JP2019043880A - Pharmaceutical composition - Google Patents

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

  The present invention relates to a pharmaceutical composition and the like.

Pitavastatin calcium (chemical name: Monocalcium bis {(3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxyhept) -6-enoate}) or the like, or a solvate thereof, has an excellent HMG-CoA reductase inhibitory activity, and is an active ingredient such as a therapeutic agent for hyperlipidemia, a therapeutic agent for hypercholesterolemia, etc. It is known that it is 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).

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 each separately suspended in a 0.5% by weight aqueous solution of sodium carboxymethylcellulose and then orally administered to guinea pigs. There is no disclosure of a pharmaceutical composition containing both ingredients and its storage stability over time.
Patent Document 6 describes that rosuvastatin calcium, which is a kind of statins similar to pitavastatin and has a similar chemical structure, has an interaction with ezetimibe, and both components are mixed to 50 ° C. and 75% relative humidity. It is disclosed that degradation products (analogous substances) of rosuvastatin including lactone form increase when stored for 2 weeks under the above conditions.

Japanese Patent No. 2567746 WO 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, the present inventors have intensively studied to solve the above problems, and surprisingly, ezetimibe or a salt thereof, or a solvate thereof, which is known to increase the decomposition product by coexistence with rosuvastatin, is surprisingly obtained. As with rosuvastatin, coexistence with pitavastatin or a salt thereof or a solvate thereof, which is a kind of statin, suppresses an increase in degradation products derived from pitavastatin and stabilizes pitavastatin or a salt thereof or a solvate thereof The present invention has been completed by finding out what can be done.

That is, the present invention includes 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 pharmaceutical composition containing this is provided.

  ADVANTAGE OF THE INVENTION According to this invention, the increase in the degradation product derived from pitavastatin can be suppressed and the pharmaceutical composition excellent in storage stability can be provided.

In this specification, “pitavastatin or a salt thereof or a solvate thereof” includes not only pitavastatin (international general name: Pitavastatin) itself, but also a pharmaceutically acceptable salt of pitavastatin (sodium salt, potassium salt, etc.). A salt of a Group 2 element metal such as a calcium salt or a magnesium salt; an organic amine salt such as a phenethylamine salt; an ammonium salt; or a solvent of pitavastatin or a pharmaceutically acceptable salt thereof with water, alcohol, etc. Japanese products are also included, and these can be used alone or in combination.
Pitavastatin or a salt thereof or a solvate thereof is preferably a calcium salt of pitavastatin or a hydrate thereof, more preferably a hemicalcium salt of pitavastatin or a hydrate thereof, 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 method described in Patent Document 1, US Pat. No. 5,856,336, etc., or a commercially available product can 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 determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, 0.1 to 16 mg, more preferably 0.5 to 8 mg, and particularly preferably 1 to 4 mg of pitavastatin calcium salt anhydride can be contained per day. In the present invention, pitavastatin 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 pitavastatin with respect to the total mass of the pharmaceutical composition, 0.7 It is more preferable to contain -18.5 mass%, and it is especially preferable to contain 1-17 mass%.

