Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• 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, 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).
• Patent Document 5 pitavastatin calcium and ezetimibe (chemical name: (3R, 4S) -1- (4-fluorophenyl) -3-[(3S) -3- (4-fluorophenyl) -3-hydroxypropyl]- Oral administration of 4-(4-hydroxyphenyl)azetidin-2-one) is disclosed.
• 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. There is no disclosure about a pharmaceutical composition containing the components together and its storage stability over time.
• 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 has been disclosed that rosuvastatin degradation products (related substances) such as lactones increase when stored for 2 weeks under the conditions of.
• An object of the present invention is to provide a new technique for stably formulating pitavastatin or a salt thereof or a solvate thereof.
• ezetimibe or a salt thereof, or a solvate thereof which is known to increase its decomposition products by coexistence with rosuvastatin.
• coexistence with pitavastatin which is a kind of statins or a salt thereof or a solvate thereof suppresses an increase in degradation products derived from pitavastatin and stabilizes pitavastatin or a salt thereof or a solvate thereof.
• the inventors have found that it is possible and completed the present invention.
• the present invention provides the following components (A) and (B): (A) Pitavastatin or a salt thereof or a solvate thereof; (B) ezetimibe or a salt thereof or a solvate thereof;
• the present invention provides a pharmaceutical composition containing:
• pitavastatin or a salt thereof or a solvate thereof includes pitavastatin (international generic name: Pitavastatin) itself, and 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 these can be used alone or in combination of two or more.
• pitavastatin or a salt thereof or a solvate thereof a calcium salt of pitavastatin or a hydrate thereof is preferable, a hemi-calcium 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 determined by appropriate examination according to the sex, age, symptoms, etc. of the recipient.
• an amount which can be taken per day is 0.1 to 16 mg, more preferably 0.5 to 8 mg, and particularly preferably 1 to 4 mg in terms of anhydrous calcium salt of pitavastatin.
• 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 anhydrous calcium salt of pitavastatin with respect to the total mass of the pharmaceutical composition. It is more preferably contained in an amount of ⁇ 18.5% by mass, and particularly preferably in an amount of 1 to 17% by mass.
• ezetimibe or a salt thereof or a solvate thereof includes ezetimibe (international generic name: Ezetimibe) itself, and pharmaceutically acceptable salts of ezetimibe (alkali metal salts such as sodium salt and potassium salt).
• 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 and water or an alcohol Japanese products are also included, and these can be used alone or in combination of two or more.
• 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, for example, by the method described in WO 95/08532 pamphlet or the like, 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 determined by appropriate examination depending on the stability of pitavastatin and the like.
• an amount that can be taken per day is 1 to 30 mg, more preferably 3 to 20 mg, and particularly preferably 5 to 15 mg in terms of free form of ezetimibe.
• ezetimibe or a salt thereof or a solvate thereof is used in an amount of 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 0.5% by mass, more preferably 0.5 to 25% by mass, still more preferably 1 to 20% by mass, and particularly preferably 3 to 15% by mass.
• the content mass ratio of pitavastatin 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 pitavastatin.
• pitavastatin or its salt or its solvate is 1 part by mass in terms of its calcium salt anhydride
• ezetimib or its salt or its solvate is 0.1 to 10 parts by mass in terms of its free form. It is preferable to contain 0.5 to 7 parts by mass, more preferably 1 to 6 parts by mass, still more preferably 2.5 to 5 parts by mass, still more preferably 5 parts by mass. It is particularly preferable to contain.
• the dosage form of the “pharmaceutical composition” is not particularly limited, and may be 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 Rules for Preparation, etc.
• tablets including, for example, ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.
• capsules granules (for example, solid preparations such as effervescent granules), powders, pills, etc .; semi-solid preparations such as oral jelly preparations; oral liquid preparations (including, for example, elixirs, suspending agents, emulsions, limonade agents, 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.
• the dosage form of the pharmaceutical composition is preferably a solid preparation from the viewpoint of suppressing an increase in pitavastatin-derived degradation products, and tablets (e.g., ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolved tablets).
• tablets e.g., ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolved tablets.
• Solid preparations selected from tablets and the like), capsules, granules (including effervescent granules and the like), powders and pills are particularly preferable.
