Pharmaceutical composition

Abstract

To provide a new technique for stably producing pharmaceuticals from pitavastatin or a salt thereof or their solvates.SOLUTION: A pharmaceutical composition contains following components (A) and (B): (A) pitavastatin or a salt thereof or their solvates; and (B) ezetimibe or a salt thereof or their solvates.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition. [Background technology]

[0002] Pitavastatin, such as pitavastatin calcium (chemical name: Monocalcium bis{(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxyhept-6-enoate}), which is a type of so-called statin, or a salt thereof, or a solvate thereof, is known to have excellent HMG-CoA reductase inhibitory activity and to be useful as an active ingredient of a therapeutic agent for hyperlipidemia, a therapeutic agent for hypercholesterolemia, and the like (Patent Document 1). Therefore, it is extremely useful to establish a technique for stably formulating pitavastatin or a salt thereof, or a solvate thereof, and various techniques for improving the stability of pitavastatin in pharmaceutical formulations have been proposed (e.g., Patent Documents 2 to 4, etc.).

[0003] Incidentally, Patent Document 5 discloses the oral administration of pitavastatin calcium and ezetimibe (chemical name: (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one). However, Patent Document 5 only discloses that pitavastatin calcium and ezetimibe were separately suspended in a 0.5% by mass aqueous solution of sodium carboxymethylcellulose and then orally administered sequentially to guinea pigs, and does not disclose at all a pharmaceutical composition containing both of these components or its storage stability over time. Furthermore, Patent Document 6 discloses that rosuvastatin calcium, which is a type of statin like pitavastatin and has a similar chemical structure, interacts with ezetimibe, and that when the two components are mixed and stored for two weeks under conditions of 50°C and 75% relative humidity, the amount of decomposition products (related substances) of rosuvastatin, including the lactone form, increases. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent No. 2569746 [Patent Document 2] International Publication No. 97 / 23200 Brochure [Patent Document 3] International Publication No. 2012 / 057103 Brochure [Patent Document 4] International Publication No. 2012 / 141160 Brochure [Patent Document 5] International Publication No. 2006 / 025378 Brochure [Patent Document 6] International Publication No. 2015 / 102400 Brochure Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a novel technique for stably formulating pitavastatin or a salt thereof, or a solvate thereof. [Means for solving the problem]

[0006] Therefore, the present inventors have conducted intensive studies to solve the above-mentioned problems, and have surprisingly found that by coexisting ezetimibe, or a salt thereof, or a solvate thereof, which is known to increase the amount of decomposition products of rosuvastatin when coexisted with ezetimibe, or a salt thereof, or a solvate thereof, with pitavastatin, which is a type of statin like rosuvastatin, the increase in decomposition products derived from pitavastatin can be suppressed and pitavastatin, or a salt thereof, or a solvate thereof can be stabilized, thereby completing the present invention.

[0007] That is, the present invention relates to a composition comprising the following components (A) and (B): (A) pitavastatin or a salt thereof, or a solvate thereof; (B) ezetimibe or a salt thereof, or a solvate thereof; The present invention provides a pharmaceutical composition comprising: Effect of the Invention

[0008] According to the present invention, it is possible to provide a pharmaceutical composition which suppresses an increase in decomposition products derived from pitavastatin and has excellent storage stability. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] In this specification, "pitavastatin or a salt thereof, or a solvate thereof" includes pitavastatin (international generic name: Pitavastatin) itself, as well as pharma- ceutically acceptable salts of pitavastatin (alkali metal salts such as sodium salt, potassium salt, etc.; salts with metals of Group 2 elements such as calcium salt, magnesium salt, etc.; organic amine salts such as phenethylamine salt; ammonium salt, etc.), and further solvates of pitavastatin or a pharma- ceutically acceptable salt thereof with water, alcohol, etc., and one or more of these can be used in combination. As pitavastatin or a salt thereof, or a solvate thereof, a calcium salt of pitavastatin or a hydrate thereof is preferred, a hemicalcium salt of pitavastatin or a hydrate thereof is more preferred, and pitavastatin calcium (chemical name: Monocalcium bis{(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxyhept-6-enoate}) is particularly preferred. Pitavastatin or a salt thereof or a solvate thereof is known and can be produced by, for example, the methods described in Patent Document 1, U.S. Patent No. 5,856,336, etc., or a commercially available product may be used. Examples of commercially available products include pitavastatin calcium manufactured by Wako Pure Chemical Industries, Ltd. and Nissan Chemical Industries, Ltd.

