JP2021008432A - Pharmaceutical composition - Google Patents

Abstract

To provide a new technique for stable formulation of pitavastatin or a salt thereof or their solvates.SOLUTION: A pharmaceutical is constituted by accommodating, in a hermetic package, a pharmaceutical composition containing 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

The present invention relates to pharmaceutical compositions and the like.

Pitavastatin calcium (chemical name: Monocalcium bis {(3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxyhept), which is a kind of so-called statins. -6-enoate}) and other pitavastatin or salts thereof or their solvates have excellent HMG-CoA reductase inhibitory activity and are active ingredients such as hyperlipidemia therapeutic agents and hypercholesterolemia therapeutic agents. It is known to be useful as (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 preparations have been proposed so far. (For example, Patent Documents 2 to 4 and the like).

By the way, in Patent Document 5, pitavastatin calcium and ezetimibe (chemical name: (3R, 4S) -1- (4-fluorophenyl) -3-[(3S) -3- (4-fluorophenyl) -3-hydroxypropyl]- It is disclosed that 4- (4-hydroxyphenyl) azetidin-2-one) was orally administered. However, Patent Document 5 only discloses that pitavastatin calcium and ezetimibe were separately suspended in a 0.5% by mass aqueous solution of sodium carboxymethyl cellulose and then orally administered to guinea pigs in sequence. No disclosure is made regarding the pharmaceutical composition containing the ingredients together or the storage stability thereof over time.
Further, in Patent Document 6, rosuvastatin calcium, which is a kind of statins and has a similar chemical structure like pitavastatin, has an interaction with ezetimibe, and both components are mixed at 50 ° C. and 75% relative humidity. It is disclosed that rosuvastatin degradation products (related substances) including lactones increase when stored for 2 weeks under the conditions of.

Japanese Patent No. 2569746 International Publication No. 97/23200 Pamphlet International Publication No. 2012-057103 Pamphlet International Publication No. 2012/141160 Pamphlet International Publication No. 2006/025378 Pamphlet International Publication No. 2015/102400 Pamphlet

An object of the present invention is to provide a new technique for stably formulating pitavastatin or a salt thereof or a solvate thereof.

Therefore, as a result of diligent studies to solve the above problems, the present inventors have surprisingly found ezetimibe or a salt thereof, or a solvate thereof, which is known to increase its decomposition products by coexistence with rosuvastatin. By coexisting with pitavastatin or a salt thereof, which is a kind of statins like rosuvastatin, or a solvate thereof, an increase in decomposition products derived from pitavastatin is suppressed, and pitavastatin or a salt thereof or a solvate thereof is stabilized. We found what we could do and completed the present invention.

That is, the present invention describes 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;
To provide a pharmaceutical composition containing the above.

According to the present invention, it is possible to provide a pharmaceutical composition having excellent storage stability by suppressing an increase in pitavastatin-derived degradation products.

In the present specification, "pitavastatin or a salt thereof or a solvent product thereof" includes not only pitavastatin (international generic name: Pitavastatin) itself, but also pharmaceutically acceptable salts of pitavastatin (alkali metal salts such as sodium salt and potassium salt). 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 pitabastatin and its pharmaceutically acceptable salts and solvents such as water and alcohol. Japanese products are also included, and one or a combination of two or more of these can be used.
As the pitavastatin or a salt thereof or a solvate thereof, a calcium salt of pitavastatin or a hydrate thereof is preferable, a hemicalcium salt of pitavastatin or a hydrate thereof is more preferable, 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 preferable.
Pitavastatin or a salt thereof or a solvate thereof is known and can be produced, for example, by the method described in Patent Document 1, US Pat. No. 5,856,336, etc., or a commercially available product may be used. Good. Examples of commercially available products include pitavastatin calcium manufactured by Wako Pure Chemical Industries, Ltd. and Nissan Chemical Industries, Ltd.

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 examined and determined according to the sex, age, symptom, etc. of the user. For example, it can contain 0.1 to 16 mg of pitavastatin in terms of calcium salt anhydride, more preferably 0.5 to 8 mg, and particularly preferably 1 to 4 mg per day. In the present invention, pitabastatin or a salt thereof or a solvate thereof is preferably contained in an amount of 0.4 to 20% by mass in terms of calcium salt anhydride of pitabastatin with respect to the total mass of the pharmaceutical composition, preferably 0.7. It is more preferably contained in an amount of ~ 18.5% by mass, and particularly preferably contained in an amount of 1 to 17% by mass.

In the present specification, "ezetimib or a salt thereof or a solvent mixture thereof" includes not only ezetimibe (international generic name: Ezetimibe) itself, but also pharmaceutically acceptable salts of ezetimib (alkali metal salts such as sodium salt and potassium salt). 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 ezetimib and its pharmaceutically acceptable salts and solvents such as water and alcohol. Japanese products are also included, and one or a combination of two or more of these can be used.
As ezetimibe or a salt thereof or a solvate thereof, ezetimibe is preferable.
Ezetimibe or a salt thereof or a solvate thereof is known, and can be produced by, for example, the method described in Pamphlet No. 95/08532 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.

