Composition

Abstract

To provide a composition with good quality stability in which solidification of garlic processed products is suppressed during high-temperature storage, or discoloration of gamma-oryzanol is suppressed. [Solution] A composition containing a phosphodiesterase 5 inhibitor and one or more selected from the group consisting of garlic processed products and gamma-oryzanol.

Description

Technical Field

[0001] The present invention relates to compositions and the like.

Background Art

[0002] Components such as processed garlic and gamma oryzanol have various pharmacological and physiological effects and are extremely useful components widely used in the fields of pharmaceuticals, quasi-drugs, cosmetics, etc. Processed garlic is known to have effects such as fatigue recovery and nourishing and strengthening effects, and is widely used as a component of nourishing and strengthening agents. Gamma oryzanol is a substance present in rice bran oil, rice germ oil, corn oil, and other cereal bran oils, and is a mixture of ferulic acid esters of triterpene alcohols (Non-Patent Document 1). It is known to have effects such as growth promotion, relaxation of autonomic nerve disorders, gonad-stimulating effects, sebum secretion promotion effects, blood flow promotion effects, skin temperature elevation effects, antioxidant effects, ultraviolet absorption effects, tyrosinase activity inhibition effects, etc., and is furthermore a highly safe substance. Therefore, it is extremely useful to establish a technique for stably formulating processed garlic and gamma oryzanol as compositions such as tablets and capsules.

[0003] By the way, phosphodiesterase 5 inhibitors such as sildenafil citrate, vardenafil hydrochloride hydrate, and tadalafil maintain and increase the cyclic GMP amount in the corpus cavernosum of the penis and sustain the state of increased intracorporeal pressure (erection) of the corpus cavernosum of the penis (Non-Patent Document 2), and combinations with other components such as L-carnitine adducts have also been reported (Patent Document 1). [[ID=IP19]] However, there has been no report whatsoever on the effects of phosphodiesterase 5 inhibitors on the storage stability of processed garlic and gamma oryzanol.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

[0005] [Non-Patent Document 1] FREGRANCE JOURNAL,3,p71-77,1998 [Non-Patent Document 2] Compendium of Medical Drugs, 2009 Edition, JAPIC, 2008 [Overview of the project] [Problems that the invention aims to solve]

[0006] The inventors of this invention first investigated the storage stability of garlic products and gamma-oryzanol in order to establish a new technology for stably formulating these ingredients. They found that when these ingredients are stored under high-temperature conditions, the garlic products solidify over time, and the gamma-oryzanol discolors over time. These changes in properties, such as the solidification of garlic products and the discoloration of gamma-oryzanol, worsen the quality stability of the composition during storage, thereby reducing its commercial value. Therefore, the object of the present invention is to provide a composition with good quality stability in which solidification of garlic processed products during high-temperature storage is suppressed, or discoloration of gamma-oryzanol is suppressed. [Means for solving the problem]

[0007] The inventors of the present invention conducted diligent research to solve the aforementioned problems and, to their surprise, discovered that by coexisting a phosphodiesterase 5 inhibitor (hereinafter sometimes referred to as "PDE5 inhibitor"), such as sildenafil, with garlic processed products and gamma-oryzanol, the solidification of the garlic processed products and the discoloration of gamma-oryzanol during high-temperature storage are suppressed, resulting in a composition with good quality stability. Thus, the present invention was completed.

[0008] In other words, the present invention provides a composition containing a phosphodiesterase 5 inhibitor and one or more selected from the group consisting of garlic processed products and gamma-oryzanol. Furthermore, the present invention provides a method for stabilizing one or more substances selected from the group consisting of garlic processed products and gamma-oryzanol, comprising the step of coexisting one or more substances selected from the group consisting of garlic processed products and gamma-oryzanol with a phosphodiesterase 5 inhibitor. [Effects of the Invention]

[0009] According to the present invention, it is possible to provide a composition with good quality stability and high commercial value in which solidification of garlic processed products during high-temperature storage is suppressed, or discoloration of gamma-oryzanol is suppressed. [Modes for carrying out the invention]

[0010] <Phosphodiesterase-5 inhibitors> In this specification, "phosphodiesterase 5 inhibitor" means a compound having phosphodiesterase 5 inhibitory activity, and specifically, for example, one or more selected from the group consisting of avanafil, udenafil, sildenafil, tadalafil, vardenafil, mirodenafil and their salts and solvates. Here, the salt of the compound is not particularly limited as long as it is a pharmaceutically acceptable salt, and specifically, for example, inorganic salts such as hydrochloride, sulfate, nitrate, hydrofluoric acid, and hydrobromide; organic salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and camphorsulfonate. Furthermore, the compound or its salt may be a solvate such as a hydrate or an alcoholic hydrate. PDE5 inhibitors are known components and may be manufactured by known methods, or commercially available ones may be used.

