Composition

Abstract

To provide a technology that suppresses the compatibility changes between phosphodiesterase 5 inhibitors and vitamin B12. [Solution] A packaged composition comprising a composition containing a phosphodiesterase 5 inhibitor and vitamin B12, contained in an airtight package.

Description

Technical Field

[0005]

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

Background Art

[0002] Phosphodiesterase 5 inhibitors such as sildenafil citrate, vardenafil hydrochloride hydrate, and tadalafil maintain and increase the amount of cyclic GMP in the corpus cavernosum of the penis and sustain the state of increased intracavernous pressure (erection) of the penis (Non-Patent Document 1), and are widely used in various countries around the world including Japan as therapeutic agents for erectile dysfunction and the like. In addition, various combinations of phosphodiesterase 5 inhibitors and other drugs have also been studied. Specifically, for example, combinations of phosphodiesterase 5 inhibitors and antidiabetic drugs, HMG-CoA reductase inhibitors, antihypertensive drugs, SSRIs, etc., and combinations of phosphodiesterase 5 inhibitors and L-arginine have been reported (Patent Documents 1, 2). <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​[Non-Patent Document 2] Journal of the Japan Endocrine Society, Vol. 98, Suppl, 2022 [Non-Patent Document 3] Andrologia Vol.53, Issue 11, 2021 [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] The inventors of this invention considered that a combination of a phosphodiesterase 5 inhibitor and vitamin B12 could be used as an excellent treatment for erectile dysfunction, and diligently studied to develop a combination formulation of a phosphodiesterase 5 inhibitor and vitamin B12. However, it was unexpectedly discovered that when phosphodiesterase 5 inhibitors and vitamin B12 are present together, changes in the composition of these components occur, leading to stability problems such as the mixture becoming wet over time. Therefore, the object of the present invention is to provide a technology that suppresses changes in the compatibility between a phosphodiesterase 5 inhibitor and vitamin B12. [Means for solving the problem]

[0007] Therefore, the inventors conducted further intensive studies and, to their surprise, discovered that changes in the composition of a composition containing a phosphodiesterase 5 inhibitor (hereinafter sometimes referred to as "PDE5 inhibitor"), such as sildenafil, and vitamin B12, such as cyanocobalamin, can be suppressed by housing it in an airtight package such as a glass bottle, thus completing the present invention.

[0008] In other words, the present invention provides a packaged composition comprising a composition containing a phosphodiesterase 5 inhibitor and vitamin B12, contained in an airtight package. Furthermore, the present invention provides a method for stabilizing a composition, comprising the steps of including a phosphodiesterase 5 inhibitor and vitamin B12 in the same composition, and containing the composition in an airtight package. [Effects of the Invention]

[0009] According to the present invention, it is possible to provide a highly valuable and commercially viable composition with good quality stability, in which changes in the combination between a phosphodiesterase 5 inhibitor and vitamin B12 are 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 aforementioned compounds or their salts may be solvates such as hydrates or alcoholic dihydrates. 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 suppressing compatibility changes, 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 suppressing changes in composition, 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. Among these, from the viewpoint of suppressing changes in composition, 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] <Vitamin B12> In this specification, "vitamin B12" includes not only cyanocobalamin and hydroxocobalamin themselves, but also their derivatives (mecobalamin, deoxyadenosylcobalamin, etc.) and their salts (inorganic salts such as hydrochloride; organic salts such as acetate, etc.), and these can be used individually or in combination of two or more. As for vitamin B12, from the viewpoint of suppressing changes in formulation, one or more selected from the group consisting of cyanocobalamin, hydroxocobalamin, mecobalamin, and deoxyadenosylcobalamin and their salts are preferred, and one or more selected from the group consisting of cyanocobalamin, hydroxocobalamin, hydroxocobalamin hydrochloride, and hydroxocobalamin acetate are particularly preferred. These vitamin B12s are well known and can be commercially available, or they can be manufactured by known methods.