In the present specification, “ezetimibe or a salt thereof or a solvate thereof” includes not only ezetimibe (international general name: Ezetimibe) itself, but also pharmaceutically acceptable salts of ezetimibe (sodium salt, potassium salt, etc.) A salt of a Group 2 element metal such as a calcium salt or a magnesium salt; an organic amine salt such as a phenethylamine salt; an ammonium salt; or a solvent of ezetimibe or a pharmaceutically acceptable salt thereof with water or alcohol; Japanese products are also included, and these can be used alone or in combination.
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 International Publication No. 95/08532 pamphlet or the like, or a commercially available product may be used. Examples of the 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 determined by appropriate examination according to the stability of pitavastatin and the like. For example, 1-30 mg, more preferably 3-20 mg, particularly preferably 5-15 mg of ezetimibe in free form equivalent per day can be contained. In the present invention, from the viewpoint of suppressing an increase in degradation products derived from pitavastatin, ezetimibe or a salt thereof or a solvate thereof is 0.1 to 85 in terms of free form of ezetimibe relative to the total mass of the pharmaceutical composition. It is preferably contained in an amount of 0.5% 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 mass ratio of pitavastatin or a salt thereof or a solvate thereof to ezetimibe or a salt thereof or a solvate thereof is not particularly limited in the pharmaceutical composition, but the increase in degradation products derived from pitavastatin is suppressed. From the viewpoint, pitavastatin or a salt thereof or a solvate thereof is 1 part by mass in terms of calcium salt anhydride, and 0.1 to 10 parts by mass of ezetimibe or a salt thereof or a solvate thereof in terms of a free form It is preferably contained, 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 even more preferably 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 any of solid, semi-solid, and liquid preparations, and can be selected according to the purpose of use. Examples of the dosage form of the pharmaceutical composition include the dosage forms described in the 17th revised Japanese Pharmacopoeia General Rules for Preparations. Specifically, for example, dosage forms for oral administration include tablets (including normal tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules ( For example, including foamed granules, etc.), solid preparations such as powders and pills; semi-solid preparations such as oral jelly preparations; oral liquids (including elixirs, suspensions, emulsions, limonades, etc.), etc. Liquid preparations and the like. In addition, dosage forms for parenteral administration include injections, inhalants, eye drops, ear drops, nasal drops, suppositories, external solid preparations, external liquid preparations, sprays, ointments, creams, gels. And patches.

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

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

  Specific examples of the excipient include, for example, aluminum silicate, anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, calcium silicate, light anhydrous silicic acid, heavy anhydrous silicic acid, calcium sulfate, monophosphate. Inorganic excipients such as calcium hydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate; candy flour, starch (wheat starch, rice starch, corn Starch, partially pregelatinized starch, etc.), fructose, caramel, agar, xylitol, paraffin, crystalline cellulose, sucrose, maltose, lactose, lactose hydrate, sucrose, glucose, pullulan, polyoxyethylene hydrogenated castor oil, maltitol, Reduced maltose water candy, powdered reduced maltose water candy, erythritol, Rubitoru, mannitol, lactitol, trehalose, reduced palatinose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylamino acetate, organic excipients such as calcium citrate and the like. 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, croscarmellose sodium, crospovidone, carmellose, carmellose calcium, starch, sucrose fatty acid ester, gelatin, sodium bicarbonate, dextrin, Dehydroacetic acid and its salt, povidone, polyoxyethylene hydrogenated castor oil 60, etc. are mentioned. These can be used alone or in combination of two or more.

  Specific examples of the binder include oils and fats such as hydrogenated beef tallow oil, hydrogenated oil, hydrogenated vegetable oil, soybean hardened oil, carnauba wax, honey beeswax, beeswax, and owl, as well as methyl cellulose, hydroxypropyl cellulose, hypromellose, carme Sodium loose, 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 Examples include diethylaminoacetate. These can be used alone or in combination of two or more.

  Specific examples of the lubricant include calcium stearate, magnesium stearate, sodium stearyl fumarate, sucrose fatty acid ester, and the like. 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, polysorbate 80 (polyoxyethylene (20) sorbitan oleate) and the like. These can be used alone or in combination of two or more.

  Specific examples of the film forming agent include alkyl celluloses such as methyl cellulose and ethyl cellulose; alginic acid such as sodium alginate or a salt thereof; carrageenan; carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, carboxymethyl cellulose potassium, carboxymethyl cellulose, carboxymethyl ethyl cellulose, and the like. Xanthan gum; hydroxyalkyl cellulose such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose (hydroxypropylmethylcellulose); hydroxyalkylcellulose phthalate such as hydroxypropylmethylcellulose phthalate; pullulan; polyvinyl acetate Polyvinyl acetate phthalate, polyvinyl pyrrolidone, and the like. These can be used alone or in combination of two or more.

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

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

  Specific examples of the corrigent include, for example, limonene, pinene, camphene, cymen, cineole, citronellol, geraniol, nerol, linalool, menthol, terpineol, rosinol, borneol, isoborneol, menthone, camphor, eugenol, synzeanol and the like. Terpenes: Spruce oil, orange oil, peppermint oil, camphor white oil, eucalyptus oil, turpentine oil, lemon oil, pepper oil, clove oil, cinnamon oil, lavender oil, fennel oil, chamomile oil, perilla oil, spearmint oil, etc. Essential oils containing terpenes such as ascorbic acid, tartaric acid, citric acid, malic acid and sour agents such as salts thereof. These can be used alone or in combination of two or more.