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 examined and determined according to the stability of pitavastatin and the like. For example, it can contain 1 to 30 mg of ezetimibe in terms of free form, more preferably 3 to 20 mg, and particularly preferably 5 to 15 mg per day. In the present invention, from the viewpoint of suppressing the increase of pitavastatin-derived degradation products, ezetimibe or a salt thereof or a solvate thereof is used at 0.1 to 85 in terms of free form of ezetimibe with respect to the total mass of the pharmaceutical composition. It is preferably contained in an amount of% by mass, more preferably 0.5 to 25% by mass, further preferably 1 to 20% by mass, and particularly preferably 3 to 15% by mass.

Further, the content mass ratio of pitabastatin or a salt thereof or a solvate thereof in the pharmaceutical composition to ezetimib or a salt thereof or a solvate thereof is not particularly limited, but suppresses an increase in decomposition products derived from pitabastatin. From the viewpoint, 1 part by mass of pitabastatin or a salt thereof or a solvate thereof in terms of calcium salt anhydride, and 0.1 to 10 parts by mass of ezetimib or a salt thereof or a solvate thereof in terms of free form. It is preferably contained, more preferably 0.5 to 7 parts by mass, further preferably 1 to 6 parts by mass, still more preferably 2.5 to 5 parts by mass, and 5 parts by mass. It is particularly preferable to contain it.

In the present specification, the dosage form of the "pharmaceutical composition" is not particularly limited, and may be a solid, semi-solid, or liquid preparation, and can be selected according to the purpose of use and the like. Examples of the dosage form of the pharmaceutical composition include the dosage forms described in the 17th revised Japanese Pharmacopoeia General Regulations for Formulation. Specifically, for example, the dosage form for oral administration includes tablets (including, for example, ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, dissolving tablets, etc.), capsules, and granules (for example, For example, solid preparations such as effervescent granules), powders, pills; semi-solid preparations such as oral jelly; oral solutions (including, for example, elixirs, suspensions, emulsions, limonades, etc.), etc. Liquid preparations and the like. Dosage forms for parenteral administration include injections, inhalants, eye drops, ear drops, nasal drops, suppositories, external solids, external solutions, sprays, ointments, creams, and gels. , Patches and the like.

As the dosage form of the pharmaceutical composition, a solid preparation is preferable from the viewpoint of suppressing an increase in decomposition products derived from pitavastatin, and tablets (for example, ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersed tablets, dissolution tablets) are preferable. Solid formulations selected from tablets and the like), capsules, granules (including effervescent granules and the like), powders and pills are particularly preferred.

The pharmaceutical composition can be produced, for example, by a known method described in the 17th revised Japanese Pharmacopoeia General Regulations for Formulation, etc., depending on the dosage form. In this case, a pharmaceutically acceptable carrier (preparation additive) may be added to the pharmaceutical composition. Examples of such preparation additives include excipients, disintegrants, binders, lubricants, plasticizers, film-forming agents, powders, poorly water-soluble polymer substances, antioxidants, flavoring agents, sweeteners and the like. However, the present invention is not limited to these. Specific examples of these additive additives are those listed in the Pharmaceutical Additives Dictionary 2016 (published by Yakuji Nippo Co., Ltd.), Handbook of Pharmaceutical Excipients, Seventh Edition (published by Pharmaceutical Press), and the like. Can be mentioned.

Specific examples of the excipient include aluminum silicate, anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, calcium silicate, light anhydrous silicic acid, heavy anhydrous silicic acid, calcium sulfate, and dicalcium phosphate. Inorganic excipients such as calcium hydrogen hydrogen, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate; candy flour, starch (maltose starch, rice starch, corn Starch, partially pregelatinized starch, etc.), fructose, caramel, canten, xylitol, paraffin, crystalline cellulose, sucrose, maltose, lactose, lactose hydrate, sucrose, glucose, purulan, polyoxyethylene hydrogenated castor oil, martitol, Examples thereof include reduced maltose water candy, powdered reduced maltose water candy, erythritol, sorbitol, mannitol, lactitol, trehalose, reduced palatinose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, and organic excipients such as calcium citrate. These can be used alone or in combination of two or more.

Specific examples of the disintegrant include super disintegrants such as sodium carboxymethyl starch, sodium croscarmellose, and crospovidone, carmellose, carmellose calcium, starch, sucrose fatty acid ester, gelatin, sodium hydrogencarbonate, dextrin, and the like. Examples thereof include dehydroacetic acid and salts thereof, povidone, and polyoxyethylene hydrogenated castor oil 60. These can be used alone or in combination of two or more.

Specific examples of the binder include fats and oils such as hydrogenated beef fat, hydrogenated oil, hydrogenated vegetable oil, hardened soybean oil, carnauba wax, sardine starch, beeswax, and mokuro, as well as methyl cellulose, hydroxypropyl cellulose, hypromerose, and carme. Sodium loin, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), dextrin, purulan, gum arabic, canten, gelatin, tragant, sodium alginate, povidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, polyvinyl acetal Examples thereof include diethylaminoacetate. These can be used alone or in combination of two or more.

