viewpoint of enhancing the skin permeability of loxoprofen. It is preferable to do this. In this case, the content of malic acid and / or citric acid hydrate 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 acid is 0.1 -5 mass parts is preferable.

  In addition, when the terpene has a hydroxyl group, from the viewpoint of suppressing ester formation between the hydroxyl group and the carboxy group of loxoprofen, carbonates such as urea, calcium carbonate and magnesium carbonate, sodium bisulfite, 2-mercaptobenzimidazole, etc. It is preferable to further contain. The content of these components in this case 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. The metal carbonate is preferably contained in an amount of 0.01 to 3 parts by mass, the sodium hydrogen sulfite is preferably contained in an amount of 0.01 to 2 parts by mass, and the 2-mercaptobenzimidazole is contained in an amount of 0.01 to 2 parts by mass. Preferably.

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

Examples of the local stimulation component include capsaicin, 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.
Herbal medicines include, for example, Arnica, melancholy, jaundice, yellow ream, psoriasis, cinnamon bark, safflower, yam, Japanese horse chestnut, persimmon, wood tempura, salmon plum skin, and extracts thereof (extracts, tinctures, etc.). Can be mentioned.

  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 an appropriate hardness that is easy to apply, and therefore has a high commercial value.
In addition, loxoprofen or a salt thereof exhibits an anti-inflammatory analgesic effect as a phenylpropionic acid-based non-steroidal anti-inflammatory analgesic agent, and terpenes exhibit an analgesic and analgesic effect due to local stimulating action. It is extremely useful as a transdermal absorption-type 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.

Moreover, the shape retention agent of this invention is excellent in the shape retention ability of the external solid agent.
Moreover, the hardness enhancer of this invention is excellent in the hardness adjustment capability of the solid agent for external use.

  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
Briton-Robinson broad-area buffer (pH 7) and absolute ethanol were mixed at a ratio of 1: 1 to prepare a mixed solution. Loxoprofen sodium hydrate, l-menthol and sodium stearate were added to the concentrations shown in Table 1 above. It was made to melt | dissolve in a liquid mixture and pH was adjusted to 8, and the liquid for external solid preparations was obtained.
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.
This was preserve | saved at room temperature, and the external appearance (presence of thinness) of the external solid preparation after one month was confirmed with the naked eye. The “skin” was evaluated by the presence or absence of a gap between the external solid agent and the inner wall of the glass bottle. The results are shown in Table 1.

As shown in Table 1, a solid preparation for external use (Reference Example 1) containing a saturated higher fatty acid salt as a base and containing sodium loxoprofen hydrate is externally used after being stored for 1 month compared with immediately after the start of storage. A gap was generated between the solid agent and the inner wall of the glass bottle, and skin was observed.
On the other hand, the external solid preparation (Example 1) further containing l-menthol did not show any gaps even after being stored for 1 month, and no skin was observed.
In addition, from this result, although 1-menthol, which is a terpene, is a volatile component, it enhances the shape retention of the external solid preparation, and the terpene is an external solid containing loxoprofen or a salt thereof. It turns out that it has an effect | action as a shape retention agent of an agent.

Test example 2
A mixture obtained by mixing Briton-Robinson broad-area buffer (pH 7) and absolute ethanol at a ratio of 1: 1 was prepared, and loxoprofen sodium hydrate, l-menthol and sodium stearate so as to have 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.
After filling 10 mL of the obtained external solid preparation liquid into a transparent 10K glass bottle and solidifying at room temperature, the external solid preparation was cut out (8 mm × 8 mm × 8 mm) using a rheometer (manufactured by FUDOH) to obtain hardness (g / cm ² ) was measured and the results are shown in Table 2.

  From Table 2, it can be seen that loxoprofen or a salt thereof has an effect of enhancing the hardness of an external solid preparation. Moreover, the solid preparation for external use of Example 2 had moderate hardness, and was suitable for application | coating to the skin and a coating.

Example 3
Each component was heated and dissolved as desired to reach the concentrations shown in Table 3, and filled in a container and cooled to room temperature to produce external preparations of Formulations 1-8.

Claims (6)

A hardness enhancers for enhancing the hardness of the external solid dosage is and tick agent containing saturated higher fatty acid salts and terpenes containing loxoprofen or a salt thereof, the hardness enhancer. The saturated higher fatty acid salt is a saturated higher fatty acid salt having 12 to 22 carbon atoms, and the terpene is one or more selected from the group consisting of camphor, geraniol, citronellal, terpineol, borneol, menthol and limonene. The hardness enhancer according to claim 1, wherein The hardness enhancer according to claim 2, wherein the saturated higher fatty acid salt is a saturated higher fatty acid salt having 14 to 22 carbon atoms. The hardness enhancer according to claim 1, wherein the saturated higher fatty acid salt is a saturated higher fatty acid salt having 14 to 22 carbon atoms, and the terpenes are one or more selected from the group consisting of camphor and menthol. The saturated higher fatty acid salt is one or more selected from the group consisting of palmitate, myristate, stearate and isostearate, and the terpenes are selected from the group consisting of camphor and menthol. The hardness enhancer of Claim 1 which is 1 or more types. The saturated higher fatty acid salt is one or more selected from the group consisting of stearates and isostearates, and the terpenes are one or more selected from the group consisting of camphor and menthol. The hardness enhancer described.