  Specific examples of the sweetening agent 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.

A pharmaceutical composition can be manufactured by a well-known method according to 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, pills, etc., pitavastatin or a salt thereof or a solvate thereof, ezetimibe or a salt thereof or a solvate thereof In addition, if necessary, formulation additives such as excipients, binders, disintegrants, lubricants, etc. are mixed, and after mixing all or part of these components, extrusion granulation, rolling granulation, stirring By granulating by a known granulation method such as granulation, fluidized bed granulation, spray granulation, melt granulation, crush granulation, etc. Can be manufactured. In addition, the obtained granulated material can also be coat | covered with a coating agent etc. by a well-known method.
Further, 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, an excipient, a binder, a disintegrant, Using appropriate formulation additives such as lubricants, mix all or part of these ingredients to obtain a mixture, which can be directly compressed (tablet compression) (direct powder compression method) The granules can be produced by classification, sizing, etc., if necessary, followed by compression (tabletting) (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.
Furthermore, when the dosage form of the pharmaceutical composition is a capsule, the above granulated product or compressed product may be filled into a capsule.

In the present invention, the pharmaceutical composition may be further accommodated in an airtight package (hereinafter, in the present specification, a product in which the pharmaceutical composition is accommodated in an airtight package is referred to as “medicine”). ). As specifically disclosed in Test Examples to be described later, by containing the pharmaceutical composition of the present invention in an airtight package, an increase in degradation products derived from pitavastatin can be further suppressed. In this case, in addition to the airtight package, the pharmaceutical may further include a package not corresponding to the following “airtight package”, and the pharmaceutical composition is contained directly or indirectly in the airtight package. It only has to be done.
In this specification, `` airtight package '' means a package that can suppress the intrusion of solid or liquid foreign substances in the state of normal handling, transportation or storage, etc., and is defined in the 17th revised Japanese Pharmacopoeia General Rules. It is a concept including “airtight container” and “sealed container”. As the airtight package, any of a regular shape and an irregular shape can be used. Specifically, for example, bottle packaging, SP (Stripe Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, etc. Is mentioned. The hermetic package may be a combination of a plurality of these. Specifically, for example, an embodiment in which the pharmaceutical composition is first packaged in PTP packaging and further packaged in pillow packaging, etc. .

  The packaging material (material) of the hermetic package is not particularly limited. For example, glass, plastic (polyester such as polyethylene terephthalate and polyethylene naphthalate); polyethylene (low density (LDPE), medium density (MDPE), high density (HDPE) Materials such as polypropylene, polyolefins such as polypropylene, polycarbonates, polystyrene, etc.), metals (aluminum, etc.) and the like used in the fields of pharmaceuticals and foods, etc., 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, metal, and the like, and one or more of these can be combined as appropriate. As a 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 a bottle, for example, an appropriate amount of the pharmaceutical composition may be stored in the bottle and then sealed with an appropriate stopper or lid. In addition, what is necessary is just to select the thing of the magnitude | size according to the quantity etc. of the pharmaceutical composition to store suitably, and, as a capacity | capacitance of a bottle, it is about 10-500 mL, for example, 14-400 mL is preferable, 24-350 mL Is more preferable.

  Moreover, the packaging material used for SP packaging, PTP packaging, pillow packaging, stick packaging, and the like is not particularly limited. For example, biaxially oriented polypropylene (OPP), biaxially oriented 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), Resin such as stretched nylon (CNy), polycarbonate (PC), polystyrene (PS), hard vinyl chloride (VSC), metal foil such as aluminum foil (AL), and the like, one or more of these Can be combined as appropriate.

  When carrying out 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 packaging materials as described above. In this case, the packaging material Can have a multilayer structure appropriately combined. Examples of a method for forming a multilayer structure using two or more kinds of packaging materials as a sheet include a method of laminating the packaging materials to produce a laminated sheet. The laminated sheet can be produced by a known method such as extrusion lamination, dry lamination, coextrusion lamination, thermal lamination, wet lamination, non-solvent lamination, heat lamination and the like. Moreover, a well-known commercial item can also be used for the sheet | seat for SP packaging, PTP packaging, pillow packaging, and stick packaging.