[0014] The vitamin B12 content in the composition is not particularly limited, but from the viewpoint of suppressing changes in formulation, it may contain 0.0001% by mass or more, preferably 0.0005% by mass or more, and particularly preferably 0.05% by mass or more, relative to the total mass of the composition, and may also contain 3% by mass or less, preferably 1% by mass or less, and particularly preferably 0.5% by mass or less. Among these, from the viewpoint of suppressing changes in formulation, it is preferable to contain 0.1 to 2% by mass, more preferably 0.02 to 0.75% by mass, and particularly preferable 0.005 to 0.1% by mass, relative to the total mass of the composition.

[0015] The mass ratio of PDE5 inhibitor to vitamin B12 in the composition is not particularly limited, but from the viewpoint of suppressing changes in composition, the composition may contain 0.00001 parts by mass or more, preferably 0.00005 parts by mass or more, and particularly preferably 0.0003 parts by mass or more of vitamin B12 per 1 part by mass of PDE5 inhibitor, and may also contain 3 parts by mass or less, preferably 1 part by mass or less, and particularly preferably 0.5 parts by mass or less. In particular, from the viewpoint of suppressing changes in composition, it is preferable to contain 0.0001 to 0.1 parts by mass of vitamin B12 per 1 part by mass of PDE5 inhibitor, more preferably 0.0005 to 0.06 parts by mass, and particularly preferably 0.001 to 0.01 parts by mass.

[0016] <Composition> In this specification, the "composition" containing a PDE5 inhibitor and vitamin B12 may be in any form of solid, semi-solid, or liquid, and can be in a form commonly used in pharmaceuticals, quasi-drugs, cosmetics, foods, etc. according to the 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, and can be in the dosage forms described in the General Rules of Preparations of the Japanese Pharmacopoeia, 18th Revision, etc. From the perspective of the inhibitory effect on formulation changes, a solid composition is preferred as the form of the composition, a dosage form selected from the group consisting of tablets, capsules, granules, powders, and pills is more preferred, and a dosage form selected from the group consisting of tablets and granules is particularly preferred.

[0017] The composition can be produced according to known methods in the pharmaceutical field, quasi-drug field, etc., for example, according to the methods described in the General Rules of Preparations of the Japanese Pharmacopoeia, 18th Revision, etc., according to the above-mentioned shape and dosage form. In addition to the above-mentioned components, one or more carriers (excipients, binders, disintegrants, lubricants, colorants, flavoring agents, coating agents, etc.) used in the pharmaceutical field, quasi-drug field, cosmetics field, food field, etc. may be blended in the composition.

[0018] Examples of excipients include lactose, crystalline cellulose, sucrose, mannitol, light anhydrous silicic acid, etc. Examples of binders include hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, etc. Examples of disintegrants include carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, etc. Examples of lubricants include magnesium stearate, talc, etc. 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.

[0019] In addition to the components mentioned above, the composition may also contain other medicinal ingredients. Such 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, alkaloids, sterols, etc. Vitamins include, specifically, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, 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 Examples include riboflavin phosphate, riboflavin butyrate, riboflavin sodium phosphate, nicotinic acid, nicotinamide, inositol hexanicotinate, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, hepronicate, panthenol, pantethine, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, 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. As for crude drugs, there are catechu, anise fruit, aloe, epimedium, fennel, turmeric, basil, cinnamon, Corydalis, Enmeiso, astragalus, scutellaria, phellodendron, coptis, yam, processed garlic, Polygonum multiflorum, zedoary, cuckoo, valerian, kale root, ginger, licorice, kijitsu, goji berry, kujin, cinnamon, cassia, gentian, geranium, ox gall, ginseng, rhizome, ginseng, kojin, evodia, pepper, gallnut, colombo, conzurango, hawthorn, coriander, sansho, sanyaku, yamana, rehmannia, perilla, Examples of crude drugs and their extracts include peony, jasmine, cardamom, ginger, cardamom, blue bark, red bud oak, sweet flag, Centaurium, Atractylodes lancea, star anise, rhubarb, ginseng, clove, uncarrot, dried tangerine peel, chili pepper, angelica, spruce, passionflower, Eucommia, scutellaria, pisiflora, quatica, nutmeg, ginseng, garlic, mint, deer antler, long pepper, angelica tree, Atractylodes macrocephala, Poria cocos, hops, venus, water lily, yakuchi, yobai bark, gentian, and lily rhizome. Examples of zinc compounds include zinc chloride, zinc oxide, zinc lactate, and zinc sulfate. Examples of alkaloids include strychnine and yohimbine. Examples of sterols include gamma-oryzanol.