• the pharmaceutical composition can be produced according to the dosage form by a known method described in, for example, the 17th Revised Japanese Pharmacopoeia General Rules for Preparation.
• a pharmaceutically acceptable carrier may be added to the pharmaceutical composition.
• formulation additives include, for example, excipients, disintegrants, binders, lubricants, plasticizers, film formers, powders, poorly water-soluble polymeric substances, antioxidants, flavoring agents, sweeteners, etc.
• formulation 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.
• excipients 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 monophosphoric acid.
• 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 (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, Examples thereof include reduced maltose starch syrup, powdered reduced maltose starch syrup, erythritol, sorbitol, mannitol, lactitol, trehalose, reduced palatinose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, calcium citrate, and other organic excipients. These can
• disintegrant examples 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.
• super disintegrants such as sodium carboxymethyl starch, sodium croscarmellose, and crospovidone
• examples include dehydroacetic acid and its salts, povidone, polyoxyethylene hydrogenated castor oil 60, and the like. These can be used alone or in combination of two or more.
• binder examples include fats and oils such as hydrogenated tallow oil, hydrogenated oil, hydrogenated vegetable oil, hydrogenated vegetable oil, soybean hydrogenated oil, carnauba wax, salix beeswax, beeswax, and mokuro, as well as methylcellulose, hydroxypropylcellulose, hypromellose, and carme.
• fats and oils such as hydrogenated tallow oil, hydrogenated oil, hydrogenated vegetable oil, hydrogenated vegetable oil, soybean hydrogenated oil, carnauba wax, salix beeswax, beeswax, and mokuro, as well as methylcellulose, hydroxypropylcellulose, hypromellose, and carme.
• Sodium loin, 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.
• lubricant examples 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.
• plasticizer examples 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.
• the film forming agent examples 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.
• the powder includes organic powder or inorganic powder 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.
• 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 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.
• corrigent examples include limonene, pinene, camphene, cymen, cineole, citronellol, geraniol, nerol, linalool, menthol, terpineol, rosinol, borneol, isoborneol, menthone, camphor, eugenol, synzeylanol and the like.
• sweetener examples include aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, and saccharin sodium, 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.
• the pharmaceutical composition when it is a solid preparation, it can be produced by appropriately combining unit operations such as crushing, mixing, granulating, drying, sizing, classifying, 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., pitabastatin or a salt thereof or a solvate thereof, ezetimib or a salt thereof or a solvate thereof.
• excipients such as binders, disintegrating agents, formulation additives such as lubricants, etc.
• extrusion granulation, tumbling granulation, stirring Granulation by a known granulation method such as granulation, fluidized bed granulation, spray granulation, melt granulation, crush granulation to obtain a granulated product, and further classifying and sizing as necessary. It can be manufactured.
• the obtained granulated product can be coated with a coating agent or the like by a known method.
• 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.
• appropriate formulation additives such as lubricants, mixing all or part of these components to obtain a mixture, and directly compressing (tabletting) (direct powder compression method)
• the granules can be produced by classifying, sizing, etc. as necessary and then compressing (tabletting) (semi-dry granule compression method, dry granule compression method, wet granule compression method, etc.).
• the obtained compressed product (tablet) can be coated with a coating agent or the like by a known method.
• the dosage form of the pharmaceutical composition is a capsule, the above-mentioned granulated product or compressed product may be filled in the capsule.
• the pharmaceutical composition may be further contained in an airtight package (hereinafter, in the present specification, the one in which the pharmaceutical composition is contained in the airtight package is referred to as “pharmaceutical product”). ).
• an airtight package the one in which the pharmaceutical composition is contained in the airtight package is referred to as “pharmaceutical product”.
• the drug product may further include a package that does not correspond to the following “airtight package”, and the pharmaceutical composition is directly or indirectly contained in the airtight package. It should have been done.
• 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 Pharmacopoeia General Rules. It is a concept that includes "airtight container” and "sealed container".
• airtight package any of a fixed form and an indeterminate form can be used, and specifically, for example, bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, etc. Is 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 this is further 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 and other polyesters; polyethylene (low density (LDPE), medium density (MDPE), high density (HDPE)).