  In the said sheet | seat, as a single layer sheet using 1 type of packaging materials, a PVC sheet, a CPP sheet, etc. are mentioned, Moreover, as a laminated sheet using 2 or more types of packaging materials, the sheet | seat structure is, for example, Laminated PVC and PVDC (PVC / PVDC; hereinafter abbreviated), 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 sheet shown on the left uses two or more types as CPP), etc., but are limited to these. Is not to be done.

As a form of PTP packaging, for example, a pharmaceutical composition is stored one by one or one dosage unit in a pocket formed in a resin sheet or the like by a known method, and then a metal foil such as an aluminum foil is used as a constituent material. It is possible to use a sheet as a lid material and cover the sheet. In addition, it is good also as what is called double-sided aluminum PTP packaging using the sheet | seat which uses aluminum foil as a constituent material as a sheet | seat which forms a pocket. In the case of PTP packaging, it is preferable that the PTP packaging is further packaged by pillow packaging (for example, aluminum pillow packaging or the like) from the viewpoint of suppressing an increase in degradation products derived from pitavastatin.
As a form of SP packaging, pillow packaging, or stick packaging, for example, a pharmaceutical composition may be packaged one by one or by one dosage unit using a resin sheet or a sheet containing aluminum foil as a constituent material by a known method. Can be mentioned. In the case of SP packaging, pillow packaging, and stick packaging, it is preferable to use a sheet containing aluminum foil as a constituent material from the viewpoint of suppressing an increase in degradation products derived from pitavastatin.

  In the present specification, the occupation ratio (volume ratio) inside the package of the pharmaceutical composition in the pharmaceutical product is usually 25 to 90%, preferably 28 to 75% when the package is a bottle package, 30 to 50% is more preferable. 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 occupation rate means the occupation rate of the pharmaceutical composition with respect to the entire volume inside the package, and the filling or inner plug for preventing damage of the pharmaceutical composition stored inside the package. Etc. are not considered in calculating the space occupancy.

  As the airtight package, a commercially available package may be used as it is, or a commercially available packaging material may be processed and used. Examples of commercially available bottle packaging bodies include glass bottles (manufactured by Saiya Glass Industry Co., Ltd.), tablet bottles (manufactured by Tokyo Glass Co., Ltd.), Z-series (manufactured by Hanshin Chemical Industry Co., Ltd.), and the like. It is done. Moreover, as a package of a commercially available pillow package, Lami Zip (registered trademark) (manufactured by Nippon Shokubai Co., Ltd.) and the like can be mentioned. Furthermore, as packaging materials for SP packaging, PTP packaging, pillow packaging and stick packaging, Sumilite VSS, Sumilite VSL, Sumilite NS, Sumilite FCL (above, manufactured by Sumitomo Bakelite Co., Ltd.), TAS series (Taisei Chemical Co., Ltd.) Manufactured), PTP vinyl foil, PTP super foil (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. It is done.

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

The disease to which the pharmaceutical composition is applied is not limited in any way, and can be widely used for the prevention or treatment of a disease known to be known at the present time 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 such as a therapeutic agent for hyperlipidemia and a therapeutic agent for hypercholesterolemia. In addition, ezetimibe or a salt thereof or a solvate 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, family It is used as an active ingredient such as a therapeutic agent for congenital hypercholesterolemia and a therapeutic agent for homozygous sitosterolemia. Further, 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 reducing blood cholesterol as disclosed in Patent Document 5, It is also known to be useful as a therapeutic agent for lipemia, a therapeutic agent for hypercholesterolemia, and the like.
Therefore, the pharmaceutical composition of the present invention containing both pitavastatin or a salt thereof or a solvate thereof and ezetimibe or a salt thereof or a solvate thereof is used as a prophylactic and / or therapeutic agent for dyslipidemia. More preferably, prevention of hypercholesterolemia (high LDL cholesterolemia) (for example, primary hypercholesterolemia, secondary hypercholesterolemia, familial hypercholesterolemia), mixed dyslipidemia and the like, and As the therapeutic agent, etc., it can be particularly preferably 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 can be determined by appropriate examination according to the disease to be applied, the type of preparation, the sex of the user, age, symptoms, etc. From the viewpoint of oral administration, oral administration is preferred. The pharmaceutical composition of the present invention can be taken before meals, between meals, after meals, before going to bed, etc., divided into about 1 to 4 times per day.