[0020] <Packaging composition> In this specification, compositions containing a PDE5 inhibitor and vitamin B12 must be contained in airtight packaging (hereinafter, in this specification, compositions contained in airtight packaging will be referred to as "packaged compositions"). As specifically disclosed in the test examples below, by co-administering a phosphodiesterase 5 inhibitor, such as sildenafil citrate, with vitamin B12, such as cyanocobalamin, and housing them in an airtight package, changes in the composition due to the co-administration of both components (wetting) can be 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"), and the composition may be directly or indirectly housed in the airtight package. An example of indirect housing in the airtight package is the configuration in which the composition is housed in the "other packaging" and then housed in the airtight package.

[0021] 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.

[0022] The packaging material (material) for the airtight packaging is not particularly limited, and for example, 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.

[0023] For example, the packaging materials used for bottle packaging are not particularly limited and include the above-mentioned glass, plastic, metal, etc., and one or more of these can be appropriately combined. 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] One form of PTP packaging involves forming a desired number of pockets in a resin sheet or the like using a known method, storing one composition or one dose unit in each pocket, and then sealing the pocket with a sheet made of metal foil such as aluminum foil as the 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 suppressing changes in the composition due to the coexistence of PDE5 inhibitors and vitamin B12. SP packaging, pillow packaging, and stick packaging methods 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 suppressing changes in the formulation due to the coexistence of PDE5 inhibitor and vitamin B12.

[0028] 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.

[0029] 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.).

[0030] 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.

[0031] 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 vitamin B12, 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.).

[0032] 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 the efficacy of the PDE5 inhibitor and vitamin B12. Furthermore, the method of use and dosage of the composition are not particularly limited and can be appropriately selected and determined according to the purpose of use, method of administration, and dosage form of the composition. 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, and the method of use and dosage of vitamin B12 can be appropriately determined according to the relative mass ratio with the PDE5 inhibitor mentioned above.

[0033] <Stabilization method> Furthermore, the present invention provides a method for stabilizing a composition, comprising the steps of including a phosphodiesterase 5 inhibitor and vitamin B12 in the same composition, and containing the composition in an airtight package. Here, "stabilization" means suppressing changes in the composition (changes in properties, specifically wetting, etc.) caused by the coexistence of the PDE5 inhibitor and vitamin B12. Here, "suppression" does not mean that changes in properties will never occur. If, by applying the stabilization method according to the present invention, the degree of changes in properties (for example, the extent of wetting and the degree of wetting progression, etc.) is relatively suppressed compared to when the method is not applied, then this corresponds to the "suppression" that "stabilization" means.

[0034] 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.

[0035] The present invention is not limited to these, but for example, the following embodiments are disclosed. [1A] A packaged composition comprising a phosphodiesterase-5 inhibitor and vitamin B12, contained in an airtight package. [2A] The packaged 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 packaged composition according to 1A or 2A, wherein vitamin B12 is one or more selected from the group consisting of cyanocobalamin, hydroxocobalamin, mecobalamin, and deoxyadenosylcobalamin and salts thereof. [4A] A solid composition, packaged as described in any of 1A to 3A. [5A] A packaged 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 packaging composition according to any one of 1A to 5A, 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.

[0036] [1B] A method for stabilizing a composition, comprising the steps of: including a phosphodiesterase 5 inhibitor and vitamin B12 in the same composition; and housing the composition in an airtight package. [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 vitamin B12 is one or more selected from the group consisting of cyanocobalamin, hydroxocobalamin, mecobalamin, and deoxyadenosylcobalamin and salts thereof. [4B] The method according to any one of 1B to 3B, wherein the composition is a solid composition. [5B] The method according to any one of 1B 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 described in any of 1B to 5B, 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]

[0037] Next, the present invention will be further explained with reference to examples, but the present invention is not limited to these examples.

[0038] [Test Example 1] Stability Test Each of the samples shown below was placed in a polypropylene tube (Eppendorf tube: manufactured by Eppendorf Co., Ltd.). Samples 1-3 were left unsealed, while sample 4 was sealed and airtight. The tubes were stored for 3 days at 40°C and 75% relative humidity (RH). The condition of the samples was visually inspected before storage and after 3 days of storage, and the changes in the properties of the samples (presence or absence of wetness) before and after storage were evaluated. The results are shown in Table 1.

[0039] [Sample 1] Sildenafil citrate (sildenafil citrate: Ryoto Fine Co., Ltd.) was used as Sample 1. [Sample 2] Cyanocobalamin (Cyanocobalamin (CBL12): Mitsubishi Chemical Corporation) was used as Sample 2. [Samples 3 and 4] One part by mass of sildenafil citrate (sildenafil citrate: Ryoto Fine Co., Ltd.) was mixed with one part by mass of cyanocobalamin (cyanocobalamin (CBL12): Mitsubishi Chemical Corporation), and the resulting mixtures were designated as Samples 3 and 4.

[0040] [Table 1]

[0041] As shown in Table 1, the test results indicate that while sample 1 (sildenafil citrate only) and sample 2 (cyanocobalamin only) showed no change in their properties after 3 days of storage at 40°C and 75% relative humidity, sample 3 (a mixture of sildenafil citrate and cyanocobalamin) showed a change in its properties (the mixture became wet and adhered to the container wall) after storage under the same conditions. This clearly demonstrates that mixing sildenafil citrate and cyanocobalamin causes a change in the composition (wetting). Furthermore, in Sample 4, which contained a mixture of sildenafil citrate and cyanocobalamin in an airtight package, no change in the properties of the sample was observed, and there was no change from the properties before storage began. This clearly shows that the airtight packaging of the mixture of sildenafil citrate and cyanocobalamin suppresses changes in the composition. From the above test results, it became clear that by coexisting a phosphodiesterase 5 inhibitor, such as sildenafil citrate, with vitamin B12, such as cyanocobalamin, and housing them in an airtight package, the changes in formulation that occur when phosphodiesterase 5 inhibitors and vitamin B12 are coexisting can be suppressed.

[0042] [Manufacturing Example 1] A solid composition (tablet) containing the following ingredients and quantities in 150 mg was manufactured by conventional methods, and 100 tablets were placed in airtight packaging (glass bottles) to obtain the packaged composition of Manufacturing Example 1. Cyanocobalamin 60 μg Sildenafil citrate 25mg Lactose hydrate 80mg Crystalline cellulose 14 mg Hydroxypropylcellulose 5mg Magnesium stearate 1 mg

[0043] [Manufacturing Example 2] A solid composition (tablet) containing the following ingredients and quantities in 150 mg was manufactured by conventional methods, and 20 tablets were placed per airtight packaging (PTP sheet) to obtain the packaged composition of Manufacturing Example 2. Hydroxocobalamin 60 μg Sildenafil citrate 25mg Lactose hydrate 80mg Crystalline cellulose 14 mg Hydroxypropylcellulose 5mg Magnesium stearate 1 mg

[0044] [Manufacturing Example 3] A solid composition (tablet) containing the following ingredients and quantities in 150 mg was manufactured by conventional methods, and 100 tablets were placed in airtight packaging (plastic bottles) to obtain the packaged composition of Manufacturing Example 3. Mecobalamin 60 μg Sildenafil citrate 25mg Lactose hydrate 80mg Crystalline cellulose 14 mg Hydroxypropylcellulose 5mg Magnesium stearate 1 mg [Industrial applicability]

[0045] According to the present invention, a packaging composition with excellent quality stability can be provided, which can be suitably used, for example, in the pharmaceutical industry.

Claims

1. A packaged composition comprising a composition containing a phosphodiesterase 5 inhibitor and vitamin B12, contained in an airtight package.

2. The packaged 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 packaged composition according to claim 1, wherein the vitamin B12 is one or more selected from the group consisting of cyanocobalamin, hydroxocobalamin, mecobalamin, deoxyadenosylcobalamin, and salts thereof.

4. The packaging composition according to claim 1, wherein the composition is a solid composition.

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

6. The packaging composition according to any one of claims 1 to 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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