Specific examples of the lubricant include calcium stearate, magnesium stearate, stearyl fumarate, and sucrose fatty acid ester. These can be used alone or in combination of two or more.

Specific examples of the plasticizer include triethyl citrate, glycerin, sesame oil, sorbitol, castor oil, and polysorbate 80 (polyoxyethylene (20) sorbitan oleic acid ester). These can be used alone or in combination of two or more.

Specific examples of the film-forming agent include alkyl cellulose such as methyl cellulose and ethyl cellulose; alginic acid such as sodium alginate or a salt thereof; carrageenan; sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, potassium carboxymethyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose and the like. Carboxymethyl cellulose; xanthan gum; hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyalkyl cellulose such as hypromellose (hydroxypropyl methyl cellulose); hydroxyalkyl cellulose phthalate such as hydroxypropyl methyl cellulose phthalate; purulan; vinyl acetate; polyvinyl acetate phthalate. ; Polyvinylpyrrolidone and the like can be mentioned. These can be used alone or in combination of two or more.

Examples of the powder include organic powders such as talc, titanium oxide, yellow iron sesquioxide, iron sesquioxide, and legal dyes, or inorganic powders. These can be used alone or in combination of two or more.

Specific examples of the poorly water-soluble polymer substance include carboxyvinyl polymers and aminoalkyl methacrylate copolymers. These can be used alone or in combination of two or more.
Specific examples of the antioxidant include ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, and butylhydroxyanisole. These can be used alone or in combination of two or more.

Specific examples of the flavoring agent include limonene, pinen, camphor, cymen, cineole, citronellol, geraniol, nerol, linalol, menthol, terpineol, loginol, borneol, isobornole, menthon, camphor, eugenol, syntheilanol and the like. Terpen; Tohi oil, orange oil, peppermint oil, camphor white oil, eucalyptus oil, terepine oil, lemon oil, ginger oil, butterfly oil, kehi oil, lavender oil, uikyo oil, chamomile oil, perilla oil, spare mint oil, etc. The essential oil containing camphor; ascorbic acid, tartrate acid, citric acid, malic acid, acidulants such as salts thereof and the like can be mentioned. These can be used alone or in combination of two or more.

Specific examples of the sweetener include aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, sodium saccharin, and the like, and one or more of these can be used in combination.

The pharmaceutical composition can be produced by a known method depending on the dosage form thereof.
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, pills, etc., pitavastatin or a salt thereof or a solvate thereof, ezetimibe or a salt thereof or a solvate thereof. In addition, if necessary, using a formulation additive such as an excipient, a binder, a disintegrant, and a lubricant, all or part of these components are mixed, and then extrusion granulation, rolling granulation, and stirring are performed. By granulating by a known granulation method such as granulation, fluid layer granulation, spray granulation, melt granulation, crush granulation, etc. to obtain granulated products, and further classifying, sizing, etc. as necessary. Can be manufactured. The obtained granulated product can also be coated with a coating agent or the like by a known method.
When the dosage form of the pharmaceutical composition is a tablet, in addition to pitabastatin or a salt thereof or a solvate thereof, ezetimib or a salt thereof or a solvate thereof, excipients, binders, disintegrants, etc. Using an appropriate formulation additive such as a lubricant, all or part of these components are mixed to obtain a mixture, which is directly compressed (tablet) (direct powder compression method), or the above-mentioned preparation. The granules can be produced by classifying, sizing, etc. as necessary and then compressing (tableting) (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 or the like by a known method.
Further, when the dosage form of the pharmaceutical composition is a capsule, the above-mentioned granulated product or compressed product may be filled in the capsule.

In the present invention, the pharmaceutical composition may be further contained in an airtight package (hereinafter, in the present specification, the pharmaceutical composition contained in the airtight package is referred to as a "pharmaceutical product". ). As specifically disclosed in the test examples described below, by containing the pharmaceutical composition of the present invention in an airtight package, an increase in pitavastatin-derived degradation products can be further suppressed. In this case, in addition to the airtight package, the drug may further include a package that does not fall under the following "airtight package", and the pharmaceutical composition is directly or indirectly contained in the airtight package. It suffices if it is done.
In the present specification, the term "airtight package" means a package capable of suppressing the invasion of solid or liquid foreign matter under normal handling, transportation, storage, etc., and is defined in the 17th revised Japanese Pharmacy Regulations. It is a concept including "airtight container" and "sealed container". As the airtight package, either a fixed form or an amorphous package can be used. Specifically, for example, a bottle package, an SP (Strip Package) package, a PTP (Press Through Package) package, a pillow package, a stick package, etc. Can be mentioned. The airtight package may be a combination of a plurality of these, and specific examples thereof include a mode in which the pharmaceutical composition is first packaged in PTP packaging and then packaged in pillow packaging. ..