In addition, although this specification is not limited to these at all, the invention of the following aspects is disclosed, for example.
[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 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, capsule, granule, powder or pill.
[6A] The pharmaceutical composition according to any one of [1A] to [5A], which is a preventive and / or therapeutic agent for dyslipidemia.
[7A] Any one 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 as described.
[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 package is at least one selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging.

[1B] The following component (A):
(A) pitavastatin or a salt thereof or a solvate thereof;
In addition to 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 preferably comprises a step of containing (preferably a method for suppressing an increase in degradation 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, capsule, granule, powder or 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. 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 addition, in this method, the order of the process of containing a component (A) and a component (B) in a pharmaceutical composition, and the process of accommodating a pharmaceutical composition in an airtight package is not specifically limited, For example, a component (A ), (B) may be contained in the pharmaceutical composition in any order, and then contained in an airtight package, and one of components (A) and (B) may be contained in the pharmaceutical composition. After that, it may be accommodated 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 at least one selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited at all by these. 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 otherwise 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 sample 1 as it was.
[Sample 2]
With respect to 1 part by mass of pitavastatin calcium (Pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.), ezetimibe (Ezetimibe: manufactured by Glenmark Pharmaceuticals) was mixed at a ratio of 5 parts by mass.
[Sample 3]
After 5 parts by mass of ezetimibe (Ezetimibe: manufactured by Glenmark Pharmaceuticals) was mixed with 1 part by mass of pitavastatin calcium (Pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.), 120 mg of the resulting mixture was added to a glass bottle (A- 102K: Saiya Glass Industry Co., Ltd.) and covered, and this was used as sample 3.

About the said various samples, the ratio of the degradation product (related substance) derived from pitavastatin before storage start and after 80 degreeC 3.5 day storage was measured using the HPLC apparatus. Specifically, the ratio of pitavastatin related substances was measured as an area percentage (%) with respect to the total peak area derived from pitavastatin and related substances.
Then, from the ratio (%) of the related substance of pitavastatin before the start of storage and after storage at 80 ° C. for 3.5 days for the obtained various samples, the increase rate of the degradation product derived from pitavastatin for the various samples according to the following formula (%) Was calculated.

Increase rate of degradation product derived from pitavastatin (%) = (Percentage of related substance of pitavastatin after storage at 80 ° C. for 3.5 days) − (Percentage of related substance of pitavastatin before start of storage (%))
The results are shown in Table 1.

From the test results shown in Table 1, sample 2 containing pitavastatin calcium and ezetimibe has a lower rate of increase in degradation products of pitavastatin than sample 1 containing only pitavastatin calcium, and is stored at 80 ° C. for 3.5 days. It was confirmed that the increase in the degradation product of pitavastatin later was suppressed.
From the above test results, it has been clarified that the increase in the degradation product derived from pitavastatin can be suppressed by allowing pitavastatin or a salt thereof or a solvate thereof to coexist with ezetimibe or a salt thereof or a solvate thereof.

In addition, from the test results shown in Table 1, the rate of increase in the degradation product of pitavastatin is lower in the sample 3 mixed with pitavastatin calcium and ezetimibe and accommodated in the glass bottle than in the sample 2 not accommodated in the glass bottle, It was confirmed that the increase in the degradation product of pitavastatin after storage at 80 ° C. for 3.5 days was further suppressed.
From the above test results, it was found that pitavastatin or a salt thereof or a solvate thereof and ezetimibe or a salt or a solvate thereof coexist, and further contained in an airtight package, thereby increasing the degradation product derived from pitavastatin. It became clear that it could be further suppressed.