• Materials such as polypropylene, polyolefins such as polypropylene; polycarbonates, polystyrenes, etc.), metals (aluminum, etc.), and the like, which are used in the fields of pharmaceuticals, foods, etc., may be used alone or in combination of two or more as appropriate. it can.
• 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.
• 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.
• LDPE low density polyethylene
• HDPE high density polyethylene
• polypropylene are particularly preferable.
• 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 number of pharmaceutical compositions to be stored, and the capacity of the bottle is, for example, about 10 to 500 mL, preferably 14 to 400 mL, and preferably 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
• SP packaging PTP packaging, pillow packaging, stick packaging, etc.
• the packaging material Can also have a multilayer structure in which they are appropriately combined.
• a method for forming a multilayer structure using two or more types of packaging materials as a sheet there is 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 laminating, dry laminating, coextrusion laminating, thermal laminating, wet laminating, non-solvent laminating or heat laminating.
• known commercial products can be used as the SP packaging, PTP packaging, pillow packaging and stick packaging sheets.
• a PVC sheet, a CPP sheet, etc. are mentioned as a single-layer sheet using one type of packaging material, and a sheet structure of a laminated sheet using two or more types of packaging materials is, for example, Laminated PVC and PVDC (PVC/PVDC; hereinafter abbreviated in the same manner), 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 on the left uses two or more types of CPP), but is limited to these. It is not something that will be done.
• PTP packaging for example, one or one dosage unit of the pharmaceutical composition is stored in a pocket formed in a desired number on 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 may be mentioned that the sheet is used as a lid material to cover the sheet.
• the sheet forming the pocket may be a so-called double-sided aluminum PTP packaging using a sheet made of aluminum foil as a constituent material.
• the PTP packaging is further packaged in pillow packaging (for example, aluminum pillow packaging) from the viewpoint of suppressing an increase in the degradation products derived from pitavastatin.
• a pharmaceutical composition may be packaged one by one or by one administration unit using a resin sheet or a sheet having an aluminum foil as a constituent material by a known method. Can be mentioned.
• a sheet made of aluminum foil 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.
• the occupation rate (volume ratio) of the pharmaceutical composition in the medicine in the package is usually 25 to 90%, preferably 28 to 75%, when the package is a bottle. 30 to 50% is more preferable.
• 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%. ..
• the occupancy rate means the occupancy rate of the pharmaceutical composition with respect to the total volume inside the package, and a filling material or a stopper for preventing damage to the pharmaceutical composition stored inside the package. Etc. are not considered when calculating the space occupancy.
• 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 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.
• Examples of commercially available pillow packages include Lamizip (registered trademark) (manufactured by Manufacturing Japan Co., Ltd.) and the like.
• packaging materials for SP packaging PTP packaging, pillow packaging and stick packaging
• Sumilite VSS Sumilite VSL, Sumilite NS, Sumilite FCL (above, Sumitomo Bakelite Co., Ltd.), TAS series (Taisei Chemicals Co., Ltd.) Products
• vinyl foil for PTP super foil for PTP (all manufactured by Mitsubishi Plastics Co., Ltd.)
• nippaku aluminum foil manufactured by Nippon Foil Co., Ltd.
• aluminum foil silver plain manufactured by Daiwa Chemical Industry Co., Ltd.
• the method for accommodating the pharmaceutical composition in the airtight package is not particularly limited, and it can be achieved by placing the pharmaceutical composition in the package by an appropriate means such as introducing the pharmaceutical composition into the package.
• a means may be used in which a desiccant (for example, a columnar (tablet type) or sheet type) is put into the package together with the pharmaceutical composition.
• 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.
• pitavastatin or a salt thereof or a solvate thereof has an 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.
• 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.
• a therapeutic agent for familial hypercholesterolemia a therapeutic agent for homozygous cytosterolemia, and the like.
• 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 lipemia, a therapeutic agent for hypercholesterolemia and the like.
• 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 a preventive and/or therapeutic agent for dyslipidemia, More preferably, prevention of hypercholesterolemia (hyperLDL hypercholesterolemia) (eg, primary hypercholesterolemia, secondary hypercholesterolemia, familial hypercholesterolemia), mixed dyslipidemia, etc.