The packaging material (material) of the airtight packaging is not particularly limited, and for example, glass, plastic (polystyrene terephthalate, polyethylene naphthalate, etc.); polyethylene (low density (LDPE), medium density (MDPE), high density (HDPE)). , Polyethylene and other polyolefins; polycarbonate; polystyrene, etc.), metals (aluminum, etc.) and other materials used in the fields of pharmaceuticals, foods, etc., may be used alone or in combination of two or more. it can.

For example, the packaging material used for bottle packaging is not particularly limited, and examples thereof include glass, plastic, and metal, and one or more of these can be appropriately combined. As the material for the bottle packaging, glass, polyethylene and polypropylene are preferable, glass, low density polyethylene (LDPE), high density polyethylene (HDPE) and polypropylene are more preferable, and glass, high density polyethylene (HDPE) and polypropylene are particularly preferable.
When packaging in a bottle, for example, the pharmaceutical composition may be stored in an appropriate quantity in the bottle, and then sealed with an appropriate stopper or lid. The size of the bottle may be appropriately selected according to the quantity of the pharmaceutical composition to be stored, and the volume of the bottle is, for example, about 10 to 500 mL, preferably 14 to 400 mL, and 24 to 350 mL. Is more preferable.

The packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging and the like are not particularly limited, and for example, biaxially stretched polypropylene (OPP), biaxially stretched polyester (PET), glycol-modified PET ( PET-G), biaxially stretched nylon (ONy, PA), cellophane, paper, low density polyethylene (LDPE), linear low density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), none Stretched polypropylene (CPP, IPP), ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially stretched polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH) ), Polyvinyl chloride (PVC), cyclic polyolefin (COC), unstretched nylon (CNy), polycarbonate (PC), polystyrene (PS), hard vinyl chloride (VSC) and other resins, and aluminum foil (AL). Metal foil and the like can be mentioned, and one or more of these can be appropriately combined.

In the case of SP packaging, PTP packaging, pillow packaging, stick packaging, etc., it may be produced by a known method using a sheet using one or more of the above-mentioned packaging materials. In this case, the packaging material. Can also have a multi-layer structure that is appropriately combined. As a method of forming a multi-layer structure using two or more kinds of packaging materials as a sheet, a method of laminating the packaging materials to produce a laminated sheet can be mentioned. The laminated sheet can be produced by a known method such as extruded laminate, dry laminate, coextruded laminate, thermal laminate, wet laminate, non-solvent laminate, heat laminate and the like. Further, as the sheet for SP packaging, PTP packaging, pillow packaging and stick packaging, known commercially available products can also be used.

In the above sheet, examples of the single-layer sheet using one kind of packaging material include a PVC sheet and a CPP sheet, and as a laminated sheet using two or more kinds of packaging materials, the sheet composition thereof is, for example, A laminate of PVC and PVCC (PVC / PVCC; hereinafter abbreviated in the same manner), PVC / PVDC / PE / PVC, PVC / PVCC / PE / PVDC / PVC, CPP / COC / CPP, PVC / PCTFE, CPP. / PCTFE, PVC / AL / PA, PVC / AL, CPP / AL, CPP / CPP / CPP (the sheet on the left uses two or more types of CPP), but is limited to these. It is not something that is done.

As a form of PTP packaging, for example, one or one administration unit of the pharmaceutical composition is stored in a pocket formed on a resin sheet or the like by a known method in a desired number, and then a metal foil such as an aluminum foil is used as a constituent material. A sheet may be used as a lid material to cover the lid. The sheet forming the pocket may also be a so-called double-sided aluminum PTP packaging using a sheet made of aluminum foil as a constituent material. In the case of PTP packaging, it is preferable to further wrap the PTP packaging with pillow packaging (for example, aluminum pillow packaging) from the viewpoint of suppressing an increase in decomposition products derived from pitavastatin.
As the form of SP packaging, pillow packaging, and stick packaging, for example, a pharmaceutical composition may be packaged one by one or one administration unit at a time by using a known method such as a resin sheet or a sheet containing aluminum foil as a constituent material. Can be mentioned. In the case of SP packaging, pillow packaging, and stick packaging, it is preferable to use a sheet made of aluminum foil as a constituent material from the viewpoint of suppressing an increase in decomposition products derived from pitavastatin.

In the present specification, the occupancy ratio (floor area ratio) of the pharmaceutical composition in the pharmaceutical product is usually 25 to 90%, preferably 28 to 75%, when the package is bottle-wrapped. More preferably, it is 30 to 50%. When the package is SP packaging, PTP packaging, pillow packaging, or stick packaging, it 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 with respect to the total volume inside the package, and the filling or inner plug for preventing damage to the pharmaceutical composition stored inside the package. Etc. are not taken into consideration when calculating the space occupancy rate.

As the airtight package, a commercially available package may be used as it is, or a commercially available package material 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.), Z-series (manufactured by Hanshin Kasei Kogyo Co., Ltd.), and the like. Be done. Examples of commercially available pillow packaging include Lamizip (registered trademark) (manufactured by Japan Co., Ltd.) and the like. Furthermore, as packaging materials for SP packaging, PTP packaging, pillow packaging and stick packaging, Sumilite VSS, Sumilite VSL, Sumilite NS, Sumilite FCL (all manufactured by Sumitomo Bakelite Co., Ltd.), TAS series (Taisei Kako Co., Ltd.) , PTP vinyl foil, PTP super foil (above, manufactured by Mitsubishi Resin Co., Ltd.), Nippaku aluminum foil (manufactured by Nippon Foil Co., Ltd.), aluminum foil silver plain (manufactured by Daiwa Chemical Industry Co., Ltd.), etc. Be done.