[0010] The content of pitavastatin or a salt thereof or a solvate thereof in the pharmaceutical composition of the present invention is not particularly limited, and can be appropriately determined depending on the gender, age, symptoms, etc. of the recipient. For example, the pharmaceutical composition may contain an amount of 0.1 to 16 mg, more preferably 0.5 to 8 mg, and particularly preferably 1 to 4 mg of pitavastatin per day in terms of the anhydrous calcium salt of pitavastatin. In the present invention, the pharmaceutical composition contains pitavastatin or a salt thereof or a solvate thereof in an amount of preferably 0.4 to 20% by mass, more preferably 0.7 to 18.5% by mass, and particularly preferably 1 to 17% by mass in terms of the anhydrous calcium salt of pitavastatin, based on the total mass of the pharmaceutical composition.

[0011] In this specification, "ezetimibe or a salt thereof, or a solvate thereof" includes ezetimibe (international generic name: Ezetimibe) itself, as well as pharma- ceutically acceptable salts of ezetimibe (alkali metal salts such as sodium salts and potassium salts; salts with metals of Group 2 elements such as calcium salts and magnesium salts; organic amine salts such as phenethylamine salts; ammonium salts, etc.), and solvates of ezetimibe or a pharma- ceutically acceptable salt thereof with water, alcohol, etc., and one or more of these can be used in combination. As ezetimibe, a salt thereof, or a solvate thereof, ezetimibe is preferred. Ezetimibe or a salt thereof or a solvate thereof is known and can be produced by, for example, the method described in the pamphlet of International Publication No. 95 / 08532, or a commercially available product may be used. Examples of commercially available products include ezetimibe manufactured by Glenmark Pharmaceuticals and Hangzhou heta Pharm&Chem.

[0012] The content of ezetimibe or a salt thereof or a solvate thereof in the pharmaceutical composition of the present invention is not particularly limited, and can be appropriately determined according to the stability of pitavastatin, etc. For example, the amount of ezetimibe that can be taken per day in terms of the free form of ezetimibe is 1 to 30 mg, more preferably 3 to 20 mg, and particularly preferably 5 to 15 mg. In the present invention, from the viewpoint of suppressing the increase of decomposition products derived from pitavastatin, ezetimibe or a salt thereof or a solvate thereof is preferably contained in an amount of 0.1 to 85 mass% in terms of the free form of ezetimibe, more preferably 0.5 to 25 mass%, even more preferably 1 to 20 mass%, and particularly preferably 3 to 15 mass% based on the total mass of the pharmaceutical composition.

[0013] Furthermore, the mass ratio of pitavastatin or a salt thereof, or a solvate thereof to ezetimibe or a salt thereof, or a solvate thereof in the pharmaceutical composition is not particularly limited, but from the viewpoint of suppressing an increase in decomposition products derived from pitavastatin, it is preferable to contain 0.1 to 10 parts by mass, more preferably 0.5 to 7 parts by mass, even more preferably 1 to 6 parts by mass, even more preferably 2.5 to 5 parts by mass, and particularly preferably 5 parts by mass of ezetimibe or a salt thereof, or a solvate thereof, calculated as free form, per 1 part by mass of pitavastatin or a salt thereof, or a solvate thereof, calculated as anhydrous calcium salt.

[0014] In the present specification, the dosage form of the "pharmaceutical composition" is not particularly limited, and may be any of solid, semi-solid, or liquid preparations, and may be selected according to the purpose of use. Examples of the dosage form of the pharmaceutical composition include those described in the General Provisions of Preparations of the 17th Revised Japanese Pharmacopoeia. Specifically, for example, dosage forms for oral administration include solid preparations such as tablets (including, for example, normal tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules (including, for example, effervescent granules, etc.), powders, and pills; semi-solid preparations such as oral jellies; and liquid preparations such as oral liquids (including, for example, elixirs, suspensions, emulsions, lemonades, etc.). In addition, dosage forms for parenteral administration include injections, inhalants, eye drops, ear drops, nasal drops, suppositories, solid preparations for external use, liquid preparations for external use, sprays, ointments, creams, gels, and patches.

[0015] As the dosage form of the pharmaceutical composition, from the viewpoint of suppressing an increase in decomposition products derived from pitavastatin, a solid preparation is preferable, and a solid preparation selected from tablets (including, for example, normal tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules (including, for example, effervescent granules, etc.), powders, and pills is particularly preferable.