• hypercholesterolemia hypercholesterolemia
• a therapeutic agent and/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 (primary hypercholesterolemia) and mixed dyslipidemia.
• the route of administration of the pharmaceutical composition of the present invention is not particularly limited, and can be appropriately examined and determined depending on the disease to be applied, the type of formulation, the sex of the recipient, age, symptoms, etc., but the ease of administration From the viewpoint of, oral administration is preferable.
• the pharmaceutical composition of the present invention can be taken 1 to 4 times per day before meals, between meals, after meals, before bedtime and the like.
• [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, 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 one of [1A] to [6A] which is a prophylactic and/or therapeutic agent for a disease selected from the group consisting of idiopathic hypercholesterolemia and mixed dyslipidemia The described pharmaceutical composition.
• [8A] A pharmaceutical product in which the pharmaceutical composition according to any one of [1A] to [7A] is contained in an airtight package.
• the airtight package is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging.
• [2B] The method according to [1B], wherein the component (A) is a calcium salt of pitavastatin (preferably a hemicalcium salt) or a hydrate thereof.
• the component (B) is ezetimibe.
• [4B] The method according to any one of [1B] to [3B], wherein the pharmaceutical composition is a solid preparation.
• 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.
• the pharmaceutical composition is a preventive and/or therapeutic agent for a disease selected from the group consisting of idiopathic hypercholesterolemia and mixed dyslipidemia, [1B] to [1B] 6B].
• [8B] The method according to any one of [1B] to [7B], which further comprises a step of containing the pharmaceutical composition in an airtight package.
• the order of the step 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 are not particularly limited.
• (B) may be contained in the pharmaceutical composition in any order and then contained in an airtight package, or 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.
• the airtight package is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging.
• the amounts (parts by mass) of various components are the amounts obtained by weighing the various components as they are, unless the converted amount is specified.
• Example 1 Pitavastatin calcium (pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.) was used as it was as sample 1.
• Sample 2 Sample 2 was prepared by mixing 5 parts by mass of ezetimibe (Glenmark Pharmaceuticals) with 1 part by mass of pitavastatin calcium (Pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.).
• Sample 3 After mixing 5 parts by mass of Ezetimibe (manufactured by Glenmark Pharmaceuticals) 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: It was put into Isoya Glass Industry Co., Ltd. and covered with a lid, and this was used as sample 3.
• 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.
• sample 2 in which pitavastatin calcium and ezetimibe were mixed showed a lower increase rate of the decomposition product of pitavastatin than sample 1 containing only pitavastatin calcium, and was stored at 80° C. for 3.5 days. It was confirmed that the subsequent increase in the degradation product of pitavastatin was suppressed. From the above test results, it was revealed that coexistence of pitavastatin or a salt thereof or a solvate thereof and ezetimibe or a salt thereof or a solvate thereof can suppress an increase in a degradation product derived from pitavastatin.
• Example 4 Pitavastatin calcium (Pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.) 100 mg is put into a polypropylene tube (slim tube: manufactured by Sumitomo Bakelite Co., Ltd.) and the lid is closed. This is further covered with an aluminum bag (Lamizip AL-E: Sample 4 was put in a product manufactured by Japan Co., Ltd. and sealed.
• Sample 5 After mixing 1 part by mass of pitavastatin calcium (Pitavastatin calcium: manufactured by Nissan Chemical Industries, Ltd.) with 5 parts by mass of Ezetimibe (manufactured by Hangzhou heta Pharm&Chem), 150 mg of the resulting 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.
• 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 the related substances of pitavastatin before the start of storage and after storage at 60° C. for 2 weeks for each of the obtained samples, the increase rate (%) of the degradation product derived from pitavastatin for each sample was calculated according to the following formula. ) Was calculated.
• a pharmaceutical composition containing a combination of pitavastatin and ezetimibe which is useful as an active ingredient of a therapeutic agent for hyperlipidemia, a therapeutic agent for hypercholesterolemia, etc., and is excellent in storage stability. It can be used in the pharmaceutical industry.

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• 2019
  • 2019-03-01 JP JP2021503235A patent/JPWO2020178878A1/ja active Pending
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