The method of accommodating the pharmaceutical composition in the airtight package is not particularly limited, and it can be achieved by arranging the pharmaceutical composition in the package by an appropriate means such as putting the pharmaceutical composition into the package. In this case, a means for charging a desiccant (for example, a columnar (tablet type) or sheet-shaped one) together with the pharmaceutical composition into the package may be used.

The applicable diseases of the pharmaceutical composition are not limited, and can be widely used for the prevention or treatment of diseases known at present or found in the future for which administration of pitavastatin is effective.
For example, pitavastatin or a salt thereof or a solvate thereof has excellent HMG-CoA reductase inhibitory activity and is used as an active ingredient of a therapeutic agent for hyperlipidemia, a therapeutic agent for hypercholesterolemia and the like. In addition, ezetimibe or a salt thereof or a mixture thereof suppresses the absorption of diet-derived and bile-derived cholesterol in the intestinal tract, has an excellent blood cholesterol lowering effect, and is a therapeutic agent for hypercholesterolemia and familial hypercholesterolemia. It is used as an active ingredient of a therapeutic agent for familial hypercholesterolemia, a therapeutic agent for homozygous cytosterolemia, and the like. Further, as disclosed in Patent Document 5, the combination of pitavastatin or a salt thereof or a solvate thereof and ezetimibe or a salt thereof or a solvate thereof has an effect of significantly lowering blood cholesterol and is highly effective. It is also known to be useful as a therapeutic agent for seborrhea and hypercholesterolemia.
Therefore, the pharmaceutical composition of the present invention containing both pitabastatin or a salt thereof or a solvent thereof and ezetimib or a salt thereof or a solvent thereof together can be used as a prophylactic and / or therapeutic agent for dyslipidemia. More preferably, prevention of hypercholesterolemia (hyperLDL hypercholesterolemia) (eg, primary hypercholesterolemia, secondary hypercholesterolemia, familial hypercholesterolemia), mixed dyslipidemia, etc. / Or as a therapeutic agent or the like, particularly preferably, it can be used as a prophylactic and / or therapeutic agent for a disease selected from the group consisting of idiopathic hypercholesterolemia and mixed dyslipidemia.

The route of administration of the pharmaceutical composition of the present invention is not particularly limited, and it can be appropriately examined and determined according to the disease to be applied, the type of preparation, the sex, age, symptom, etc. of the user, but the ease of administration. Oral administration is preferable from the viewpoint of. In addition, the pharmaceutical composition of the present invention can be taken before meals, between meals, after meals, before going to bed, etc., in 1 to 4 divided doses per day.

The present specification is not limited to these, but discloses, for example, the invention of the following aspects.
[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 containing.
[2A] The pharmaceutical composition according to [1A], wherein the component (A) is a calcium salt of pitavastatin (preferably a hemicalcium salt) or a hydrate thereof.
[3A] The pharmaceutical composition according to [1A] or [2A], wherein the component (B) is ezetimibe.
[4A] The pharmaceutical composition according to any one of [1A] to [3A], which is a solid preparation.
[5A] The pharmaceutical composition according to any one of [1A] to [4A], wherein the dosage form is a tablet, a capsule, a granule, a powder or a pill.
[6A] The pharmaceutical composition according to any one of [1A] to [5A], which is a prophylactic and / or therapeutic agent for dyslipidemia.
[7A] Any of [1A] to [6A], which is a preventive and / or therapeutic agent for a disease selected from the group consisting of idiopathic hypercholesterolemia and mixed dyslipidemia. The pharmaceutical composition described.
[8A] A pharmaceutical product in which the pharmaceutical composition according to any one of [1A] to [7A] is contained in an airtight package.
[9A] The pharmaceutical product according to [8A], wherein the airtight package is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging.