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

[Sample 4]
100 mg of pitavastatin calcium (Pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.) is placed in a polypropylene tube (slim tube: manufactured by Sumitomo Bakelite Co., Ltd.), covered, and further covered with an aluminum bag (Lamizip AL-E: Sample 4 was sealed after being put in (manufactured by Japan Corporation).
[Sample 5]
After mixing 5 parts by mass of Ezetimibe (Ezetimibe: manufactured by Hangzhou heta Pharm & Chem) with 1 part by mass of pitavastatin calcium (Pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.), 150 mg of the resulting mixture was made of polypropylene. Sample 5 was placed in a tube (slim tube: manufactured by Sumitomo Bakelite Co., Ltd.), covered, and further sealed in an aluminum bag (Lamidip AL-E: produced by Nihonsha Co., Ltd.).

About the said various samples, the ratio of the degradation product (related substance) derived from pitavastatin before storage start and after 60-degree-C 2 week storage was measured using the HPLC apparatus. Specifically, the ratio of pitavastatin related substances was measured as an area percentage (%) with respect to the total peak area derived from pitavastatin and related substances.
From the ratio (%) of pitavastatin related substances before the start of storage and after storage at 60 ° C. for 2 weeks for each of the various samples obtained, the rate of increase in degradation products derived from pitavastatin (%) for each sample according to the following formula: ) Was calculated.

Increase rate of degradation product derived from pitavastatin (%) = (Percentage of related substance of pitavastatin after storage at 60 ° C. for 2 weeks) − (Percentage of related substance of pitavastatin before start of storage (%))
The results are shown in Table 2.

  As is apparent from the test results shown in Table 2, even when accommodated in polypropylene tubes and aluminum bags, as in Test Example 1, pitavastatin or a salt thereof, or a solvate thereof, and ezetimibe or a salt thereof, or their It was confirmed that the increase in degradation products derived from pitavastatin can be suppressed by coexisting with the 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.

[Production Example 1]
A tablet containing the following components per tablet (100 mg) was produced by a conventional method.
Pitavastatin calcium hydrate 1.04 mg (1 mg 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

[Production Example 2]
A tablet containing the following components per tablet (120 mg) was produced by a conventional method.
Pitavastatin calcium hydrate 2.09 mg (2 mg 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

[Production Example 3]
A tablet containing the following components per tablet (150 mg) was produced by a conventional method.
Pitavastatin calcium hydrate 4.13 mg (4 mg 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

[Production Example 4]
The following A granule and B granule were each produced by a conventional method, and then both granules were tableted together with the following lubricant to produce a tablet containing the following ingredients per tablet (220 mg). .
(A granule)
Ezetimibe 10mg
D-mannitol 47.7mg
Crystalline cellulose 20mg
Hydroxypropylcellulose 2.5mg
Croscarmellose sodium 8mg
Sodium lauryl sulfate 1.8mg
(B granule)
Pitavastatin calcium hydrate 2.09 mg (2 mg as anhydrous)
Lactose hydrate appropriate amount low substituted hydroxypropylcellulose 6mg
Hypromellose 1.2mg
Magnesium aluminate metasilicate 1.2mg
(lubricant)
Magnesium stearate 2mg

[Production Examples 5 to 8]
The tablets of Production Examples 1 to 4 were each PTP-packaged by a conventional method to produce the pharmaceuticals of Production Examples 5 to 8.
[Production Examples 9-12]
The tablets of Production Examples 1 to 4 were respectively accommodated in polypropylene bottles by a conventional method to produce pharmaceuticals of Production Examples 9 to 12.

  According to the present invention, a pharmaceutical composition containing a combination of pitavastatin and ezetimibe that is useful as an active ingredient such as a therapeutic agent for hyperlipidemia, a therapeutic agent for hypercholesterolemia, and the like can be provided. It can be used in the pharmaceutical industry.

Claims (5)

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:   The pharmaceutical composition according to claim 1, which is a solid preparation.   The pharmaceutical composition according to claim 1 or 2, wherein the dosage form is a tablet, capsule, granule, powder or pill.   The medicament according to any one of claims 1 to 3, which is used for the prevention and / or treatment of one or more diseases selected from the group consisting of idiopathic hypercholesterolemia and mixed dyslipidemia. Composition.   A pharmaceutical product comprising the pharmaceutical composition according to any one of claims 1 to 4 housed in an airtight package.