[0016] The pharmaceutical composition can be manufactured by a known method described in, for example, the General Provisions for Preparations of the 17th Revised Japanese Pharmacopoeia, etc., depending on the dosage form. In this case, a pharmaceutical carrier (formulation additive) may be added to the pharmaceutical composition. Examples of such formulation additives include, but are not limited to, excipients, disintegrants, binders, lubricants, plasticizers, film-forming agents, powders, poorly water-soluble polymeric substances, antioxidants, flavoring agents, sweeteners, etc. In addition, specific examples of these formulation additives include those listed in the Pharmaceutical Excipients Dictionary 2016 (published by Yakuji Nippo Co., Ltd.), Handbook of Pharmaceutical Excipients, Seventh Edition (published by Pharmaceutical Press), etc.

[0017] Specific examples of the excipient include inorganic excipients such as aluminum silicate, anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, calcium silicate, light anhydrous silicic acid, heavy anhydrous silicic acid, calcium sulfate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate; candy powder, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, and the like), fruit excipients such as corn starch, corn starch, partially pregelatinized starch, and the like; Examples of organic excipients include sugar, caramel, agar, xylitol, paraffin, crystalline cellulose, sucrose, maltose, lactose, lactose hydrate, sucrose, glucose, pullulan, polyoxyethylene hydrogenated castor oil, maltitol, reduced maltose starch syrup, powdered reduced maltose starch syrup, erythritol, sorbitol, mannitol, lactitol, trehalose, reduced palatinose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, calcium citrate, etc. These can be used alone or in combination of two or more.

[0018] Specific examples of disintegrants include super disintegrants such as sodium carboxymethyl starch, croscarmellose sodium, and crospovidone, as well as carmellose, carmellose calcium, starch, sucrose fatty acid esters, gelatin, sodium hydrogen carbonate, dextrin, dehydroacetic acid and its salts, povidone, and polyoxyethylene hydrogenated castor oil 60. These may be used alone or in combination of two or more.

[0019] Specific examples of binders include fats and oils such as hardened beef tallow oil, hardened oil, hydrogenated vegetable oil, hardened soybean oil, carnauba wax, white beeswax, beeswax, and Japan wax, as well as methylcellulose, hydroxypropylcellulose, hypromellose, carmellose sodium, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), dextrin, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, povidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, etc. These can be used alone or in combination of two or more.

[0020] Specific examples of lubricants include calcium stearate, magnesium stearate, sodium stearyl fumarate, sucrose fatty acid esters, etc. These may be used alone or in combination of two or more.

[0021] Specific examples of the plasticizer include triethyl citrate, glycerin, sesame oil, sorbitol, castor oil, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), etc. These may be used alone or in combination of two or more.

[0022] Specific examples of the film-forming agent include alkyl celluloses such as methyl cellulose and ethyl cellulose; alginic acid or a salt thereof such as sodium alginate; carrageenan; carboxyalkyl celluloses such as sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, potassium carboxymethyl cellulose, carboxymethyl cellulose, and carboxymethyl ethyl cellulose; xanthan gum; hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hypromellose (hydroxypropyl methylcellulose); hydroxyalkyl cellulose phthalates such as hydroxypropyl methylcellulose phthalate; pullulan; polyvinyl acetate; polyvinyl acetate phthalate; polyvinylpyrrolidone, etc. These may be used alone or in combination of two or more.

[0023] Examples of the powder include organic or inorganic powders such as talc, titanium oxide, yellow ferric oxide, ferric oxide, legal dyes, etc. These can be used alone or in combination of two or more kinds.

[0024] Specific examples of poorly water-soluble polymeric substances include carboxyvinyl polymers, aminoalkyl methacrylate copolymers, etc. These may be used alone or in combination of two or more. Specific examples of antioxidants include ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole, etc. These may be used alone or in combination of two or more.

[0025] Specific examples of flavoring agents include terpenes such as limonene, pinene, camphene, cymene, cineole, citronellol, geraniol, nerol, linalool, menthol, terpineol, rhodinol, borneol, isoborneol, menthone, camphor, eugenol, and cinzeylanol; essential oils containing terpenes such as spruce oil, orange oil, peppermint oil, camphor white oil, eucalyptus oil, turpentine oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender oil, fennel oil, chamomile oil, perilla oil, and spearmint oil; and acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid, and salts thereof. These may be used alone or in combination of two or more.

[0026] Specific examples of sweeteners include aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, and saccharin sodium, and these can be used alone or in combination of two or more.

[0027] The pharmaceutical composition can be prepared by a known method depending on the dosage form. For example, when the pharmaceutical composition is a solid preparation, it can be produced by appropriately combining unit operations such as pulverization, mixing, granulation, drying, sizing, classification, filling, tableting, and coating. More specifically, for example, when the dosage form of the pharmaceutical composition is a granular preparation such as granules, powders, or pills, in addition to pitavastatin or a salt thereof or a solvate thereof, ezetimibe or a salt thereof or a solvate thereof, and formulation additives such as excipients, binders, disintegrants, lubricants, etc. are used as necessary, and all or a part of these components are mixed, and then granulated by a known granulation method such as extrusion granulation, tumbling granulation, stirring granulation, fluidized bed granulation, spray granulation, melt granulation, or crushing granulation to obtain a granulated product, which is further classified, sized, etc., as necessary, to produce the product. The obtained granulated product can also be coated with a coating agent, etc., by a known method. In addition, when the dosage form of the pharmaceutical composition is a tablet, in addition to pitavastatin or a salt thereof or a solvate thereof, ezetimibe or a salt thereof or a solvate thereof, if necessary, suitable formulation additives such as excipients, binders, disintegrants, lubricants, etc. are used, and all or a part of these components are mixed to obtain a mixture, which is then directly compressed (tableted) (direct powder compression method), or the above granules are classified, sized, etc. as necessary, and then compressed (tableted) (semi-dry granule compression method, dry granule compression method, wet granule compression method, etc.). The obtained compressed product (tablet) can also be coated with a coating agent, etc. by a known method. Furthermore, when the pharmaceutical composition is in the form of a capsule, the above-mentioned granulated or compressed product may be filled into the capsule.

[0028] In the present invention, the pharmaceutical composition may further be contained in an airtight package (hereinafter, in this specification, a pharmaceutical composition contained in an airtight package will be referred to as a "drug"). As specifically disclosed in the test examples described later, by containing the pharmaceutical composition of the present invention in an airtight package, the increase of decomposition products derived from pitavastatin can be further suppressed. In this case, in addition to the airtight package, the pharmaceutical may further comprise a package that does not fall under the category of "airtight package" described below, and the pharmaceutical composition may be directly or indirectly contained in the airtight package. In this specification, the term "airtight packaging" refers to packaging that can prevent the intrusion of solid or liquid foreign matter under normal handling, transportation, storage, etc., and is a concept that includes "airtight container" and "sealed container" defined in the General Rules of the 17th Revised Japanese Pharmacopoeia. As the airtight packaging, either a fixed shape or an irregular shape can be used, and specific examples include bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, etc. As the airtight packaging, a combination of these may be used, and specific examples include a form in which a pharmaceutical composition is first packaged in a PTP package and then further packaged in a pillow package.

[0029] The packaging material (raw material) of the airtight package is not particularly limited, and may be, for example, glass, plastic (polyesters such as polyethylene terephthalate, polyethylene naphthalate, etc.; polyethylene (including low density (LDPE), medium density (MDPE), high density (HDPE)), polyolefins such as polypropylene, etc.; polycarbonate; polystyrene, etc.), metals (aluminum, etc.), etc., which are used in the fields of medicine, food, etc., may be used alone or in combination of two or more kinds as appropriate.

[0030] For example, packaging materials used for bottle packaging are not particularly limited, and examples thereof include glass, plastic, metal, etc., and these may be used in combination of one or more of them as appropriate. As materials for bottle packaging, glass, polyethylene, and polypropylene are preferred, glass, low-density polyethylene (LDPE), high-density polyethylene (HDPE), and polypropylene are more preferred, and glass, high-density polyethylene (HDPE), and polypropylene are particularly preferred. In packaging in a bottle, for example, an appropriate amount of the pharmaceutical composition is placed in the bottle, and then the bottle is sealed with an appropriate stopper or lid. The size of the bottle may be appropriately selected according to the amount of the pharmaceutical composition to be placed, 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.

[0031] In addition, packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, and the like are not particularly limited, and examples thereof 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), non-oriented polypropylene (CPP, IPP), ionomer resin (IO ), 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), rigid polyvinyl chloride (VSC), and other resins; and metal foils such as aluminum foil (AL), and one or more of these can be appropriately combined.

[0032] When SP packaging, PTP packaging, pillow packaging, stick packaging, etc. are used, a sheet using one or more of the above-mentioned packaging materials may be produced by a known method, and in this case, the packaging materials may be appropriately combined to form a multi-layer structure. As a method for producing a multi-layer structure using two or more packaging materials as a sheet, a method of laminating the packaging materials to produce a laminated sheet may be mentioned. The laminated sheet may be produced by a known method such as extrusion lamination, dry lamination, co-extrusion lamination, thermal lamination, wet lamination, non-solvent lamination, heat lamination, etc. In addition, the sheets for SP packaging, PTP packaging, pillow packaging, and stick packaging may be known commercially available products.

[0033] Among the above-mentioned sheets, examples of single-layer sheets using one type of packaging material include PVC sheets and CPP sheets, while examples of laminated sheets using two or more types of packaging materials include sheet configurations such as a laminate of PVC and PVDC (PVC / PVDC; hereinafter the same abbreviation), 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-mentioned sheets use two or more types of CPP), but are not limited to these.

[0034] The form of PTP packaging may be, for example, a desired number of pockets formed in a resin sheet or the like by a known method, in which the pharmaceutical composition is stored one by one or one dosage unit, and then the pockets are covered with a sheet made of a metal foil such as aluminum foil as a lid material. The sheet used to form the pockets may also be a so-called double-sided aluminum PTP package, in which a sheet made of aluminum foil is used as a constituent material. When using PTP packaging, it is preferable to further package the PTP packaging in a pillow package (e.g., aluminum pillow package, etc.) from the viewpoint of suppressing an increase in decomposition products derived from pitavastatin. Examples of the form of SP packaging, pillow packaging, and stick packaging include packaging the pharmaceutical composition one piece or one dosage unit by using a known method using a resin sheet, a sheet made of aluminum foil, etc. In the case of SP packaging, pillow packaging, and stick packaging, it is preferable to use a sheet made of aluminum foil from the viewpoint of suppressing an increase in decomposition products derived from pitavastatin.

[0035] In this specification, the occupancy rate (volume rate) of the pharmaceutical composition in the package of a pharmaceutical product is usually 25 to 90%, preferably 28 to 75%, and more preferably 30 to 50% when the package is a bottle package. When the package is a SP package, PTP package, pillow package, or stick package, the occupancy rate is usually 30 to 98%, preferably 40 to 95%, more preferably 45 to 93%, and particularly preferably 50 to 90%. In this case, the occupancy rate means the occupancy rate of the pharmaceutical composition relative to the total volume inside the package, and fillers, inner stoppers, etc. for preventing damage to the pharmaceutical composition stored inside the package are not taken into consideration when calculating the space occupancy rate.

[0036] As the airtight packaging body, a commercially available packaging body may be used as it is, or a commercially available packaging material may be processed and used. Examples of commercially available bottle packaging packaging bodies include glass bottles (manufactured by Isoya Glass Industry Co., Ltd.), tablet bottles (manufactured by Tokyo Glass Co., Ltd.), and Z-series (manufactured by Hanshin Chemical Industry Co., Ltd.). Examples of commercially available pillow packaging packaging bodies include Lamizip (registered trademark) (manufactured by Nippon Seisakusho Co., Ltd.). Furthermore, examples of packaging materials for SP packaging, PTP packaging, pillow packaging, and stick packaging include SUMILITE VSS, SUMILITE VSL, SUMILITE NS, and SUMILITE FCL (all manufactured by Sumitomo Bakelite Co., Ltd.), TAS series (manufactured by Taisei Kako Co., Ltd.), PTP vinyl foil, and PTP super foil (all manufactured by Mitsubishi Plastics Co., Ltd.), Nippaku aluminum foil (manufactured by Nippon Foil Co., Ltd.), and plain silver aluminum foil (manufactured by Daiwa Chemical Industry Co., Ltd.).

[0037] The method of housing the pharmaceutical composition in the airtight package is not particularly limited, and can be achieved by placing the pharmaceutical composition in the package by an appropriate means such as pouring the pharmaceutical composition into the package. In this case, a means of pouring a desiccant (e.g., a cylindrical (tablet) or sheet-shaped one) together with the pharmaceutical composition into the package may be used.

[0038] There is no limitation on the disease to which the pharmaceutical composition is applicable, and the pharmaceutical composition can be widely used for the prevention or treatment of diseases for which administration of pitavastatin is effective, which are currently known or will be discovered in the future. For example, pitavastatin or its salt or its solvate has excellent HMG-CoA reductase inhibitory activity and is used as an active ingredient of hyperlipidemia therapeutic agent, hypercholesterolemia therapeutic agent, etc. In addition, ezetimibe or its salt or its solvate suppresses the absorption of cholesterol derived from food and bile in the intestine, has excellent blood cholesterol lowering effect, and is used as an active ingredient of hypercholesterolemia therapeutic agent, familial hypercholesterolemia therapeutic agent, homozygous sitosterolemia therapeutic agent, etc. Furthermore, it is also known that the combination of pitavastatin or its salt or its solvate with ezetimibe or its salt or its solvate has a remarkable blood cholesterol lowering effect as disclosed in Patent Document 5, and is useful as a hyperlipidemia therapeutic agent, hypercholesterolemia therapeutic agent, etc. Therefore, the pharmaceutical composition of the present invention containing both pitavastatin or a salt thereof, or a solvate of either of them and ezetimibe or a salt of either of them, can be used as a prophylactic and / or therapeutic agent for dyslipidemia, more preferably as a prophylactic and / or therapeutic agent for hypercholesterolemia (high LDL cholesterolemia) (e.g., primary hypercholesterolemia, secondary hypercholesterolemia, familial hypercholesterolemia), mixed dyslipidemia, etc., and particularly preferably as a prophylactic and / or therapeutic agent for a disease selected from the group consisting of primary hypercholesterolemia and mixed dyslipidemia.

[0039] The route of administration of the pharmaceutical composition of the present invention is not particularly limited and can be appropriately determined depending on the disease to be treated, the type of preparation, the gender, age, symptoms, etc. of the recipient, but oral administration is preferred from the viewpoint of ease of administration. In addition, the pharmaceutical composition of the present invention can be administered in about 1 to 4 divided doses per day before meals, between meals, after meals, before bedtime, etc.

[0040] In addition, the present specification discloses the following aspects of the invention, for example, but is not limited to these. [1A] The following components (A) and (B): (A) pitavastatin or a salt thereof, or a solvate thereof; (B) ezetimibe or a salt thereof, or a solvate thereof; A pharmaceutical composition comprising: [2A] The pharmaceutical composition according to [1A], wherein component (A) is a calcium salt of pitavastatin (preferably, the hemicalcium salt) or a hydrate thereof. [3A] The pharmaceutical composition according to [1A] or [2A], wherein component (B) is ezetimibe. [4A] The pharmaceutical composition according to any one of [1A] to [3A], which is a solid formulation. [5A] The pharmaceutical composition according to any one of [1A] to [4A], which has a dosage form of a tablet, capsule, granule, powder or pill. [6A] The pharmaceutical composition according to any one of [1A] to [5A], which is an agent for preventing and / or treating dyslipidemia. [7A] The pharmaceutical composition according to any one of [1A] to [6A], which is an agent for preventing and / or treating a disease selected from the group consisting of primary hypercholesterolemia and mixed dyslipidemia. [8A] A pharmaceutical product comprising the pharmaceutical composition according to any one of [1A] to [7A] contained in an airtight package. [9A] The pharmaceutical product according to [8A], wherein the airtight packaging is one or more types selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging.

[0041] [1B] The following component (A): (A) pitavastatin or a salt thereof, or a solvate thereof; The pharmaceutical composition further comprises the following component (B): (B) ezetimibe or a salt thereof, or a solvate thereof; A method for stabilizing pitavastatin or a salt thereof, or a solvate thereof in a pharmaceutical composition (preferably, a method for suppressing an increase in decomposition products derived from pitavastatin), comprising the step of incorporating component (A) and component (B) in the pharmaceutical composition. In this case, the order of the steps of incorporating component (A) and component (B) in the pharmaceutical composition is not particularly limited. [2B] The method according to [1B], wherein component (A) is a calcium salt of pitavastatin (preferably, the hemicalcium salt) or a hydrate thereof. [3B] The method described in [1B] or [2B], wherein component (B) is ezetimibe. [4B] The method according to any one of [1B] to [3B], wherein the pharmaceutical composition is a solid formulation. [5B] The method according to any one of [1B] to [4B], wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, powder or pill. [6B] The method according to any one of [1B] to [5B], wherein the pharmaceutical composition is an agent for preventing and / or treating dyslipidemia. [7B] The method according to any one of [1B] to [6B], wherein the pharmaceutical composition is an agent for preventing and / or treating a disease selected from the group consisting of primary hypercholesterolemia and mixed dyslipidemia. [8B] The method according to any one of [1B] to [7B], further comprising a step of packaging the pharmaceutical composition in an airtight package. In this method, the order of the step of incorporating component (A) and component (B) in the pharmaceutical composition and the step of packaging the pharmaceutical composition in an airtight package is not particularly limited, and for example, the components (A) and (B) may be incorporated in the pharmaceutical composition in any order and then packaged in an airtight package, or one of components (A) and (B) may be incorporated in the pharmaceutical composition and then packaged in an airtight package, and then the remaining component may be incorporated in the pharmaceutical composition. [9B] The method described in [8B], wherein the airtight packaging is one or more types selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging. EXAMPLES

[0042] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. In the following examples, the amounts (parts by mass) of various components indicate the amounts obtained by weighing the various components as they are, unless the converted amounts are specified.

[0043] [Test Example 1] Stability test Part 1 Each sample shown below was stored at 80°C for 3.5 days.

[0044] [Sample 1] Pitavastatin calcium (pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.) was used as sample 1 as it was. [Sample 2] 1 part by mass of pitavastatin calcium (pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.) was mixed with 5 parts by mass of ezetimibe (manufactured by Glenmark Pharmaceuticals), and the resulting mixture was designated as Sample 2. [Sample 3] One part by mass of pitavastatin calcium (pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.) was mixed with 5 parts by mass of ezetimibe (manufactured by Glenmark Pharmaceuticals), and 120 mg of the resulting mixture was placed in a glass bottle (A-102K: manufactured by Isoya Glass Industry Co., Ltd.) and the bottle was capped. This was designated as Sample 3.

[0045] The proportion of decomposition products (related substances) derived from pitavastatin in each of the above samples was measured using an HPLC device before and after storage at 80°C for 3.5 days. Specifically, the proportion of related substances of pitavastatin was measured as an area percentage (%) relative to the total peak area derived from pitavastatin and its related substances. Then, from the proportions (%) of pitavastatin-related substances in each obtained sample before the start of storage and after storage at 80°C for 3.5 days, the increase rates (%) of decomposition products derived from pitavastatin in each sample were calculated according to the following formula.

[0046] Increase rate (%) of decomposition products derived from pitavastatin = (proportion (%) of related substances of pitavastatin after storage at 80°C for 3.5 days) - (proportion (%) of related substances of pitavastatin before storage started) The results are shown in Table 1.

[0047] [Table 1]

[0048] The test results shown in Table 1 confirm that Sample 2, which was a mixture of pitavastatin calcium and ezetimibe, had a lower increase in pitavastatin decomposition products compared to Sample 1, which was pitavastatin calcium alone, and that the increase in pitavastatin decomposition products after storage at 80°C for 3.5 days was suppressed. From the above test results, it was revealed that the coexistence of pitavastatin or a salt thereof, or a solvate thereof with ezetimibe or a salt thereof, or a solvate thereof can suppress an increase in decomposition products derived from pitavastatin.

[0049] Furthermore, from the test results shown in Table 1, it was confirmed that Sample 3, in which pitavastatin calcium and ezetimibe were mixed and then placed in a glass bottle, had an even lower increase rate of pitavastatin decomposition products compared to Sample 2, which was not placed in a glass bottle, and that the increase in pitavastatin decomposition products after storage at 80°C for 3.5 days was further suppressed. From the above test results, it was revealed that by allowing pitavastatin or a salt thereof, or a solvate thereof to coexist with ezetimibe or a salt thereof, or a solvate thereof, and further storing them in an airtight package, the increase in decomposition products derived from pitavastatin can be further suppressed.

[0050] [Test Example 2] Stability test Part 2 Each sample shown below was stored at 60°C for two weeks.

[0051] [Sample 4] 100 mg of pitavastatin calcium (pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.) was placed in a polypropylene tube (slim tube: manufactured by Sumitomo Bakelite Co., Ltd.) and the tube was capped. This was then placed in an aluminum bag (Lamizip AL-E: manufactured by Nippon Seisakusho Co., Ltd.) and sealed to prepare Sample 4. [Sample 5] 1 part by mass of pitavastatin calcium (pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.) was mixed with 5 parts by mass of ezetimibe (Ezetimibe: manufactured by Hangzhou heta Pharm & Chem Co., Ltd.), and 150 mg of the resulting mixture was placed in a polypropylene tube (Slim Tube: manufactured by Sumitomo Bakelite Co., Ltd.) and the tube was capped. This was then placed in an aluminum bag (Lamizip AL-E: manufactured by Nippon Seisakusho Co., Ltd.) and sealed to prepare Sample 5.

[0052] The proportion of decomposition products (related substances) derived from pitavastatin in each of the above samples was measured using an HPLC device before the start of storage and after 2 weeks of storage at 60° C. Specifically, the proportion of related substances of pitavastatin was measured as an area percentage (%) relative to the total peak area derived from pitavastatin and its related substances. Then, from the proportions (%) of pitavastatin-related substances in each obtained sample before the start of storage and after storage at 60°C for 2 weeks, the increase rates (%) of decomposition products derived from pitavastatin in each sample were calculated according to the following formula.

[0053] Increase rate (%) of decomposition products derived from pitavastatin = (proportion (%) of related substances of pitavastatin after storage at 60°C for 2 weeks) - (proportion (%) of related substances of pitavastatin before storage started) The results are shown in Table 2.

[0054] [Table 2]

[0055] As is clear from the test results shown in Table 2, even when contained in a polypropylene tube and an aluminum bag, it was confirmed that, as in Test Example 1, the coexistence of pitavastatin or a salt thereof, or a solvate thereof and ezetimibe or a salt thereof, or a solvate thereof can suppress an increase in decomposition products derived from pitavastatin.

[0056] It should be noted that similar test results can be obtained even when PTP packaging is used instead of the polypropylene tube and aluminum bag used in Test Example 2.

[0057] [Production Example 1] Tablets containing the following ingredients per tablet (100 mg) were produced by conventional methods. Pitavastatin calcium hydrate 1.04mg (1mg as anhydrous) Ezetimibe 10mg Crystalline cellulose 18mg Lactose (appropriate amount) Hypromellose 2mg Croscarmellose sodium 3mg Citric acid 0.25mg Propyl gallate 0.005mg BHA 0.02mg Magnesium stearate 1.5mg

[0058] [Production Example 2] Tablets containing the following ingredients per tablet (120 mg) were produced by conventional methods. Pitavastatin calcium hydrate 2.09mg (2mg as anhydrous) Ezetimibe 10mg Crystalline cellulose 18mg Lactose (appropriate amount) Hypromellose 2mg Croscarmellose sodium 3mg Citric acid 0.25mg Propyl gallate 0.005mg BHA 0.02mg Magnesium stearate 1.5mg

[0059] [Production Example 3] Tablets containing the following ingredients per tablet (150 mg) were produced by conventional methods. Pitavastatin calcium hydrate 4.13mg (4mg as anhydrous) Ezetimibe 10mg Crystalline cellulose 18mg Lactose (appropriate amount) Hypromellose 2mg Croscarmellose sodium 3mg Citric acid 0.25mg Propyl gallate 0.005mg BHA 0.02mg Magnesium stearate 1.5mg

[0060] [Production Example 4] The following granules A and B were prepared by standard methods, and then both granules were combined with the following lubricant and compressed into tablets to produce tablets containing the following ingredients per tablet (220 mg). (A granule) Ezetimibe 10mg D-Mannitol 47.7mg Crystalline cellulose 20mg Hydroxypropyl cellulose 2.5mg Croscarmellose sodium 8mg Sodium lauryl sulfate 1.8mg (B granule) Pitavastatin calcium hydrate 2.09mg (2mg as anhydrous) Lactose hydrate appropriate amount Low-substituted hydroxypropyl cellulose 6mg Hypromellose 1.2mg Magnesium aluminometasilicate 1.2mg (lubricant) Magnesium stearate 2mg

[0061] [Manufacturing Examples 5 to 8] The tablets of Production Examples 1 to 4 were each packed in PTP packages by a conventional method to produce the pharmaceutical products of Production Examples 5 to 8. [Manufacturing Examples 9-12] The tablets of Production Examples 1 to 4 were each placed in a polypropylene bottle in a conventional manner to produce the pharmaceutical products of Production Examples 9 to 12. [Industrial Applicability]

[0062] INDUSTRIAL APPLICABILITY The present invention provides a pharmaceutical composition containing a combination of pitavastatin and ezetimibe, which are useful as active ingredients for treating hyperlipidemia, hypercholesterolemia, etc., and which has excellent storage stability, and can be used, for example, in the pharmaceutical industry.

Claims

[Claim 1] The invention described in the application.

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