[1B] Next component (A):
(A) Pitavastatin or a salt thereof or a solvate thereof;
In addition to the pharmaceutical composition containing 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, which comprises a step of incorporating pitavastatin (preferably, a method for suppressing an increase in decomposition products derived from pitavastatin). In this case, the order of the steps of incorporating the component (A) and the component (B) in the pharmaceutical composition is not particularly limited.
[2B] The method according to [1B], wherein the component (A) is a calcium salt of pitavastatin (preferably a hemicalcium salt) or a hydrate thereof.
[3B] The method according to [1B] or [2B], wherein the component (B) is ezetimibe.
[4B] The method according to any one of [1B] to [3B], wherein the pharmaceutical composition is a solid preparation.
[5B] The method according to any one of [1B] to [4B], wherein the dosage form of the pharmaceutical composition is a tablet, a capsule, a granule, a powder or a pill.
[6B] The method according to any one of [1B] to [5B], wherein the pharmaceutical composition is a prophylactic and / or therapeutic agent for dyslipidemia.
[7B] The pharmaceutical composition is a prophylactic and / or therapeutic agent for a disease selected from the group consisting of idiopathic hypercholesterolemia and mixed dyslipidemia [1B] to [ 6B].
[8B] The method according to any one of [1B] to [7B], further comprising a step of accommodating the pharmaceutical composition in an airtight package. In this method, the order of the steps of incorporating the component (A) and the component (B) in the pharmaceutical composition and the step of accommodating the pharmaceutical composition in the airtight package is not particularly limited, and for example, the component (A). ), (B) may be contained in the pharmaceutical composition in any order and then contained in an airtight package, and one of the components (A) and (B) may be contained in the pharmaceutical composition. After that, this may be contained in an airtight package, and then the remaining components may be further contained in the pharmaceutical composition.
[9B] The method according to [8B], wherein the airtight package is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. In the following examples, the amount (part by mass) of the various components indicates the amount obtained by weighing the various components as they are, unless the converted amount is specified.

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

[Sample 1]
Pitavastatin calcium (pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.) was used as it was as sample 1.
[Sample 2]
Ezetimibe (manufactured by Glenmark Pharmaceuticals Co., Ltd.) was mixed at a ratio of 5 parts by mass with 1 part by mass of pitavastatin calcium (pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.), and the obtained mixture was used as sample 2.
[Sample 3]
After mixing ezetimibe (manufactured by Glenmark Pharmaceuticals) in a proportion of 5 parts by mass with 1 part by mass of pitavastatin calcium (pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.), 120 mg of the obtained mixture was placed in a glass bottle (A-). 102K: It was put into Isoya Glass Industry Co., Ltd. and covered with a lid, and this was used as sample 3.

For each of the above samples, the proportion of pitavastatin-derived degradation products (related substances) before the start of storage and after storage at 80 ° C. for 3.5 days was measured using an HPLC apparatus. Specifically, the proportion of pitavastatin relatives was measured as an area percentage (%) of the total peak area derived from pitavastatin and its relatives.
Then, based on the ratio (%) of pitavastatin-related substances before the start of storage of the obtained various samples and after storage at 80 ° C. for 3.5 days, the rate of increase in pitavastatin-derived degradation products for the various samples was determined according to the following formula. (%) Was calculated.

Increase rate of pitavastatin-derived degradation products (%) = (Ratio of pitavastatin relatives after storage at 80 ° C for 3.5 days (%))-(Ratio of pitavastatin relatives before start of storage (%))
The results are shown in Table 1.

From the test results shown in Table 1, sample 2 in which pitavastatin calcium and ezetimibe were mixed had a lower rate of increase in pitavastatin degradation products than sample 1 in which pitavastatin calcium alone was stored, and was stored at 80 ° C. for 3.5 days. It was confirmed that the increase in the later degradation products of pitavastatin was suppressed.
From the above test results, it was clarified that the increase of pitavastatin-derived degradation products can be suppressed by coexisting pitavastatin or a salt thereof or a solvate thereof with ezetimibe or a salt thereof or a solvate thereof.

Further, from the test results shown in Table 1, the increase rate of the decomposition product of pitavastatin was further lower in the sample 3 in which pitavastatin calcium and ezetimibe were mixed and further contained in the glass bottle than in the sample 2 not contained in the glass bottle. It was confirmed that the increase of pitavastatin degradation products after storage at 80 ° C. for 3.5 days was further suppressed.
From the above test results, by coexisting pitavastatin or a salt thereof or a solvate thereof with ezetimibe or a salt thereof or a solvate thereof and further storing the pitavastatin or a salt thereof or a solvate thereof in an airtight package, the decomposition product derived from pitavastatin is increased. It became clear that it could be further suppressed.

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

[Sample 4]
Put 100 mg of pitavastatin calcium (pitavastatin calcium: manufactured by Nissan Chemical Industry Co., Ltd.) in a polypropylene tube (slim tube: manufactured by Sumitomo Bakelite Co., Ltd.), cover it, and put it in an aluminum bag (Lamizip AL-E:). It was put in (manufactured by Japan Co., Ltd.) and sealed to make sample 4.
[Sample 5]
Ezetimibe (Hangzhou heta Pharm & Chem) was mixed with 1 part by mass of pitavastatin calcium (Pitavastatin calcium: manufactured by Nissan Chemical Industry Co., Ltd.) at a ratio of 5 parts by mass, and then 150 mg of the obtained mixture was made of polypropylene. It was placed in a tube (slim tube: manufactured by Sumitomo Bakelite Co., Ltd.), covered, and further placed in an aluminum bag (Lamizip AL-E: manufactured by Japan Co., Ltd.) and sealed to prepare sample 5.

