JP6194400B2 - Pharmaceutical composition containing crude drugs (組成) - Google Patents

Description

  The present invention relates to a herbal medicine-containing pharmaceutical composition, and a storage stabilizer and a stabilization method for a herbal medicine-containing pharmaceutical composition.

  Herbal medicines such as oak and licorice have various pharmacological actions and are widely used as components of pharmaceuticals. However, since there are components having various properties in herbal medicines, in pharmaceutical compositions containing herbal medicines, the storage stability tends to be a problem, and development of a technology for improving storage stability is required. It has been. In particular, pharmaceuticals should be stored, stored, transported, etc. under temperature controlled conditions (at least 30 ° C. or lower, so-called room temperature), but are not always sufficiently temperature-controlled at the hands of consumers. In view of the recent climate change and the trend of power saving due to the world situation, it is often possible to store the product at a temperature exceeding 30 ° C., so it is very important to ensure the storage stability under the high temperature condition.

  The problem of storage stability in a pharmaceutical composition containing a crude drug or the like includes precipitation in a liquid pharmaceutical composition caused by a low-solubility component that is abundantly contained in the crude drug. Techniques for blending solubilizers are being studied. For example, Patent Document 1 describes blending a polyoxyethylene hydrogenated castor oil and a polyoxyethylene polyoxypropylene condensate with a crude drug extract. Patent Document 2 describes a solubilized liquid composition in which a polyglycerin fatty acid ester and a polyoxyethylene nonionic surfactant are blended at a specific ratio in addition to a herbal extract and an oil component. .

By the way, loxoprofen is a kind of non-steroidal anti-inflammatory analgesic (NSAID) which is also known as an active ingredient of loxonin (registered trademark) (Non-patent document 1), osteoarthritis, myalgia, swelling after trauma It is used as an active ingredient of external preparations such as gels, poultices, tapes and the like, which are effective for treating diseases such as pain and symptom anti-inflammatory and analgesic (Non-patent Document 2).
However, until now, it has not been known at all how the loxoprofen affects the storage stability of a pharmaceutical composition containing a crude drug or the like.

Japanese Patent Publication No. 5-9408 JP 2002-128703 A

The 16th revision Japanese Pharmacopoeia Manual Sasakawa Shoten Co., Ltd. C-5359-5364 Loxonin (registered trademark) gel 1% pharmaceutical interview form Daiichi Sankyo Co., Ltd. Revised October 2010 (3rd edition)

  An object of the present invention is to provide a medicinal-containing pharmaceutical composition excellent in storage stability, and a storage stabilizer and a stabilization method for a medicinal-containing pharmaceutical composition.

  Therefore, the present inventors have intensively studied to solve the above-mentioned problems, and found that loxoprofen or a salt thereof together with herbal medicines or extracts thereof selected from duck, licorice, salamander, cypress seeds and pepper, or glycyrrhetinic acid. As a result, it was found that a pharmaceutical composition having excellent storage stability can be obtained.

That is, the present invention provides the following components (A) and (B)
(A) One or more types selected from the following components (A-1) to (A-6) (A-1) Oat or its extract (A-2) Daylily or its extract (A-3) Glycyrrhetinic acid Or a salt thereof (A-4) a salamander or an extract thereof (A-5) a horse chestnut seed or an extract thereof (A-6) a pepper or an extract thereof (B) a pharmaceutical composition containing loxoprofen or a salt thereof It is to provide.

  The present invention also includes loxoprofen or a salt thereof, a buckwheat or an extract thereof, licorice or an extract thereof, glycyrrhetinic acid or a salt thereof, salamander or an extract thereof, a horse chestnut seed or an extract thereof, or a red pepper or A storage stabilizer for a pharmaceutical composition containing the extract is provided.

  The present invention also includes loxoprofen or a salt thereof, a buckwheat or an extract thereof, licorice or an extract thereof, glycyrrhetinic acid or a salt thereof, salamander or an extract thereof, a horse chestnut seed or an extract thereof, or a red pepper or A method for stabilizing a pharmaceutical composition containing the extract is provided.

  ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical composition excellent in storage stability can be provided, containing a crude drug etc.

<Component (A-1)>
“Owaku” (yellow jade) means bark excluding the pericarp of yellowfin (Phellodendron amurense Ruprecht or Phellodendron chinense Schneider (Rutaceae)) as described in the 16th revision Japanese Pharmacopoeia. The form of the buckwheat can be adjusted as necessary, and can be cut or crushed into small pieces, small clumps, or pulverized into powder. For example, “Owaku powder” with powdered buckwheat is also used in the present invention. Can do. In addition, considering the convenience of handling at the time of production of the pharmaceutical composition, what has been subjected to some kind of extraction treatment on the buckwheat (hereinafter referred to as “the extract of buckwheat”) may be used.
In addition, the above-mentioned “extract of buckwheat” includes those subjected to processing such as heating, drying and pulverization in addition to extraction processing. Specifically, after making the appropriate size of the buckwheat, if necessary, a suitable leachate (extraction solvent) was added to the leachate, the leachate was concentrated (soft extract, tincture, etc.), and further A dried product (dried extract or the like) is also included in the “extract of buckwheat” of the present invention.
In the present invention, as the buckwheat or an extract thereof, the buckwheat soft extract and the buckwheat powder described in the 16th revision Japanese Pharmacopoeia are preferable, and the buckwheat soft extract is particularly preferable.

  There are no particular restrictions on the method for producing the extract of the acorn. For example, the description of the "Extract", "Dipping Agent", "Tincture", and "Flower Extract" in the 16th revised Japanese Pharmacopoeia General Rules for Preparations, etc. It can be produced with reference to known methods for producing plant extracts. Specifically, for example, it can be produced by cutting, heating, drying, pulverizing, etc., if necessary, and extracting by adding an appropriate extraction solvent. The obtained extract may be further concentrated, dried, etc. as necessary.

Examples of the extraction solvent include lower monohydric alcohols such as methanol, ethanol, isopropanol, and n-butanol; lower polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol, and glycerin; ethers such as diethyl ether. Ketones such as acetone and ethyl methyl ketone; esters such as ethyl acetate; nitriles such as acetonitrile; alkanes such as pentane, hexane, cyclopentane and cyclohexane; halogenoalkanes such as dichloromethane and chloroform; benzene, toluene and the like Aromatic hydrocarbons; dimethylformamide; dimethylsulfoxide; water (including hot water) and the like. These may be used alone or in combination of two or more. In the present invention, water, ethanol, or a water / ethanol mixture is preferred.
The extraction operation is not particularly limited, and a known method used for the extraction operation from plants can be adopted. Specifically, for example, immersion in extraction solvent (cooling, digestion, percolation, etc.), super For example, extraction using a critical fluid or a subcritical fluid may be mentioned. In addition, in order to raise extraction efficiency, you may homogenize in stirring or an extraction solvent.
The extraction temperature is not particularly limited and varies depending on the extraction solvent to be used, the extraction operation, and the like.
The extraction time is not particularly limited and varies depending on the extraction solvent to be used, the extraction operation, etc., but is preferably about 1 hour to 14 days.

  In the present invention, commercially available products can be used as the buckwheat or its extract. Specific examples of the commercially available products include soft buckwheat extract, dried dry extract (above, manufactured by Nippon Powder Chemical Co., Ltd.) and the like. It is done.

  The content of buckwheat or an extract thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination. In this invention, what contains 0.01-10 mass% of a buckwheat or its extract with a crude drug equivalent amount with respect to the pharmaceutical composition total mass is preferable, and what contains 0.05-8 mass% is more. Those containing 0.1 to 5% by mass are particularly preferable.

  Further, the content ratio of the buckwheat or its extract contained in the pharmaceutical composition of the present invention and loxoprofen or its salt is not particularly limited, but from the viewpoint of storage stability, loxoprofen or its salt is converted to loxoprofen sodium anhydride. It is preferable to contain 0.01 to 10 parts by mass of a buckwheat or an extract thereof in terms of the active ingredient based on 1 part by mass, more preferably 0.05 to 8 parts by mass, and more preferably 0.1 to 5 parts by mass. Those containing parts are particularly preferred.

<Component (A-2)>
The term “licorice” (licorice) means Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra Linne (Leguminosae) roots and strons. Japanese Pharmacopoeia). The form of licorice can be adjusted as needed, and can be cut or crushed into small pieces, small clumps, or pulverized into powders. For example, "licorice powder" made from licorice powder is also used in the present invention. Can do. In addition, for the convenience of handling during production of the pharmaceutical composition, licorice that has been subjected to some kind of extraction treatment (hereinafter referred to as “licorice extract”) may be used.
In addition to the extraction process, the above-mentioned “liquorice extract” includes those subjected to processing such as heating, drying, and pulverization. Specifically, after making the licorice into an appropriate size as needed, an appropriate leachate (extraction solvent) was added to the leachate, and the leachate was concentrated (soft extract, tincture, etc.), A dried product (dried extract or the like) is also included in the “extract of licorice” of the present invention.
Furthermore, in the present invention, as an extract of licorice, glycyrrhizic acid which is a component of licorice or a salt thereof may be used. Examples of the salt of glycyrrhizic acid include dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, disodium glycyrrhizinate, and trisodium glycyrrhizinate.
In the present invention, licorice or an extract thereof is preferably dipotassium glycyrrhizinate or licorice, licorice powder, licorice extract or crude licorice extract described in the 16th revised Japanese Pharmacopoeia, and licorice is particularly preferable.

  The method for producing the extract of licorice is not particularly limited, and for example, it can be produced by the same method as the method for producing the extract of apricot.

  In the present invention, as the licorice or an extract thereof, a commercially available product can be used. Specific commercial products include, for example, (local) licorice extract, (local) licorice powder, (local) licorice crude extract (above, Nippon Powdery Chemical Co., Ltd.).

  The content of licorice or its extract in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination. In this invention, what contains 0.01-10 mass% of licorice or its extract with a crude drug equivalent amount with respect to the pharmaceutical composition total mass is preferable, and what contains 0.05-8 mass% is more. Those containing 0.1 to 5% by mass are particularly preferable.

  Further, the content ratio of licorice or its extract contained in the pharmaceutical composition of the present invention and loxoprofen or its salt is not particularly limited, but from the viewpoint of storage stability, loxoprofen or its salt is converted to loxoprofen sodium anhydride in terms of storage stability. What contains 0.01-10 mass parts of licorice or its extract in terms of bulk drug substance with respect to 1 mass part is preferable, What contains 0.05-8 mass parts is more preferable, 0.1-5 mass Those containing parts are particularly preferred.

<Component (A-3)>
“Glycyrrhetinic acid” is a hydrolyzate of the above-mentioned “licorice” component (glycyrrhizic acid). In the present invention, in addition to glycyrrhetinic acid itself, pharmaceutically acceptable salts thereof, glycyrrhetinic acid and pharmacologically Also included are solvates of acceptable salts with water or alcohol. These are known compounds, and can be produced by known methods, or commercially available products can be used.
In the present invention, glycyrrhetinic acid described in Japanese Pharmacopoeia Standards for Pharmaceuticals 2002 is preferred.

  The content of glycyrrhetinic acid or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination. In this invention, what contains 0.005-10 mass% of glycyrrhetic acid or its salt with respect to the pharmaceutical composition total mass in conversion of the free form of glycyrrhetic acid is preferable, and what contains 0.01-8 mass% Are more preferable, and those containing 0.05 to 5% by mass are particularly preferable.

  In addition, the content ratio of glycyrrhetinic acid or a salt thereof and loxoprofen or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of storage stability, loxoprofen or a salt thereof is converted to loxoprofen sodium anhydride. What contains 0.005-10 mass parts of glycyrrhetic acid or its salt in conversion of a free body is preferable with respect to 1 mass part, What contains 0.01-8 mass parts is more preferable, 0.05-5 mass parts What is contained is particularly preferable.

<Component (A-4)>
“Sauna” (Yamabuchi) means the mature pericarp of Zanthoxylum piperitum De Candolle (Rutaceae) as described in the 16th revision Japanese Pharmacopoeia. The shape of the salam can be adjusted as necessary, and can be cut or crushed into small pieces, small clumps, or pulverized into a powder. Can be used. In addition, in consideration of the convenience of handling at the time of manufacturing the pharmaceutical composition, a product obtained by performing some kind of extraction treatment on the salam (hereinafter referred to as “the extract of salamander”) may be used.
In addition to the extraction process, the above-mentioned “extract of salamander” includes those subjected to processing such as heating, drying, and pulverization. Specifically, after the salamander is appropriately sized as necessary, a liquid leached by adding an appropriate leachate (extraction solvent), a liquid obtained by concentrating the leachate (soft extract, tincture, etc.), and these Those obtained by drying (such as a dried extract) are also included in the “extract of salamander” of the present invention.
In the present invention, the salamander or extract thereof is preferably a salamander extract or a salamander or a salamander powder described in the 16th revised Japanese Pharmacopoeia, particularly preferably a salamander soft extract.

  The manufacturing method of the extract of a salamander is not specifically limited, For example, it can manufacture by the method similar to the manufacturing method of the above-mentioned extract of a buckwheat.

  In the present invention, a commercially available product can be used as a salamander or an extract thereof. Specific examples of commercially available products include a salamander extract (manufactured by Alps Yakuhin Kogyo Co., Ltd.), Nippon Powdery Chemical Co., Ltd.).

  The content of the salam or extract thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination. In this invention, what contains 0.01-10 mass% with respect to the total mass of a pharmaceutical composition is preferable, and what contains 0.05-8 mass% is the amount of raw materials of a salamander or its extract with the amount of active ingredient. More preferably, 0.1 to 5% by mass is particularly preferable.

  Further, the content ratio of the salamander or extract thereof and loxoprofen or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of storage stability, loxoprofen or a salt thereof is converted to loxoprofen sodium anhydride. 1 to 10 parts by mass, preferably 0.01-10 parts by mass of the salam or extract thereof in terms of bulk drug substance, more preferably 0.05-8 parts by mass. What contains 5 mass parts is especially preferable.

<Component (A-5)>
The “Acecilia seed” is a seed of Aceculus hippocastanum Linne (Hippocastanaceae). The form of horse chestnut seeds can be adjusted as necessary, and can be cut or crushed into small pieces, small chunks, or ground into powder. In addition, in consideration of the convenience of handling at the time of manufacturing the pharmaceutical composition, what is subjected to some kind of extraction treatment for horse chestnut seeds (hereinafter, referred to as “the extract of horse chestnut seeds”) may be used.
In addition, the above “extract of horse chestnut seed” includes those subjected to processing such as heating, drying, and pulverization in addition to extraction processing. Specifically, after adjusting the size of horse chestnut seeds to an appropriate size as needed, a solution that has been leached by adding an appropriate leachate (extraction solvent), a solution obtained by concentrating the leachate (soft extract, tincture, etc.), What dried these (dry extract etc.) etc. are also included in the "extract of horse chestnut seed" of this invention.
In the present invention, the horse chestnut seed or the extract thereof is preferably the horse chestnut seed extract described in the Japanese Pharmacopoeia Pharmaceutical Standard 2002.

  The method for producing the extract of horse chestnut seeds is not particularly limited, and for example, it can be produced by the same method as the method for producing the extract of the above-mentioned alum.

  In the present invention, a commercially available product can be used as the horse chestnut seed or an extract thereof, and specific examples of the commercially available product include Falco Rex Maronie B (manufactured by Ichimaru Falcos Co., Ltd.).

  The content of the horse chestnut seed or the extract thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination. In the present invention, it is preferable to contain 0.01 to 10% by mass, based on the total mass of the pharmaceutical composition, of 0.05 to 8.5% by mass of the horse chestnut seed or extract thereof in terms of the active ingredient. More preferred are those containing 0.1 to 6.5% by mass.

  In addition, the content ratio of horse chestnut seeds or an extract thereof and loxoprofen or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of storage stability, loxoprofen or a salt thereof is added to loxoprofen sodium anhydride. In terms of 1 part by mass in terms of conversion, it is preferable to contain 0.01 to 10 parts by mass of the seed of horse chestnut seed or its extract in terms of the active ingredient, more preferably 0.05 to 8.5 parts by mass, What contains 0.1-6.5 mass parts is especially preferable.

<Component (A-6)>
“Capsicum” (蕃 椒) means the fruit of Capsicum annuum Linne (Solanaceae) as described in the 16th revision Japanese Pharmacopoeia. The shape of the pepper can be adjusted as needed, and can be cut or crushed into small pieces, small clumps, or pulverized into a powder. For example, “powder powder” made from powdered pepper is also used in the present invention. Can do. In addition, in consideration of the convenience of handling at the time of manufacturing the pharmaceutical composition, a product obtained by subjecting the pepper to some kind of extraction treatment (hereinafter referred to as a “pepper extract”) may be used.
In addition, the above “pepper extract” includes those subjected to processing such as heating, drying and pulverization in addition to the extraction. Specifically, after the capsicum is appropriately sized as required, an appropriate leaching solution (extraction solvent) is added and leached, or the leaching solution is concentrated (soft extract, tincture, etc.), A dried product (dried extract or the like) is also included in the “capsicum extract” of the present invention.
Furthermore, in this invention, you may use the well-known capsaicinoid which is a main component of a pepper as an extract of a pepper. As the capsaicinoid, capsaicin and nonanoic acid vanillylamide are preferable.
In the present invention, the chili pepper or its extract is preferably chili soft extract, capsaicin, nonanoic acid vanillylamide, chili pepper, chili powder and chili pepper tincture described in the 16th revised Japanese Pharmacopoeia, and chili soft extract is particularly preferred.

  The method for producing the pepper extract is not particularly limited, and for example, it can be produced by a method similar to the method for producing the above-mentioned extract of apricot.

  In the present invention, a commercially available product can be used as the pepper or an extract thereof. Specific examples of commercially available products include pepper extract B, (local) pepper powder (manufactured by Nippon Powdery Chemical Co., Ltd.), and the like. Can be mentioned.

  The content of the pepper or the extract thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination. In this invention, what contains 0.01-15 mass% of capsicum or its extract by the amount of active pharmaceutical ingredients with respect to the pharmaceutical composition total mass is preferable, and what contains 0.05-10 mass% is more Those containing 0.1 to 8% by mass are particularly preferable. In addition, when capsaicinoids such as capsaicin and nonanoic acid vanillylamide are used as capsicum or an extract thereof, those containing 0.0001 to 1% by mass of capsaicinoid with respect to the total mass of the pharmaceutical composition are preferable, and 0.0005 to 0 Those containing 0.5 mass% are more preferable, those containing 0.001 to 0.1 mass% are more preferable, and those containing 0.005 to 0.02 mass% are particularly preferable.

  Further, the content ratio of the pepper or the extract thereof contained in the pharmaceutical composition of the present invention and loxoprofen or a salt thereof is not particularly limited, but from the viewpoint of storage stability, loxoprofen or a salt thereof is converted to loxoprofen sodium anhydride in terms of storage stability. It is preferable to contain 0.01 to 15 parts by mass of the pepper or its extract in terms of the active ingredient relative to 1 part by mass, more preferably 0.05 to 10 parts by mass, and more preferably 0.1 to 8 parts by mass. Those containing parts are particularly preferred. When capsaicinoids such as capsaicin and nonanoic acid vanillylamide are used as capsicum or an extract thereof, 0.0001 to 1 part by mass of capsaicinoid per 1 part by mass of loxoprofen or a salt thereof in terms of anhydrous loxoprofen sodium The thing containing 0.0005-0.5 mass part is more preferable, The thing containing 0.001-0.1 mass part is further more preferable, The thing containing 0.005-0.02 mass part is especially preferable preferable.

<Component (B)>
In the present invention, “loxoprofen or a salt thereof” includes not only loxoprofen itself but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate of loxoprofen or a pharmaceutically acceptable salt thereof with water, alcohol or the like. It is. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).

  The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the storage stability improving action. From the viewpoint of storage stability, loxoprofen or a salt thereof is used. 0.01-30% by mass in terms of loxoprofen sodium anhydride is preferable, 0.1-25% by mass is more preferable, 0.5-20% by mass is further preferable, and 0.5-20% by mass relative to the total mass of the pharmaceutical composition. Is more preferably from 10 to 10% by weight, further preferably from 0.5 to 5% by weight, particularly preferably from 0.5 to 3% by weight.

The pharmaceutical composition of the present invention can be produced by, for example, a known method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.
The dosage form is not particularly limited, and may be any of solid, semi-solid, and liquid shapes, and may be a shape usually used in pharmaceuticals depending on the purpose of use and the like. it can. For example, preparations for oral administration (tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, etc.), preparations for application to the vagina (vagina tablets, vaginal suppositories, etc.), skin, etc. The dosage form described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations such as preparations (solid preparations for external use, liquid preparations for external use, sprays, ointments, creams, gels, patches, etc.) can be used. Among these, a semi-solid or liquid preparation is preferable, and in particular, a dosage form selected from oral liquids, syrups, liquids for external use, sprays, ointments, creams, gels and patches. It is particularly preferable that the dosage form is selected from liniments, lotions, aerosols for external use, pump sprays, ointments, creams, gels, tapes and cataplasms.

  In addition, the pharmaceutical composition of the present invention is preferably a semi-solid or liquid composition, and a water-containing composition (meaning a semi-solid or liquid composition containing water, more specifically a composition More preferably, it means a composition containing water in an amount of 1% by mass or more, more preferably 5% by mass or more, and particularly preferably 10 to 80% by mass. The semi-solid or liquid composition can be formulated as the semi-solid or liquid preparation. As specifically disclosed in Examples below, it is confirmed that loxoprofen or a salt thereof suppresses precipitation, insoluble matter formation, separation, or coloring caused by herbal medicines in solution, solubilizing herbal medicines, etc. Has been suggested.

  Examples of the route of taking the pharmaceutical composition of the present invention include oral, transdermal, and parenteral such as transvaginal. In the present invention, parenteral is preferred, and transdermal administration is particularly preferred.

  In the pharmaceutical composition of the present invention, as a pharmaceutical component, a drug other than the above components, for example, analgesic component, anti-inflammatory component, antihistamine component, bactericidal component, astringent / protective component, blood circulation promoting component, local anesthetic component, antitussive agent, One or two selected from the group consisting of noscapine, bronchodilator, expectorant, hypnotic sedative, vitamins, anti-inflammatory agent, gastric mucosa protective agent, antacid, anticholinergic agent, herbal medicine, herbal medicine, etc. It may contain more than seeds.

As an analgesic component, for example, aspirin, aspirin aluminum, acetaminophen, isopropylantipyrine, ibuprofen, ethenzamide, sazapyrine, salicylamide, salicylic acid, ethylene glycol salicylate, glycol salicylate, sodium salicylate, methyl salicylate, thiaramide hydrochloride, lactylphenetidine Etc.
Examples of the anti-inflammatory component include sodium guaiazulene sulfonate.

  Antihistamine components include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, carbinoxamine diphenyldisulfonate, carbinoxamine Maleate, clemastine fumarate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, dipheterol hydrochloride, difeterol phosphate, diphenylpyraline hydrochloride, diphenylpyraline Theocurate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cetirizine hydrochloride, triprolyzine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, fe Sofenajin, fenethazine hydrochloride, promethazine hydrochloride, promethazine methylene two salicylates, bepotastine besilate, homochlorcyclizine hydrochloride, mequitazine, methdilazine hydrochloride, main blanking hydro Linna Paji sill acid salts.

  Examples of the sterilizing component include benzalkonium chloride. Examples of the astringent / protective component include zinc oxide. Examples of the blood circulation promoting component include tocopherol acetate, benzyl nicotinate, heparin-like substances, sodium polyethylene sulfonate, and the like. Examples of the local anesthetic component include lidocaine, clove oil, belladonna extract and the like.

  Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, dibutate sodium, dimemorphan phosphate, tipepidine citrate, And tipepidine hibenzate.

Examples of noscapine include noscapine hydrochloride and noscapine.
Examples of the bronchodilator include trimethquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride and the like.

  Examples of expectorants include ammonia, fennel, ammonium chloride, and 1-menthol.

Examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromvalerylurea.
Vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₅ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, hesperidin and derivatives thereof, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, thiamine nitrification) , Dicetiamine hydrochloride, cetothiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisbutiamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate , Riboflavin butyrate, sodium riboflavin phosphate, panthenol, panthetin, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, ascorb Sodium binate, calcium ascorbate, hesperidin, etc.).

  Examples of the anti-inflammatory agent include seaprose, semi-alkaline proteinase, serrapeptase, proctase, pronase, bromelain and the like.

Examples of the gastric mucosa protective agent include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride and the like.
Antacids include aminoacetic acid, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, magnesium alumina hydroxide, aluminum hydroxide gel, dry hydroxide Aluminum gel, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide, magnesium hydroxide / sulfuric acid Co-precipitation product of aluminum potassium, magnesium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium metasilicate magnesium aluminate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, bandit bone, stone decision, Rei, and the like.

  Examples of the anticholinergic agents include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, chipepidium bromide, methylbenactidium bromide, pirenzepine hydrochloride, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, and the like. .

  Herbal medicines include Akamegashiwa (red buds), Asenyaku (Asenyaku), Arnica, Yinakukaku (Oyakukan), Fennel (Yellow), Turmeric (Yongyin), Engosaku (Yankou), Ogon (Yellow), Ousei (Yellow) , Ohi (cherry bark), Ouren (yellow ream), Onji (distant), Gajutsu (Iso), Kanokosou (Deer herb), Chamomile, Caronin (Karojin), Kyokyo (Kikkyo), Kyonin (Kyojin), Kokushi (Lion), cucumber (leaf), kei-gu (silk), keihi (cinnamon), katsumeishi (Keiko), gentian, gennoshouko (current evidence), kouka (safflower), kobushi (kosuke), goo (cow yellow), Goshishi (Gomiko), Saishin (Spicy), Sanshishi (Yamako), Zion (Purple), Zicopi (Skin), Sikon (Purple), Peonies (Glue), Musk (Chinese), Shaji (Shasan), shazenshi (car front child), shazenso (car front grass), beast gall (including yutan (bear gall)), gyoza (ginger), giryu (land dragon), shin ii (hot potato), sexan (stone wall) ), Senega, Senkyu (river cucumber), Zenko (mae-hu), Senburi (Senhwa), Sojutsu (蒼朮), Sohakuhi (mulberry white skin), Soyo (Soba), Taisan (Daegu), Chiksetsu carrot (Bamboo ginseng) ), Chinpi (Chinese skin), Toki (homecoming), Tokon (Nanten), Nantenjitsu (Nan Tenji), Carrot (Ginseng), Baimo (Shell mother), Bakumondou (Bakumon winter), Hange (half-summer), Bankouuka Herbal medicines such as (Banka), Hampi (anti-nasal), peony (white), peanut (white moth), bukkuri (茯苓), button pi (peony skin), yellow bay (pepper skin), loquat (deer moth) and their extraction Product (extract, tincture, dry extract, etc.) etc. Is mentioned.

  Kampo recipes include Keishito (Katsurayu), Kousosan (Kousosan), Psychokeito (Shibako Keiyu), Shosaikou (Koshisaifuto), Bakumondou (Bakumon Fuyuto), Hangekou Bokuto (Hankatsu Koboku-yu).

  The pharmaceutical composition of the present invention can be used as appropriate for the treatment and alleviation of the corresponding diseases and symptoms according to the known efficacy of various herbal medicines. Among them, since the pharmaceutical composition of the present invention contains loxoprofen, which is a kind of NSAID, or a salt thereof, it can be used as a medical drug or an OTC drug. Specifically, for example, osteoarthritis, myalgia and It is effective as an analgesic / anti-inflammatory agent, etc. because it has a disease selected from swelling / pain after trauma and symptom anti-inflammatory / analgesic effect.

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.
[Test Example 1] Examination of storage stability of pharmaceutical composition containing buckwheat or extract thereof The following samples 1-A and 1-B were prepared, and the appearance after storage immediately before starting storage and at 80 ° C for 1 week (Presence or absence of precipitation) was visually evaluated.
The results are shown in Table 1.

<Sample 1-A>
Ogaku soft extract (made by Nippon Powder Chemical Co., Ltd .: trade name Ogaku soft extract) 0.7g (2.31g in terms of bulk drug substance) was dissolved and suspended in purified water to obtain 100g of sample 1-A.
<Sample 1-B>
Ogaku soft extract (Nippon Powder Pharmaceutical Co., Ltd .: trade name: Oubak soft extract) 0.7 g (2.31 g of raw drug equivalent) and loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen 1.13 g of sodium hydrate) was dissolved and suspended in purified water to obtain a total amount of 100 g of sample 1-B.

As is apparent from the test results shown in Table 1, in the sample solution containing only the soft buckwheat extract (Sample 1-A), precipitation was observed immediately before the start of storage, but in addition to the soft buckwheat extract In the sample solution containing loxoprofen sodium hydrate (Sample 1-B), a slight amount of precipitation was observed even after storage at 80 ° C. for 1 week.
From such test results, it has been clarified that loxoprofen or a salt thereof has an action of suppressing the formation of a precipitate of a water-containing composition containing a buckwheat or an extract thereof and improving storage stability. This is presumably because loxoprofen or a salt thereof solubilizes buckwheat or an extract thereof in the water-containing composition.

  From the above test results, it became clear that a pharmaceutical composition containing loxoprofen or a salt thereof together with a buckwheat or an extract thereof exhibits excellent storage stability.

[Test Example 2] Examination of storage stability of pharmaceutical composition containing licorice or extract thereof The following samples 2-A and 2-B were prepared, and the appearance immediately after starting storage and after storing at 80 ° C. for 2 days (Presence or absence of precipitation) was visually evaluated.
The results are shown in Table 2.

<Sample 2-A>
1 g of licorice extract (manufactured by Nippon Powder Chemical Co., Ltd .: trade name (local) licorice extract) (4 g in terms of bulk drug substance) was dissolved and suspended in purified water to obtain 100 g of sample 2-A.
<Sample 2-B>
Licorice extract (manufactured by Nippon Flour Pharmaceutical Co., Ltd .: trade name (local) licorice extract) 1 g (concentration of active ingredient 4 g) and loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia loxoprofen sodium hydrate) ) 1.13 g was dissolved and suspended in purified water to obtain 100 g of sample 2-B.

As apparent from the test results shown in Table 2, in the sample solution containing only licorice alone (Sample 2-A), precipitation was observed after storage at 80 ° C. for 2 days, but in addition to licorice, loxoprofen In the sample solution containing sodium hydrate (Sample 2-B), no precipitation was observed even after storage at 80 ° C. for 2 days.
From such test results, it was revealed that loxoprofen or a salt thereof has an action of suppressing the formation of a precipitate of a water-containing composition containing licorice or an extract thereof and improving the storage stability. This is presumably because loxoprofen or a salt thereof solubilizes licorice or an extract thereof in a water-containing composition.

  From the above test results, it was revealed that a pharmaceutical composition containing loxoprofen or a salt thereof together with licorice or an extract thereof exhibits excellent storage stability.

[Test Example 3] Examination of storage stability of pharmaceutical composition containing glycyrrhetinic acid or a salt thereof Appearance after preparing the following Samples 3-A and 3-B and immediately storing them at 80 ° C for 1 day (Presence or absence of separation) was visually evaluated.
The results are shown in Table 3.

<Sample 3-A>
1 g of glycyrrhetic acid (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: glycyrrhetinic acid) was dissolved and suspended in a 10% aqueous ethanol solution to obtain 100 g of sample 3-A.
<Sample 3-B>
1 g of glycyrrhetinic acid (Alps Yakuhin Kogyo Co., Ltd .: trade name: glycyrrhetinic acid) and 1.13 g of loxoprofen sodium hydrate (Yamato Yakuhin Kogyo Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) in 10% ethanol aqueous solution It melt | dissolved and suspended and sample 3-B of 100 g of whole quantity was obtained.

As is apparent from the test results shown in Table 3, in the sample solution containing only glycyrrhetic acid (Sample 3-A), powdery substances were separated immediately before the start of storage, but in addition to glycyrrhetic acid, In the sample solution (sample 3-B) containing loxoprofen sodium hydrate, no separation was observed even after storage at 80 ° C. for 1 day.
From these test results, loxoprofen or a salt thereof has an effect of improving the storage stability by suppressing the separation of a hydrated composition containing glycyrrhetinic acid or a salt thereof, which is a hydrolyzate of licorice extract (glycyrrhizic acid). It became clear to have. This is presumably because loxoprofen or a salt thereof solubilizes glycyrrhetic acid or a salt thereof, which is a hydrolyzate of licorice extract in a water-containing composition.

  From the above test results, it has been clarified that a pharmaceutical composition containing loxoprofen or a salt thereof together with glycyrrhetinic acid or a salt thereof exhibits excellent storage stability.

[Test Example 4] Examination of storage stability of pharmaceutical composition containing salamander or extract thereof The following samples 4-A and 4-B were prepared, and immediately after starting storage and after storing at 80 ° C for 1 week. The appearance (presence / absence of precipitation) was visually evaluated.
The results are shown in Table 4.

<Sample 4-A>
Salam soft extract (Alps Yakuhin Kogyo Co., Ltd .: trade name Sansho soft extract) 0.3g (1g in terms of bulk drug substance) was dissolved and suspended in purified water to obtain 100g of sample 4-A.
<Sample 4-B>
Sansho soft extract (Alps Yakuhin Kogyo Co., Ltd .: trade name Sansho soft extract) 0.3 g (1 g of raw drug equivalent) and loxoprofen sodium hydrate (Yamato Yakuhin Kogyo Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium) Hydrate) 1.13 g was dissolved and suspended in purified water to obtain a total amount of 100 g of sample 4-B.

As apparent from the test results shown in Table 4, in the sample solution containing only the salamander soft extract alone (sample 4-A), precipitation was observed immediately before the start of storage. In addition, in the sample solution containing loxoprofen sodium hydrate (Sample 4-B), no precipitation was observed even after storage at 80 ° C. for 1 week.
From such test results, it has been clarified that loxoprofen or a salt thereof has an action of suppressing the formation of a precipitate of a water-containing composition containing a salamander or an extract thereof and improving storage stability. This is presumably because loxoprofen or a salt thereof solubilizes salamander or an extract thereof in a water-containing composition.

  From the above test results, it was revealed that a pharmaceutical composition containing loxoprofen or a salt thereof together with salamander or an extract thereof exhibits excellent storage stability.

[Test Example 5] Examination of storage stability of pharmaceutical composition containing horse chestnut seed or extract thereof Samples 5-A and 5-B below were prepared and stored at 80 ° C for 1 day immediately before starting storage. The appearance (presence / absence of coloring) was evaluated visually.
The results are shown in Table 5.

<Sample 5-A>
Horse chestnut seed extract (manufactured by Ichimaru Falcos Co., Ltd .: trade name Falco Rex Maronie B) 0.5 g (powder equivalent amount 5 g) was dissolved and suspended in purified water to obtain a total amount 100 g of Sample 5-A.
<Sample 5-B>
Horse chestnut seed extract (Ichimaru Falcos Co., Ltd .: trade name Falco Rex Maronie B) 0.5g (concentration of active ingredient 5g) and loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium water 1.13 g (Japanese product) was dissolved and suspended in purified water to obtain a total amount of 100 g of sample 5-B.

As is apparent from the test results shown in Table 5, in the sample solution containing only the horse chestnut seed extract alone (sample 5-A), yellow coloring was seen immediately before the start of storage. In addition, in the sample solution containing loxoprofen sodium hydrate (Sample 5-B), the coloring was slight.
From such test results, it has been clarified that loxoprofen or a salt thereof has an action of suppressing the coloration of a water-containing composition containing a horse chestnut seed or an extract thereof and improving storage stability. This is presumably because loxoprofen or a salt thereof solubilizes horse chestnut seed or an extract thereof in the water-containing composition.

  From the above test results, it was revealed that a pharmaceutical composition containing loxoprofen or a salt thereof together with horse chestnut seed or an extract thereof exhibits excellent storage stability.

Test Example 6 Examination of Storage Stability of Pharmaceutical Composition Containing Pepper or Extracts The following samples 6-A and 6-B were prepared, and the appearance after storage immediately before starting storage and at 80 ° C. for 1 day (Presence / absence of insoluble matter) was evaluated visually.
The results are shown in Table 6.

<Sample 6-A>
Pepper extract (Nippon Powder Pharmaceutical Co., Ltd .: trade name Pepper extract B) 0.5 g (pure drug equivalent 6.25 g) was dissolved and suspended in purified water to obtain a total amount of 100 g of sample 6-A.
<Sample 6-B>
Pepper extract (Nippon Powder Pharmaceutical Co., Ltd .: trade name Pepper extract B) 0.5g (pure drug equivalent 6.25g) and loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium water 20 g of the product was dissolved and suspended in purified water to obtain a total amount of 100 g of sample 6-B.

As is clear from the test results shown in Table 6, in the sample solution containing only the pepper extract alone (Sample 6-A), a small amount of insoluble matter was observed immediately before the start of storage, and after storage at 80 ° C. for 1 day. In the sample solution containing loxoprofen sodium hydrate in addition to the pepper extract, no precipitation was observed even after storage at 80 ° C. for 1 day. .
From such test results, it was revealed that loxoprofen or a salt thereof has an action of suppressing the formation of a precipitate of a water-containing composition containing a red pepper or an extract thereof and improving storage stability. This is presumably because loxoprofen or a salt thereof solubilizes pepper or an extract thereof in the water-containing composition.

  From the above test results, it became clear that a pharmaceutical composition containing loxoprofen or a salt thereof together with a pepper or an extract thereof exhibits excellent storage stability.

Production Example 1 (Gel)
By a conventional method, a gel containing the following components in 100 g was produced.
Loxoprofen sodium hydrate 1.13g
Glycyrrhetinic acid 0.2g
Nonanoic acid vanillylamide 0.025 g
l-Menthol 3g
Chlorpheniramine maleate 0.1g
Hydroxypropyl methylcellulose 1g
Carboxyvinyl polymer 1.2g
1,3-butylene glycol 5g
Triethanolamine 1.5g
Ethanol 20g
100g of purified water

Production Example 2 (Tape)
By a conventional method, a tape preparation (plaster agent) containing the following components in 100 g was produced.
Loxoprofen sodium hydrate 1.13g
Pepper extract 0.4g (Drug substance equivalent: 4g)
l-Menthol 6g
Chlorpheniramine maleate 0.1g
SIS copolymer 30g
Polyisobutylene 20g
Hydrogenated rosin glycerin ester 25g
Dibutylhydroxytoluene 0.5g
Crotamiton 2g
100g liquid paraffin

Production Example 3 (Gel)
By a conventional method, a gel (gel cream) containing the following components in 100 g was produced.
Loxoprofen sodium hydrate 1.13g
Licorice extract 0.4g (Drug substance equivalent: 4g)
l-Menthol 2g
Polyvinyl alcohol 0.2g
Salicylic acid glycol ester 2g
Carboxy vinyl polymer 1g
Glycerin 10g
Octyldodecanol 10g
0.5 g of glyceryl monostearate
Polyoxyl stearate 0.5g
5g isopropyl myristate
Lauro Macrogol 1.5g
Triethanolamine 1g
100g of purified water

Production Example 4 (cataplasm)
By a conventional method, a cataplasm containing 100% of the following components was produced.
Loxoprofen sodium hydrate 1.13g
Oowaku powder 1g (Drug equivalent: 5g)
1g of salamander
Horse chestnut seed 3g
l-Menthol 3g
Polyvinyl alcohol 0.8g
7g of partially neutralized polyacrylic acid
Carmellose sodium 5g
N-methyl-2-pyrrolidone 2g
Concentrated glycerin 25g
Polysorbate 80 0.3g
Aluminum hydroxide gel 0.05g
Titanium oxide 1g
Talc 2g
Tartaric acid 0.6g
Edetate sodium hydrate 0.1g
Kaolin 2.5g
Sodium bisulfite 0.3g
100g of purified water

Production Example 5 (Lotion)
By a conventional method, a lotion preparation containing the following components in 100 g was produced.
Loxoprofen sodium hydrate 1.13g
Glycyrrhetinic acid 0.1g
Nonanoic acid vanillylamide 0.1 g
Peppermint oil 6g
Chlorpheniramine maleate 0.5g
Diisopropyl adipate 5g
Isopropanol 40g
Hydroxypropyl methylcellulose 0.1g
Polyethylene glycol 1g
Sodium bisulfite 0.2g
100g of purified water

Production Example 6 (Tape)
By a conventional method, a tape preparation (plaster agent) containing the following components in 100 g was produced.
Loxoprofen sodium hydrate 1.13g
Nonanoic acid vanillylamide 0.12 g
l-Menthol 1g
Chlorpheniramine maleate 0.5g
SIS copolymer 30g
Polyisobutylene 20g
Hydrogenated rosin glycerin ester 25g
Dibutylhydroxytoluene 0.5g
Crotamiton 2g
100g liquid paraffin

Production Example 7 (Cream)
A cream containing the following components in 100 g was produced by a conventional method.
Loxoprofen sodium hydrate 1.13g
Horse chestnut seed extract 0.3g (Drug equivalent: 3g)
Nonanoic acid vanillylamide 0.12 g
dl-Camphor 4g
Polyvinyl alcohol 0.2g
Carboxy vinyl polymer 0.8g
Edetate sodium hydrate 1g
Sodium bisulfite 0.1g
Octyldodecyl myristate 10g
Diisopropyl adipate 5g
2g glyceryl monostearate
Sorbitan monostearate 0.5g
1g polyoxyethylene sorbitan monostearate
Paraben 0.2g
Sodium hydroxide 0.1g
100g of purified water

Production Example 8 (cataplasm)
By a conventional method, a cataplasm containing 100% of the following components was produced.
Loxoprofen sodium hydrate 1.13g
Horse chestnut seed extract 0.3g (Drug equivalent: 3g)
Nonanoic acid vanillylamide 0.1 g
l-Menthol 3g
Polyvinyl alcohol 1g
7g of partially neutralized polyacrylic acid
Methyl acrylate and 2-ethylhexyl acrylate copolymer resin emulsion
5g
Carmellose sodium 5g
Crotamiton 2g
Concentrated glycerin 25g
Polysorbate 80 0.3g
Aluminum hydroxide gel 0.05g
Titanium oxide 1g
Talc 2g
Tartaric acid 0.6g
Edetate sodium hydrate 0.1g
Kaolin 2.5g
Sodium bisulfite 0.3g
100g of purified water

Production Example 9 (cataplasm)
By a conventional method, a cataplasm containing 100% of the following components was produced.
Loxoprofen sodium hydrate 1.13g
1g of end of the sunshow
l-Menthol 3g
Polyvinyl alcohol 0.8g
7g of partially neutralized polyacrylic acid
Carmellose sodium 5g
N-methyl-2-pyrrolidone 2g
Concentrated glycerin 25g
Polysorbate 80 0.3g
Aluminum hydroxide gel 0.05g
Titanium oxide 1g
Talc 2g
Tartaric acid 0.6g
Edetate sodium hydrate 0.1g
Kaolin 2.5g
Sodium bisulfite 0.3g
100g of purified water

  ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical composition which contains a crude drug etc. and was excellent in storage stability (especially storage stability in high temperature conditions) can be provided, and can be utilized in the pharmaceutical industry etc.

Claims (5)

The following components (A) and (B):
(A) One or more selected from the following components (A-4) and (A-5) (A-4) Salamander or its extract (A-5) Horse chestnut seed or its extract (B) Loxoprofen Or the pharmaceutical composition which contains the salt and is a water-containing composition . Component (A) is
(A-4) The pharmaceutical composition according to claim 1, which is a salamander or an extract thereof. Component (A) is
The pharmaceutical composition according to claim 1, which is (A-5) horse chestnut seed or an extract thereof.   The pharmaceutical composition according to any one of claims 1 to 3, which is semi-solid or liquid. The pharmaceutical composition according to any one of claims 1 to 4 , which is a liniment, a lotion, an external aerosol, a pump spray, an ointment, a cream, a gel, a tape or a poultice.