[0011] As PDE5 inhibitors, from the viewpoint of inhibiting the solidification of garlic products or inhibiting the discoloration of gamma-oryzanol, one or more selected from the group consisting of avanafil, udenafil, sildenafil, tadalafil, vardenafil, mirodenafil and their salts and solvates are preferred, one or more selected from the group consisting of sildenafil, tadalafil, vardenafil and their salts and solvates are more preferred, one or more selected from the group consisting of sildenafil, vardenafil and their salts and solvates are even more preferred, and one or more selected from the group consisting of sildenafil citrate and vardenafil hydrochloride hydrate are particularly preferred. Note that sildenafil and vardenafil have particularly similar chemical structures among PDE5 inhibitors.

[0012] The amount of PDE5 inhibitor in the composition is not particularly limited, but from the viewpoint of inhibiting the solidification of garlic processed products or inhibiting the discoloration of gamma-oryzanol, it may be 0.1% by mass or more, preferably 1% by mass or more, and particularly preferably 2% by mass or more, relative to the total mass of the composition, and may also be 50% by mass or less, preferably 40% by mass or less, and particularly preferably 35% by mass or less. In particular, from the viewpoint of inhibiting the solidification of garlic processed products or inhibiting the discoloration of gamma-oryzanol, it is preferable to contain 3 to 30% by mass, more preferably 5 to 25% by mass, and particularly preferable to contain 10 to 20% by mass, relative to the total mass of the composition.

[0013] Garlic products In this specification, "garlic processed product" can refer to any product obtained by processing garlic (Allium Sativum). The part of the garlic used is not particularly limited; the whole plant or a part thereof (above ground, underground, bulb, leaves, stem, flower, etc.) or a combination of two or more of these can be used, but the bulb is preferred. Furthermore, "processing" can include cutting, heating, drying, grinding, and extraction, and the type of processing is not particularly limited. Specifically, examples include heat treatment; drying and then powdering raw garlic; and extraction with a solvent. Examples of extraction solvents include alcohols such as methanol, ethanol, isopropanol, n-butanol, 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 or cycloalkanes such as pentane, hexane, cyclopentane, and cyclohexane; halogenoalkanes such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene and toluene; dimethylformamide; dimethyl sulfoxide; water (including hot water); and edible vegetable oils such as rapeseed oil, olive oil, and soybean oil. "Garlic processed products" include one or more selected from the group consisting of processed garlic, garlic extract, garlic extract, and dried garlic, with processed garlic being preferred. Examples of commercially available processed garlic include oxoamidine (registered trademark), oxoamidine (registered trademark) powder, and oxolezin (registered trademark) powder (all manufactured by Riken Chemical Industry Co., Ltd.).

[0014] The amount of garlic processed product in the composition is not particularly limited, but it may be 0.01% by mass or more, preferably 0.1% by mass or more, and especially preferably 0.5% by mass or more, relative to the total mass of the composition, and may also be 70% by mass or less, preferably 60% by mass or less, and especially preferably 50% by mass or less. In particular, it is preferable to have 1 to 40% by mass relative to the total mass of the composition, more preferably 3 to 30% by mass, and especially preferable to have 5 to 20% by mass.

[0015] The mass ratio of the PDE5 inhibitor to the processed garlic in the composition is not particularly limited. From the perspective of the effect of suppressing the solidification of the processed garlic, the composition may contain 0.005 parts by mass or more, preferably 0.01 parts by mass or more, particularly preferably 0.05 parts by mass or more of the processed garlic with respect to 1 part by mass of the PDE inhibitor. Also, it may contain 30 parts by mass or less, preferably 20 parts by mass or less, particularly preferably 15 parts by mass or less. Among them, from the perspective of the effect of suppressing the solidification of the processed garlic, it is preferable that the composition contains 0.1 to 10 parts by mass of the processed garlic with respect to 1 part by mass of the PDE5 inhibitor, more preferably 0.2 to 5 parts by mass, and particularly preferably 0.4 to 3 parts by mass.

[0016] <Gamma-oryzanol> "Gamma-oryzanol" is obtained from the seed coat of rice (Oryza sativa L.) and mainly consists of ferulic acid (3-methoxy-4-hydroxycinnamic acid) esters of triterpene alcohols. In the present invention, the raw material, purification method, production method, etc. of gamma-oryzanol are not particularly limited, but gamma-oryzanol described in the Quasi-drug Raw Material Standards 2006 is preferable. Gamma-oryzanol is a known component, and commercially available products may be used, or it can also be produced by known methods.

[0017] The content of gamma-oryzanol in the composition is not particularly limited. With respect to the total mass of the composition, it may contain 0.005% by mass or more, preferably 0.01% by mass or more, particularly preferably 0.05% by mass or more, and may also contain 50% by mass or less, preferably 40% by mass or less, particularly preferably 30% by mass or less. Among them, with respect to the total mass of the composition, it is preferable to contain 0.1 to 20% by mass, more preferably 0.5 to 10% by mass, and particularly preferably 1 to 5% by mass.

[0018] The mass ratio of the PDE5 inhibitor to gamma oryzanol in the composition is not particularly limited. From the perspective of the discoloration inhibitory effect of gamma oryzanol, the composition may contain 0.0001 parts by mass or more, preferably 0.0005 parts by mass or more, particularly preferably 0.001 parts by mass or more of gamma oryzanol with respect to 1 part by mass of the PDE inhibitor. Also, it may contain 40 parts by mass or less, preferably 20 parts by mass or less, particularly preferably 10 parts by mass or less. Among them, from the perspective of the discoloration inhibitory effect of gamma oryzanol, it is preferable that the composition contains 0.005 to 5 parts by mass of gamma oryzanol with respect to 1 part by mass of the PDE5 inhibitor, more preferably 0.01 to 2 parts by mass, and particularly preferably 0.05 to 1 part by mass.

[0019] <Composition> As used herein, the "composition" may be in any of solid, semi-solid, or liquid forms, and may be in a form commonly used in pharmaceuticals, quasi-drugs, cosmetics, foods, etc. according to its intended use. Specifically, for example, tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, oral tablets (including troches, sublingual tablets, buccal tablets, adherent tablets, gums).), capsules, granules (including effervescent granules.), powders, pills, and other solid preparations; oral liquids (including elixirs, suspensions, emulsions, lemonades.), syrups, oral liquids, and other liquid preparations; oral jellies, oral semi-solid preparations, and other semi-solid preparations, which can be in the dosage forms described in the General Rules of Preparations of the Japanese Pharmacopoeia, 17th Revision, etc. As the shape of the composition, a solid composition is preferable from the perspective of the solidification inhibitory effect of garlic processed products or the discoloration inhibitory effect of gamma oryzanol. An agent form selected from the group consisting of tablets, capsules, granules, powders, and pills is more preferable, and an agent form selected from the group consisting of tablets and granules is particularly preferable.

[0020] The composition can be produced according to a method known in the pharmaceutical field, quasi-drug field, etc. according to the above-described shape and dosage form, for example, according to the method described in the General Rules of Preparations of the Japanese Pharmacopoeia, 18th Revision, etc. In addition to the above-mentioned components, the composition may also contain one or more carriers (excipients, binders, disintegrants, lubricants, colorants, flavoring agents, coating agents, etc.) used in the pharmaceutical, quasi-drug, cosmetic, and food industries.

[0021] Excipients include lactose, crystalline cellulose, sucrose, mannitol, and light anhydrous silicic acid. Examples of binders include hydroxypropyl methylcellulose, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, and pullulan. Examples of disintegrants include carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose. Examples of lubricants include magnesium stearate and talc. Examples of coloring agents include tar dyes and iron(III) oxide. Examples of flavoring agents include stevia and aspartame. Examples of coating agents include film-forming polymers such as carboxymethyl ethyl cellulose, cellulose acetate phthalate, methacrylic acid copolymer S, methacrylic acid copolymer L, methacrylic acid copolymer LD, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate. When forming the film, plasticizers such as triethyl citrate, triacetin, and polyethylene glycol; and powders such as talc, titanium dioxide, yellow ferric oxide, ferric oxide, legal dyes, light anhydrous silicic acid, and hydrated silicon dioxide may also be incorporated. The composition may contain one or more of these carriers in appropriate combinations.

[0022] In addition to the components mentioned above, the composition may also contain other medicinal ingredients. These medicinal ingredients are not particularly limited and should be appropriately selected depending on the disease or symptoms to which the composition is applied. Examples include vitamins, xanthine derivatives, amino acids, herbal medicines, zinc compounds, and monoterpene alkaloids. Vitamins include, specifically, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B12, vitamin C, hesperidin and its derivatives, and their salts, etc. (specifically, for example, thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, cetothiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, shikotiamine, thiamine disulfide, bis-ibthiamine, bis-bentiamine, prosultiamine, benfotiamine, riboflavin, ribo Examples include flavin phosphate esters, riboflavin butyrate ester, riboflavin sodium phosphate, nicotinic acid, nicotinamide, inositol hexanicotinate, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, hepronicate, panthenol, pantethine, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate ester, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc. Examples of xanthine derivatives include caffeine (specifically, caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, caffeine citrate, etc.), theophylline, theobromine, paraxanthine, proxyphylline, and diprophylline. Examples of amino acids include L-arginine, L-arginine hydrochloride, L-cysteine ​​hydrochloride, L-cysteine, L-lysine hydrochloride, L-arginine hydrochloride, L-carnitine hydrochloride, L-methionine, DL-methionine, L-isoleucine, L-leucine, L-phenylalanine, L-threonine, L-tryptophan, L-valine, and aminoethylsulfonic acid. The herbal medicines include: Asenyaku, Anise fruit, Aloe, Epimedium, Fennel, Turmeric, Ubai, Uyaku, Corydalis, Enmeiso, Astragalus, Scutellaria, Phellodendron, Coptis, Polygala, Processed garlic, Polygonum multiflorum, Curcuma longa, Cuckoo, Valerian, Calamus root, Ginger, Licorice, Citrus aurantium, Lycium barbarum, Sophora japonica, Cinnamon bark, Cassia seed, Gentian, Geranium thunbergii, Ox gall, Coriander, Evodia, Pepper, Gallnut, Colombo, Condyloma, Hawthorn, Cornus officinalis, Zanthoxylum piperitum, Dioscorea, Ziziphus, Zanthoxylum piperitum Examples of crude drugs and their extracts include Sociophyllum ulmoides, Paeonia lactiflora, Citrus aurantium, Cardamom, Zingiber officinale, Citrus aurantium, Cyperus rotundus, Atractylodes macrocephala, Cyperus rotundus, Centaurea cyanus, Atractylodes macrocephala, Star anise, Rheum officinale, Ginseng, Clove, Uncaria rhynchophylla, Citrus unshiu peel, Capsicum umbellatum, Angelica acutiloba, Spruce, Passiflora rhizome, Eucommia ulmoides, Pseudocarpus nigra, Nutmeg, Ginseng, Mint, Pinellia ternata, Mentha arvensis, Long pepper, Angelica dahurica, Atractylodes macrocephala, Poria cocos, Hops, Vigna angularis, Water lily, Yakko, Youbaihi, Gentian, and Ligustrum lucidum. Examples of zinc compounds include zinc chloride, zinc oxide, zinc lactate, and zinc sulfate. Examples of monoterpene alkaloids include strychnine and yohimbine.

[0023] <Packaging composition> Furthermore, the above composition may be contained in an airtight package (hereinafter, in this specification, a composition contained in an airtight package will be referred to as a "packaged composition"). As specifically disclosed in the test examples below, by co-administering a phosphodiesterase 5 inhibitor, such as sildenafil citrate, with garlic processed products and housing them in an airtight package, the change in properties (solidification) of the garlic processed products during high-temperature storage can be further suppressed. Furthermore, by co-administering a phosphodiesterase 5 inhibitor with gamma-oryzanol and housing them in an airtight package, the change in properties (discoloration) of gamma-oryzanol during high-temperature storage can be further suppressed. In this case, the packaged composition may also include other packaging that does not fall under the category of "airtight package" (hereinafter also referred to as "other packaging") in addition to the airtight package, and the composition may be directly or indirectly contained in the airtight package. An example of indirectly containing the composition in the airtight package is a configuration in which the composition is contained in the "other packaging" and then housed in the airtight package.

[0024] In this specification, "airtight packaging" means packaging that can prevent the intrusion of solid or liquid foreign matter under normal handling, transportation, or storage conditions, and is a concept that encompasses "airtight containers" and "sealed containers" as defined in the General Rules of the 18th Edition of the Japanese Pharmacopoeia. Airtight packaging can be either fixed-shaped or irregular-shaped, and specific examples include bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, etc. Airtight packaging may also be a combination of multiple types of these, and specific examples include packaging the composition first in PTP packaging and then further packaging it in pillow packaging.

[0025] The packaging material (material) for the airtight packaging is not particularly limited, and materials used in fields such as pharmaceuticals and food, such as glass, plastics (polyesters such as polyethylene terephthalate and polyethylene naphthalate; polyethylene (including low-density (LDPE), medium-density (MDPE), and high-density (HDPE))), polyolefins such as polypropylene; polycarbonate; polystyrene, etc.), and metals (aluminum, etc.), can be used individually or in combination of two or more as appropriate.

[0026] For example, the packaging materials used for bottle packaging are not particularly limited and include the above-mentioned glass, plastic, and metal, and one or more of these can be combined as appropriate. Preferred materials for bottle packaging are glass, polyethylene, and polypropylene; more preferably glass, low-density polyethylene (LDPE), high-density polyethylene (HDPE), and polypropylene; even more preferably glass, high-density polyethylene (HDPE), and polypropylene; and particularly preferred glass. When packaging in bottles, for example, an appropriate quantity of the composition can be placed in the bottle, and then sealed with a suitable stopper or cap. The size of the bottle should be appropriately selected according to the quantity of composition to be stored, and the capacity of the bottle is, for example, about 10 to 500 mL, preferably 14 to 400 mL, and more preferably 24 to 350 mL.

[0027] Furthermore, the packaging materials used in SP packaging, PTP packaging, pillow packaging, stick packaging, etc., are not particularly limited. Examples include biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), glycol-modified PET (PET-G), biaxially oriented nylon (ONy, PA), cellophane, paper, low-density polyethylene (LDPE), linear low-density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), unoriented polypropylene (CPP, IPP), and ionomer resin (IO). Examples include resins such as ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially oriented polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC), cyclic polyolefin (COC), unoriented nylon (CNy), polycarbonate (PC), polystyrene (PS), and rigid polyvinyl chloride (VSC), as well as metal foils such as aluminum foil (AL). One or more of these can be appropriately combined.

[0028] When producing SP packaging, PTP packaging, pillow packaging, stick packaging, etc., the packaging can be manufactured using a sheet made of one or more of the above-mentioned packaging materials by a known method, and in this case, a multilayer structure can be formed by appropriately combining the packaging materials. One method for creating a multilayer structure using two or more types of packaging materials as a sheet is to produce a laminated sheet by laminating the packaging materials. Laminated sheets can be manufactured by known methods such as extrusion lamination, dry lamination, co-extrusion lamination, thermal lamination, wet lamination, non-solvent lamination, and heat lamination. In addition, commercially available sheets known to be used for SP packaging, PTP packaging, pillow packaging, and stick packaging can also be used.

[0029] In the above-mentioned sheets, single-layer sheets using one type of packaging material include PVC sheets and CPP sheets, and laminated sheets using two or more types of packaging materials include, for example, sheets laminated with PVC and PVDC (PVC / PVDC; hereinafter abbreviated similarly), PVC / PVDC / PE / PVC, PVC / PVDC / PE / PVDC / PVC, CPP / COC / CPP, PVC / PCTFE, CPP / PCTFE, PVC / AL / PA, PVC / AL, CPP / AL, CPP / CPP / CPP (the above sheets use two or more types of CPP), but are not limited to these.

[0030] One form of PTP packaging involves forming a desired number of pockets in a resin sheet or the like using a known method, storing the composition one unit or one dose in each pocket, and then sealing it with a sheet made of metal foil such as aluminum foil as a lid material. Alternatively, a so-called double-sided aluminum PTP packaging may be used, where the sheet forming the pockets is also made of aluminum foil. When using PTP packaging, it is preferable to further package the PTP packaging in pillow packaging (e.g., aluminum pillow packaging) from the viewpoint of inhibiting the solidification of garlic products or inhibiting the discoloration of gamma-oryzanol. Examples of SP packaging, pillow packaging, and stick packaging include packaging the composition one unit or one dose unit at a time using a sheet made of resin sheet or aluminum foil as a constituent material, using known methods. When using SP packaging, pillow packaging, or stick packaging, it is preferable to use a sheet made of aluminum foil as a constituent material from the viewpoint of inhibiting the solidification of garlic processed products or inhibiting the discoloration of gamma-oryzanol.

[0031] In this specification, the occupancy rate (volume ratio) of the composition within the packaging is typically 25-90%, preferably 28-75%, and more preferably 30-50% when the packaging is a bottle. When the packaging is SP packaging, PTP packaging, pillow packaging, or stick packaging, the occupancy rate is typically 30-98%, preferably 40-95%, more preferably 45-93%, and particularly preferably 50-90%. In this case, the occupancy rate refers to the occupancy rate of the composition relative to the total volume inside the packaging, and packing materials or stoppers used to prevent damage to the composition stored inside the packaging are not considered when calculating the space occupancy rate.

[0032] As airtight packaging, commercially available packaging may be used as is, or commercially available packaging materials may be processed and used. Examples of commercially available bottle packaging include glass bottles (manufactured by Isoya Glass Industry Co., Ltd.), tablet bottles (manufactured by Tokyo Glass Co., Ltd.), and the Z-series (manufactured by Hanshin Chemical Industries, Ltd.). Examples of commercially available pillow packaging include Lamizip (registered trademark) (manufactured by Seisan Nipponsha Co., Ltd.). Furthermore, examples of packaging materials for SP packaging, PTP packaging, pillow packaging, and stick packaging include Sumilight VSS, Sumilight VSL, Sumilight NS, Sumilight FCL (all manufactured by Sumitomo Bakelite Co., Ltd.), the TAS series (manufactured by Taisei Chemical Co., Ltd.), PTP vinyl foil, PTP super foil (both manufactured by Mitsubishi Plastics, Inc.), Nippaku aluminum foil (manufactured by Nippon Foil Co., Ltd.), and plain silver aluminum foil (manufactured by Yamato Chemical Industry Co., Ltd.).

[0033] The method for containing the composition in an airtight package is not particularly limited and can be achieved by placing the composition inside the package by appropriate means such as introducing the composition into the package. In this case, a means of introducing a desiccant (for example, cylindrical (tablet-type) or sheet-type) together with the composition into the package may also be used.

[0034] The composition and packaged composition of the present invention can be used as pharmaceuticals, quasi-drugs, cosmetics, foods, etc., and their use is not particularly limited. However, because they contain a phosphodiesterase 5 inhibitor and garlic processed products and / or gamma-oryzanol, which have various effects such as nourishing and strengthening the body, they can preferably be used as pharmaceuticals, and more preferably as pharmaceuticals for erectile dysfunction (e.g., organic erectile dysfunction, psychogenic erectile dysfunction, mixed erectile dysfunction, etc.).

[0035] The method of administering the composition and packaged composition of the present invention is not particularly limited, and can be either oral or parenteral administration. However, oral administration is preferred from the viewpoint of facilitating the efficacy of the PDE5 inhibitor, garlic product, and gamma-oryzanol. Furthermore, the method of use and dosage of the composition are not particularly limited and can be appropriately selected and determined according to the intended use of the composition, the method of administration, the dosage form of the composition, etc. For example, the amount of PDE5 inhibitor that can be taken once a day at a dose of 1 to 200 mg, preferably 2 to 75 mg, and particularly preferably 5 to 50 mg, is sufficient. The method of use and dosage of the garlic product and gamma-oryzanol can be appropriately determined according to the relative mass ratio with the PDE5 inhibitor mentioned above.

[0036] <Stabilization method> The present invention also relates to a method for stabilizing one or more substances selected from the group consisting of garlic processed products and gamma-oryzanol, comprising the step of coexisting one or more substances selected from the group consisting of garlic processed products and gamma-oryzanol with a phosphodiesterase 5 inhibitor; and a method for stabilizing one or more substances selected from the group consisting of garlic processed products and gamma-oryzanol, comprising the step of coexisting one or more substances selected from the group consisting of garlic processed products and gamma-oryzanol with a phosphodiesterase 5 inhibitor, and the step of housing the substances in an airtight package. "Stabilization" in the context of garlic products refers to the suppression of solidification during high-temperature storage, and in the context of gamma-oryzanol, it refers to the suppression of discoloration during high-temperature storage. Here, "suppression" does not mean that phenomena such as solidification or discoloration will never occur. By applying the stabilization method according to the present invention, if the degree of solidification (such as the extent of solidification and the rate of solidification) and the degree of discoloration (such as the extent of discoloration and the rate of discoloration) are relatively suppressed compared to cases where the method is not applied, then this constitutes "suppression" as defined by "stabilization".

[0037] In the stabilization method, the meaning of various terms and the amounts of each component are all the same as those explained for the "composition" described above.

[0038] The present invention is not limited to these, but for example, the following embodiments are disclosed. [1A] A composition containing a phosphodiesterase-5 inhibitor and one or more selected from the group consisting of garlic processed product and gamma-oryzanol. [2A] The composition according to 1A, wherein the phosphodiesterase-5 inhibitor is one or more selected from the group consisting of avanafil, udenafil, sildenafil, tadalafil, vardenafil, mirodenafil and salts thereof and solvates thereof. [3A] The composition according to 1A or 2A, wherein the garlic processed product is one or more selected from the group consisting of processed garlic, garlic extract, garlic extract, and dried garlic. [4A] A solid composition, as described in any of 1A to 3A. [5A] The composition according to any one of 1A to 4A, wherein the composition is in a dosage form selected from the group consisting of tablets, capsules, granules, powders, and pills. [6A] A packaged composition comprising any of the compositions described in 1A to 5A, contained in an airtight package. [7A] The packaging composition according to 6A, wherein the airtight packaging is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging.

[0039] [1B] A method for stabilizing one or more selected from the group consisting of garlic processed products and gamma-oryzanol, comprising the step of coexisting one or more selected from the group consisting of garlic processed products and gamma-oryzanol with a phosphodiesterase 5 inhibitor. [2B] The method according to 1B, wherein the phosphodiesterase-5 inhibitor is one or more selected from the group consisting of avanafil, udenafil, sildenafil, tadalafil, vardenafil, mirodenafil and salts thereof and solvates thereof. [3B] The method according to 1B or 2B, wherein the garlic processed product is one or more selected from the group consisting of processed garlic, garlic extract, garlic extract, and dried garlic. [4B] A method according to any one of 1B to 3B for coexistence in a solid composition. [5B] The method according to 4B, wherein the composition is in a dosage form selected from the group consisting of tablets, capsules, granules, powders, and pills. [6B] The method according to 4B or 5B, further comprising the step of housing the composition in an airtight package. [7B] The method according to 6B, wherein the airtight packaging is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging. [Examples]

[0040] Next, the present invention will be further explained with reference to examples, but the present invention is not limited to these examples.

[0041] [Test Example 1] Stability Test Part 1 Each of the samples shown below was placed in a polypropylene tube (Eppendorf tube: manufactured by Eppendorf Co., Ltd.) and stored at 80°C for one day without a lid. The condition of the samples was visually inspected before storage and after one day of storage, and the changes in the properties of the samples (presence or absence of solidification) before and after storage were evaluated. The results are shown in Table 1.

[0042] [Sample 1] Garlic processed product (oxoamidine powder: Riken Chemical Industry Co., Ltd.) was used as Sample 1. [Sample 2] One part by mass of garlic processed product (oxoamidine powder: Riken Chemical Industry Co., Ltd.) was mixed with one part by mass of sildenafil citrate (sildenafil citrate: Ryoto Fine Co., Ltd.), and the resulting mixture was designated as Sample 2.

[0043] [Table 1]

[0044] As shown in Table 1, the test results confirmed that the garlic processed product alone (Sample 1) solidified after being stored at 80°C for one day, while the mixture of the garlic processed product and sildenafil citrate (Sample 2) suppressed such solidification. The above test results revealed that by co-administering phosphodiesterase 5 inhibitors, such as sildenafil citrate, with garlic processed products, it is possible to suppress changes in the properties (solidification) of the garlic processed products during high-temperature storage.

[0045] [Test Example 2] Stability Test Part 2 Each of the samples shown below was placed in a polypropylene tube (Eppendorf tube: manufactured by Eppendorf Co., Ltd.) and stored at 60°C for two weeks without a lid. The condition of the samples was visually inspected before storage and after two weeks of storage, and changes in the properties of the samples (presence or absence of discoloration) before and after storage were evaluated. The results are shown in Table 2.

[0046] [Sample 3] Gamma-oryzanol (Okayasu Co., Ltd.) was used as Sample 3. [Sample 4] One part by mass of gamma-oryzanol (Okayasu Co., Ltd.) was mixed with one part by mass of sildenafil citrate (Ryoto Fine Co., Ltd.), and the resulting mixture was designated as Sample 4.

[0047] [Table 2]

[0048] As shown in the test results in Table 2, gamma-oryzanol alone (Sample 3) discolored (yellowing) after storage at 60°C for two weeks, while the mixture of gamma-oryzanol and sildenafil citrate (Sample 4) showed suppressed discoloration. The above test results revealed that co-administration of phosphodiesterase-5 inhibitors, such as sildenafil citrate, with gamma-oryzanol can suppress changes in the properties (discoloration) of gamma-oryzanol during high-temperature storage.

[0049] [Test Example 3] Stability Test Part 3 Each of the samples shown below was placed in a polypropylene tube (Eppendorf tube: manufactured by Eppendorf Co., Ltd.). Sample 5 was left unsealed, while Sample 6 was sealed with a cap and airtightly packaged. The samples were stored for two weeks at 40°C and 75% relative humidity (RH). The condition of the samples was visually inspected before storage, after one day, and after two weeks, and the changes in the properties of the samples before and after storage (presence or absence of solidification) were evaluated. The results are shown in Table 3.

[0050] [Sample 5] Garlic processed product (oxoamidine powder: Riken Chemical Industry Co., Ltd.) was used as Sample 5. [Sample 6] Sample 6 was prepared by mixing 1 part by mass of sildenafil citrate (sildenafil citrate: Ryoto Fine Co., Ltd.) with 1 part by mass of garlic processed product (oxoamidine powder: Riken Chemical Industry Co., Ltd.), and the resulting mixture was designated as Sample 6.

[0051] [Table 3]

[0052] As shown in the test results in Table 3, solidification occurred in garlic processed product alone (Sample 5) after 1 day of storage under conditions of 40°C and 75% RH, whereas in Sample 6, which contained a mixture of garlic processed product and sildenafil citrate in an airtight package, solidification was suppressed even after 2 weeks of storage. The above test results show that by co-administering phosphodiesterase 5 inhibitors, such as sildenafil citrate, with garlic processed products or gamma-oryzanol, and by housing them in airtight packaging, the changes in the properties of the garlic processed products or gamma-oryzanol during high-temperature storage can be further suppressed.

[0053] [Manufacturing Example 1] A solid composition containing the following ingredients and quantities in 150 mg was prepared by conventional methods to obtain the tablets of Production Example 1. Garlic processed product 25mg Sildenafil citrate 25mg Lactose hydrate 80mg Crystalline cellulose 14 mg Hydroxypropylcellulose 5mg Magnesium stearate 1 mg

[0054] [Manufacturing Example 2] A solid composition containing the following ingredients and quantities in 150 mg was prepared by conventional methods to obtain the tablets of Production Example 2. Gamma-oryzanol 10mg Sildenafil citrate 25mg Lactose hydrate 80mg Crystalline cellulose 14 mg Hydroxypropylcellulose 5mg Magnesium stearate 1 mg

[0055] [Manufacturing Example 3] A solid composition containing the following ingredients and quantities in 150 mg was prepared by conventional methods to obtain the tablets of Production Example 3. Cyanocobalamin 60 μg Sildenafil citrate 25mg Lactose hydrate 80mg Crystalline cellulose 14 mg Hydroxypropylcellulose 5mg Magnesium stearate 1 mg

[0056] [Manufacturing Examples 4-6] The 200 tablets obtained in Production Examples 1-3 were each bottled to obtain the packaged compositions of Production Examples 4-6.

[0057] [Manufacturing Examples 7-9] The 12 tablets obtained in Production Examples 1-3 were each packaged in PTP packaging to obtain the packaged compositions of Production Examples 7-9. [Industrial applicability]

[0058] According to the present invention, a composition with excellent quality stability can be provided, which can be suitably used, for example, in the pharmaceutical industry.

Claims

1. A composition containing a phosphodiesterase 5 inhibitor and a garlic product.

2. The composition according to claim 1, wherein the phosphodiesterase-5 inhibitor is one or more selected from the group consisting of sildenafil, tadalafil, vardenafil and their salts and their solvates.

3. The composition according to claim 1, which is a solid composition.

4. The composition according to claim 1, wherein the dosage form is selected from the group consisting of tablets, capsules, granules, powders, and pills.

5. A packaged composition comprising the composition according to any one of claims 1 to 4, contained in an airtight package.

6. The packaging composition according to claim 5, wherein the airtight packaging is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging.

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