For each of the above samples, the proportion of pitavastatin-derived degradation products (related substances) before the start of storage and after storage at 60 ° C. for 2 weeks was measured using an HPLC apparatus. Specifically, the proportion of pitavastatin relatives was measured as an area percentage (%) of the total peak area derived from pitavastatin and its relatives.
Then, from the ratio (%) of pitavastatin-related substances before the start of storage of the obtained various samples and after storage at 60 ° C. for 2 weeks, the rate of increase (%) of the decomposition products derived from pitavastatin for the various samples was followed by the following formula. ) Was calculated.

Increase rate of pitavastatin-derived degradation products (%) = (Ratio of pitavastatin relatives after storage at 60 ° C for 2 weeks (%))-(Ratio of pitavastatin relatives before start of storage (%))
The results are shown in Table 2.

As is clear from the test results shown in Table 2, even when stored in a polypropylene tube and an aluminum bag, pitavastatin or a salt thereof or a solvate thereof and ezetimibe or a salt thereof or a salt thereof, as in Test Example 1 It was confirmed that the increase of pitavastatin-derived degradation products can be suppressed by coexisting with a solvate.

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.

[Manufacturing Example 1]
Tablets containing the following components per tablet (100 mg) were produced by a conventional method.
Pitavastatin calcium hydrate 1.15 mg (1 mg as pitavastatin)
Ezetimibe 10 mg
Crystalline cellulose 18 mg
Lactose hydrate Appropriate amount hypromellose 2 mg
Croscarmellose sodium 3 mg
Citric acid 0.25 mg
Propyl gallate 0.005 mg
BHA 0.02 mg
Magnesium stearate 1.5 mg

[Manufacturing Example 2]
Tablets containing the following components per tablet (120 mg) were produced by a conventional method.
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Ezetimibe 10 mg
Crystalline cellulose 18 mg
Lactose hydrate Appropriate amount hypromellose 2 mg
Croscarmellose sodium 3 mg
Citric acid 0.25 mg
Propyl gallate 0.005 mg
BHA 0.02 mg
Magnesium stearate 1.5 mg

[Manufacturing Example 3]
Tablets containing the following components per tablet (150 mg) were produced by a conventional method.
Pitavastatin calcium hydrate 4.61 mg (4 mg as pitavastatin)
Ezetimibe 10 mg
Crystalline cellulose 18 mg
Lactose hydrate Appropriate amount hypromellose 2 mg
Croscarmellose sodium 3 mg
Citric acid 0.25 mg
Propyl gallate 0.005 mg
BHA 0.02 mg
Magnesium stearate 1.5 mg

[Manufacturing Example 4]
The following A granules and B granules were produced by a conventional method, and then both granules were tableted together with the following lubricants to produce tablets containing the following components per tablet (220 mg). ..
(A granule)
Ezetimibe 10 mg
D-mannitol 47.7 mg
Crystalline cellulose 20 mg
Hydroxypropyl cellulose 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount Low degree of substitution Hydroxypropyl cellulose 6 mg
Hypromellose 1.2 mg
Magnesium aluminate aluminate 1.2 mg
(lubricant)
Magnesium stearate 2 mg

[Manufacturing Example 5]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.2 mg (2 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 4 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg
Carnauba wax 0.011 mg

[Manufacturing Example 6]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.2 mg (2 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 4 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 7]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.2 mg (2 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 12 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 8]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.2 mg (2 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 12 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 9]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin Calcium Hydrate 4.4 mg (4 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 4 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg
Carnauba wax 0.011 mg

[Manufacturing Example 10]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin Calcium Hydrate 4.4 mg (4 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 4 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 11]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin Calcium Hydrate 4.4 mg (4 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 12 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 12]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin Calcium Hydrate 4.4 mg (4 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 12 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 13]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.2 mg (2 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 2 mg
Hypromellose 1.2 mg
Magnesium aluminate aluminate 1.2 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg
Carnauba wax 0.008 mg

[Manufacturing Example 14]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.2 mg (2 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 2 mg
Hypromellose 1.2 mg
Magnesium aluminate aluminate 1.2 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg

[Manufacturing Example 15]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.2 mg (2 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 6 mg
Hypromellose 1.2 mg
Magnesium aluminate aluminate 1.2 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg

[Manufacturing Example 16]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.2 mg (2 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 6 mg
Hypromellose 1.2 mg
Magnesium aluminate aluminate 1.2 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg

[Manufacturing Example 17]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 4.18 mg
Hypromellose 2.508 mg
Magnesium aluminate aluminate 2.508 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 18]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 4.61 mg (4 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 4.18 mg
Hypromellose 2.508 mg
Magnesium aluminate aluminate 2.508 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 19]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 4.18 mg
Hypromellose 2.508 mg
Magnesium aluminate aluminate 2.508 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 20]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 4.61 mg (4 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 4.18 mg
Hypromellose 2.508 mg
Magnesium aluminate aluminate 2.508 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 21]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 12.54 mg
Hypromellose 2.508 mg
Magnesium aluminate aluminate 2.508 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg
Carnauba wax 0.011 mg

[Manufacturing Example 22]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 4.61 mg (4 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 12.54 mg
Hypromellose 2.508 mg
Magnesium aluminate aluminate 2.508 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg
Carnauba wax 0.011 mg

[Manufacturing Example 23]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 12.54 mg
Hypromellose 2.508 mg
Magnesium aluminate aluminate 2.508 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 24]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 4.61 mg (4 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 12.54 mg
Hypromellose 2.508 mg
Magnesium aluminate aluminate 2.508 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 25]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 4 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 26]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 4.61 mg (4 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 4 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 27]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 4 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 28]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (220 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 4.61 mg (4 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 4 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg

[Manufacturing Example 29]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 2.09 mg
Hypromellose 1.254 mg
Magnesium aluminate 1.254 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg

[Manufacturing Example 30]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 6.27 mg
Hypromellose 1.254 mg
Magnesium aluminate 1.254 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg

[Manufacturing Example 31]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 2.09 mg
Hypromellose 1.254 mg
Magnesium aluminate 1.254 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg

[Manufacturing Example 32]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 6.27 mg
Hypromellose 1.254 mg
Magnesium aluminate 1.254 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg
Carnauba wax 0.008 mg

[Manufacturing Example 33]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 2 mg
Hypromellose 1.2 mg
Magnesium aluminate aluminate 1.2 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg

[Manufacturing Example 34]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 2.5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 6 mg
Hypromellose 1.2 mg
Magnesium aluminate aluminate 1.2 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg

[Manufacturing Example 35]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 2 mg
Hypromellose 1.2 mg
Magnesium aluminate aluminate 1.2 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg

[Manufacturing Example 36]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (160 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 6 mg
Hypromellose 1.2 mg
Magnesium aluminate aluminate 1.2 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg

[Manufacturing Example 37]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (218 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 1.1 mg (1 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 4 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg
Carnauba wax 0.0109 mg

[Manufacturing Example 38]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (156 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 1.1 mg (1 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 2 mg
Hypromellose 1.2 mg
Magnesium aluminate aluminate 1.2 mg
(lubricant)
Magnesium stearate 1.5 mg
(Film coating)
Opadry White03O28659 6mg
Carnauba wax 0.0078 mg

[Manufacturing Example 39]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (218 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.2 mg (2 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 4 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg
Carnauba wax 0.0109 mg

[Manufacturing Example 40]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (218 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin Calcium Hydrate 4.4 mg (4 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 4 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg
Carnauba wax 0.0109 mg

[Manufacturing Example 41]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following per tablet (223.31 mg). A tablet containing the ingredients of was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.30 mg (2 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 4.18 mg
Hypromellose 2.508 mg
Magnesium aluminate aluminate 2.508 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg
Carnauba wax 0.0112 mg

[Manufacturing Example 42]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following per tablet (223.31 mg). A tablet containing the ingredients of was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 4.61 mg (4 mg as pitavastatin)
Lactose hydrate Appropriate amount crospovidone 4.18 mg
Hypromellose 2.508 mg
Magnesium aluminate aluminate 2.508 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg
Carnauba wax 0.0112 mg

[Manufacturing Example 43]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (120 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.2 mg (2 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 2 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 6mg
Carnauba wax 0.011 mg

[Manufacturing Example 44]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (260 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin calcium hydrate 2.2 mg (2 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 6 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg
Carnauba wax 0.005 mg

[Manufacturing Example 45]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (120 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin Calcium Hydrate 4.4 mg (4 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 2 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 6mg
Carnauba wax 0.011 mg

[Manufacturing Example 46]
After producing the following A granules and B granules by a conventional method, both granules are tableted together with the following lubricants and film-coated by a conventional method to obtain the following components per tablet (260 mg). A tablet containing the above was produced.
(A granule)
Ezetimibe 10 mg
Lactose hydrate Appropriate amount of crystalline cellulose 20 mg
Povidone 5 mg
Croscarmellose sodium 8 mg
Sodium lauryl sulfate 1.8 mg
(B granules)
Pitavastatin Calcium Hydrate 4.4 mg (4 mg as pitavastatin calcium)
Lactose hydrate Appropriate amount crospovidone 6 mg
Hypromellose 2.4 mg
Magnesium aluminate aluminate 2.4 mg
(lubricant)
Magnesium stearate 2 mg
(Film coating)
Opadry White03O28659 8mg
Carnauba wax 0.005 mg

[Manufacturing Examples 47 to 92]
The tablets of Production Examples 1 to 46 were PTP-wrapped by a conventional method to produce the pharmaceutical products of Production Examples 47 to 92.
[Manufacturing Examples 93 to 138]
The tablets of Production Examples 1 to 46 were each housed in polypropylene bottles by a conventional method to produce the pharmaceutical products of Production Examples 93 to 138.

According to the present invention, it is possible to provide a pharmaceutical composition containing a combination of pitavastatin and ezetimibe, which are useful as active ingredients for a therapeutic agent for hyperlipidemia, a therapeutic agent for hypercholesterolemia, etc., and having excellent storage stability. It can be used in the pharmaceutical industry, etc.

Claims (2)

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 product in which a pharmaceutical composition containing the above is contained in an airtight package. The pharmaceutical product according to claim 1, wherein the airtight package is at least one selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging.