WO2020111089A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO2020111089A1
WO2020111089A1 PCT/JP2019/046268 JP2019046268W WO2020111089A1 WO 2020111089 A1 WO2020111089 A1 WO 2020111089A1 JP 2019046268 W JP2019046268 W JP 2019046268W WO 2020111089 A1 WO2020111089 A1 WO 2020111089A1
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Prior art keywords
pharmaceutical composition
weight
parts
composition according
coating
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PCT/JP2019/046268
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English (en)
Japanese (ja)
Inventor
見二 岩田
誠 蔵本
和徳 小阪
Original Assignee
協和キリン株式会社
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Application filed by 協和キリン株式会社 filed Critical 協和キリン株式会社
Priority to KR1020217019409A priority Critical patent/KR20210096162A/ko
Priority to CN201980077536.4A priority patent/CN113164436A/zh
Priority to JP2020557755A priority patent/JPWO2020111089A1/ja
Publication of WO2020111089A1 publication Critical patent/WO2020111089A1/fr

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    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition, and more particularly to a pharmaceutical composition containing bardoxolone methyl or a pharmaceutically acceptable salt thereof.
  • bardoxolone methyl represented by the following formula (Methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate) (hereinafter sometimes referred to as "Compound A”) Is known (see Patent Document 1), and its bardoxolone methyl is known to have a polymorphic form (see Patent Document 2).
  • Bardoxolone methyl is a small molecule compound that activates the transcription factor Nrf2, which plays a central role in the stress defense reaction in the body, has a wide range of antioxidant stress and anti-inflammatory effects, and is used in preclinical studies and human clinical studies. Tests have shown to have effective anti-inflammatory and antitumor effects.
  • bardoxolone methyl shows significant anticancer activity in patients with advanced cancer, and also in renal function, insulin resistance, glycemic control measurements, and systemic system in patients with chronic kidney disease due to type 2 diabetes. It is also known to have the ability to improve cardiovascular disease (see Patent Document 3).
  • clinical studies have shown that administration of bardoxolone methyl significantly improves the eGFR level (index of renal function) (see Non-Patent Document 1, Non-Patent Document 2, and Non-Patent Document 3). ..
  • the present invention provides a stable pharmaceutical composition which contains bardoxolone methyl or a pharmacologically acceptable salt thereof and is pharmaceutically acceptable.
  • the present invention relates to the following (1) to (26).
  • a pharmaceutical composition having a coating film, containing bardoxolone methyl or a pharmaceutically acceptable salt thereof, a disintegrating agent, and a binder.
  • the disintegrant is one selected from the group consisting of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, partially pregelatinized starch, and starch.
  • the above is the pharmaceutical composition according to (1).
  • the pharmaceutical composition according to (2), wherein the disintegrant is one or more selected from the group consisting of crospovidone, croscarmellose sodium, and low-substituted hydroxypropylcellulose.
  • the binder is hydroxypropyl cellulose, methyl cellulose, hypromellose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl starch, carboxy vinyl polymer, polyvinyl pyrrolidone, polyvinyl pyrrolidone.
  • any one of (1) to (4) which is one or more selected from the group consisting of vinyl acetate copolymer, polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol, starch, gelatin, dextrin, pullulan, agar, and gum arabic.
  • a pharmaceutical composition according to the above. (6) The pharmaceutical composition according to (5), wherein the binder is one or more selected from the group consisting of hydroxypropylcellulose, hypromellose, polyvinyl alcohol, and polyvinylpyrrolidone.
  • Coating The coating film contains one or more coating agents selected from the group consisting of water-soluble polymers, lactose, sucrose, mannitol, titanium oxide, talc, calcium carbonate, and triacetin, (1) to (10) The pharmaceutical composition according to any one of 1.
  • the water-soluble polymer is one selected from the group consisting of polyethylene glycol, polyvinyl alcohol polyethylene glycol graft copolymer, polyvinylpyrrolidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, and polyvinyl alcohol methyl acrylate methacrylate copolymer.
  • the above is the pharmaceutical composition according to (11).
  • the colorant contains one or more selected from the group consisting of yellow ferric oxide, iron oxide, and titanium oxide.
  • the brightening agent is carnauba wax and/or magnesium stearate.
  • a blister package comprising the pharmaceutical composition according to any one of (1) to (21), a film laminated with a polymer, and an aluminum foil.
  • a pharmaceutical composition having a coating film containing bardoxolone methyl or a pharmacologically acceptable salt thereof, a disintegrating agent, and a binder, whereby bardoxolone methyl or The stability of the pharmacologically acceptable salt can be improved.
  • the pharmaceutical composition of the present invention has a coating film containing bardoxolone methyl (hereinafter sometimes referred to as “compound A”) or a pharmaceutically acceptable salt thereof, a binder, and a disintegrant. It is a pharmaceutical composition.
  • compound A bardoxolone methyl
  • the chemical structure of Compound A is as described above, and it can be produced by the method disclosed in International Publication No. 1999/65478 (Patent Document 1) or a method analogous thereto.
  • pharmaceutically acceptable refers to generally useful for preparing pharmaceutical compositions that are safe, non-toxic, and not biologically or otherwise undesirable. Is meant and includes acceptance for veterinary applications as well as human pharmaceutical applications.
  • the “pharmaceutically acceptable salt” means a salt which is pharmaceutically acceptable as defined above and has a desired pharmacological activity.
  • Such salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or acid addition salts formed with organic acids such as maleic acid, methanesulfonic acid, and oxalic acid. Is mentioned.
  • Pharmaceutically acceptable salts also include base addition salts that can be formed when the acidic protons present can react with inorganic or organic bases.
  • Pharmaceutically acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide.
  • Examples of the pharmaceutically acceptable organic base include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
  • Examples of the pharmaceutically acceptable salt of Compound A include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and organic base salts such as amine salt.
  • the compound A of the present invention or a pharmaceutically acceptable salt thereof includes any of its inner salt, adduct, solvate thereof, hydrate and the like.
  • Some compound A or a pharmaceutically acceptable salt thereof may have geometrical isomers, stereoisomers such as optical isomers, tautomers and the like, and the present invention includes these. , All possible isomers and mixtures thereof.
  • each atom in Compound A or a pharmaceutically acceptable salt thereof may be replaced with a corresponding isotope atom, and the present invention also includes a derivative in which these isotope atoms are replaced. ..
  • the compound A or a pharmaceutically acceptable salt thereof of the present invention also includes an active metabolite of the compound A (active metabolites include, for example, various conjugates) or a pharmaceutically acceptable salt thereof. Include.
  • the content of compound A or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 0.1 to 20 relative to 100 parts by weight of the pharmaceutical composition. Parts by weight, more preferably 1 to 20 parts by weight, further preferably 2 to 15 parts by weight, particularly preferably 2 to 10 parts by weight.
  • Compound A may be crystalline (Form A), amorphous (Form B) or a mixture thereof, but according to a preferred embodiment of the present invention, Compound A is mainly amorphous (form). B), and preferably 50 parts by weight to 100 parts by weight, more preferably 80 parts by weight to 99.9 parts by weight, more preferably 95 parts by weight, of amorphous (form B) with respect to 100 parts by weight of compound A It is more preferable that the amount is from about 99 parts by weight.
  • compound A is an amorphous solid dispersion in a glassy matrix, for example by spray drying a solution or suspension of a mixture of compound A and a methacrylic acid copolymer.
  • Such a solid dispersion is preferably a mixture of compound A and a methacrylic acid copolymer mixed in a weight ratio of 4:6, more preferably a product obtained by spray drying the mixture of compound A and a methacrylic acid copolymer. Is mentioned.
  • a variety of preparative techniques can be used to obtain amorphous solid dispersions of Compound A.
  • Suitable methods of producing solid dispersions of amorphous Compound A include various conventional thermal methods (eg, hot melt extrusion), solvent methods, and thermal/solvent methods (eg, spray drying of granules). Or a fluidized immersion method).
  • thermal methods eg, hot melt extrusion
  • solvent methods e.g, solvent methods
  • thermal/solvent methods eg, spray drying of granules.
  • a fluidized immersion method e.g., spray drying of granules.
  • a fluidized immersion method e.g., spray drying of granules.
  • stability of amorphous drug in solid dispersion is described. From the viewpoint of the above, it is desirable that the glass transition point of the solid dispersion is high.
  • the exhaust temperature at the time of spray drying is preferably equal to or lower than the glass transition point of the solid dispersion (see page 195 of Reference Document 1).
  • typical solvents used for the solid dispersion by the spray drying method include water, methanol, ethanol, acetone, dichloromethane and the like, and an appropriate solvent is selected from these depending on the drug and the carrier. It is described that it is desirable that the drug concentration of the spray solution be 50 mg/mL or more, because it is possible to improve the production efficiency when the drug and the carrier are dissolved in a high concentration (see Reference 1 at page 196).
  • the pharmaceutical composition of the present invention typically comprises a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the “therapeutically effective” amount is an amount that can obtain a desired pharmacological effect when the pharmaceutical composition of the present invention is administered to a patient.
  • a therapeutically effective amount can be empirically determined by reference to the patient's clinical parameters.
  • the disintegrant contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medicine.
  • a PVP disintegrant such as crospovidone; croscarmellose sodium, low-substituted hydroxypropylcellulose.
  • Cellulose-based disintegrators such as carboxymethyl cellulose and carboxymethyl cellulose calcium; starch-based disintegrators such as carboxymethyl starch sodium, partially pregelatinized starch, and starch, and preferably crospovidone, croscarmellose sodium, low-substituted.
  • One or more selected from the group consisting of agents more preferably one or more selected from the group consisting of crospovidone, croscarmellose sodium, and low-substituted hydroxypropylcellulose, and more preferably cross.
  • the low-substituted hydroxypropyl cellulose is a low-substituted hydroxypropyl ether of cellulose, and the dried low-substituted hydroxypropyl cellulose has a hydroxypropoxy group (-OC 3 H 6 OH:75) when quantified. 0.09) 5.0 to 16.0% is included.
  • the content of the disintegrant in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine, but it may be 0.1 to 20 parts by weight per 100 parts by weight of the pharmaceutical composition. It is more preferable to contain 0.1 to 18 parts by weight, more preferably 0.1 to 15 parts by weight.
  • the binder contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medicine, but preferably hydroxypropyl cellulose, hypromellose (hydroxypropyl methyl cellulose), methyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, Hydroxyethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl starch, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol, starch (more preferably corn starch.
  • Potato starch gelatin, dextrin, pullulan, agar, and gum arabic, and more preferably selected from the group consisting of hydroxypropylcellulose, hypromellose, polyvinyl alcohol, and polyvinylpyrrolidone. At least one of them, more preferably hydroxypropyl cellulose or hypromellose, particularly preferably hypromellose.
  • the content of the binder in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine, but it should be 0.1 to 30 parts by weight per 100 parts by weight of the pharmaceutical composition. Is preferred, more preferably 0.5 to 25 parts by weight, still more preferably 3 to 20 parts by weight.
  • the pharmaceutical composition of the present invention may contain other additives used as pharmaceuticals in addition to the compound A, the disintegrating agent, and the binder.
  • stabilizers used in pharmaceutical preparations and excipients may contain one or more additives selected from the group consisting of agents, lubricants, colorants, superplasticizers, and brighteners.
  • the stabilizers, excipients, lubricants, colorants, superplasticizers, and brighteners in the present specification are not limited to the uses (functions) described, but may be used for other uses (functions). Can also be used (eg, using a binder as an excipient, using an excipient as a binder, etc.).
  • the stabilizer contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medicine, and examples thereof include organic acids and calcium carbonate, and preferably organic acids. ..
  • examples of the organic acid contained in the pharmaceutical composition of the present invention include fumaric acid, malic acid, citric acid, citric acid hydrate, citric acid anhydride, succinic acid, adipic acid, tartaric acid, and maleic acid. Fumaric acid and/or malic acid are preferred, and fumaric acid is more preferred.
  • the content of the stabilizer (preferably, organic acid) in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount that can be used as a medicine, but relative to 100 parts by weight of the pharmaceutical composition,
  • the stabilizer is preferably contained in an amount of 0.01 to 30 parts by weight, more preferably 0.05 to 10 parts by weight, still more preferably 0.1 to 5 parts by weight.
  • the excipient contained in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine.
  • Crystalline cellulose inorganic salts and the like, and preferably lactose, sucrose, maltose, sucrose, mannitol, sorbitol, erythritol, maltitol, xylitol, glucose, crystalline cellulose, silicic acid-treated crystalline cellulose, calcium monohydrogen phosphate, phosphorus.
  • Calcium dihydrogen acid, sodium dihydrogen phosphate, and calcium phosphate may be used in combination of two or more kinds thereof, more preferably lactose (preferably lactose hydrate), mannitol, silicic acid treatment It is crystalline cellulose, and these excipients may be used in combination of two or more kinds.
  • the content of the excipient in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine, but the excipient content is 0.1% with respect to 100 parts by weight of the pharmaceutical composition. It is preferably contained in an amount of 9 to 99.9 parts by weight, more preferably 1 to 95 parts by weight, still more preferably 10 to 90 parts by weight.
  • the lubricant contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medicine, for example, magnesium stearate, calcium stearate, sodium lauryl sulfate, talc, glyceryl monostearate, light anhydrous.
  • Silicic acid, sodium stearyl fumarate, sucrose fatty acid esters eg, sucrose stearate ester, sucrose palmitate ester, sucrose oleate ester, sucrose laurate ester, etc.
  • the above lubricants may be used in combination.
  • the content of the lubricant in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine, but it should be 0.05 to 10 parts by weight with respect to 100 parts by weight of the pharmaceutical composition. Is preferred, more preferably 0.1 to 5 parts by weight, even more preferably 0.5 to 3 parts by weight.
  • the colorant contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medicine, but yellow iron sesquioxide, titanium oxide, talc, iron sesquioxide, black iron oxide, iron oxide, copper chlorophyll. , Sodium copper chlorophyllin, carbon black, medicinal charcoal, food dye, licorice extract, green tea powder, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, and octyldodecyl myristate are preferred. More preferably, at least one selected from the group consisting of yellow ferric oxide, iron oxide, and titanium oxide is included.
  • the content of the colorant in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine, but is, for example, 0.01 to 5 parts by weight relative to 100 parts by weight of the pharmaceutical composition. You can
  • the fluidizing agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medicine, for example, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, synthetic hydrotalcite, dried.
  • examples thereof include aluminum hydroxide gel, kaolin, calcium silicate, magnesium aluminometasilicate, talc, and the like, and two or more kinds of these fluidizing agents may be used in combination.
  • the content of the superplasticizer in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine, but is, for example, 0.01 to 5 parts by weight relative to 100 parts by weight of the pharmaceutical composition. Can be included.
  • the brightening agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medicine, and examples thereof include carnauba wax, shellac, beeswax, hardened oil, magnesium stearate, and the like.
  • the above brighteners may be used in combination, preferably carnauba wax and/or magnesium stearate.
  • the content of the brightening agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine, but is contained in 0.0001 parts by weight to 100 parts by weight per 100 parts by weight of the pharmaceutical composition. It is preferable that it is contained in an amount of 0.001 to 10 parts by weight, more preferably 0.01 to 1 part by weight.
  • the pharmaceutical composition of the present invention has a coating film.
  • This coating film can be provided by, for example, coating a plain preparation (for example, a plain tablet) containing Compound A or a pharmaceutically acceptable salt thereof, a disintegrating agent, and a binder. ..
  • the coating treatment can be carried out, for example, by spraying a coating solution containing a coating agent onto a plain preparation (for example, plain tablet) containing the compound A by a spray coating method or the like.
  • the coating agent is used by dissolving, suspending, dispersing, etc. in the coating liquid, and examples of the solvent constituting the coating liquid include water and alcohols such as methanol and ethanol. More preferably.
  • the coating film of the pharmaceutical composition of the present invention is not particularly limited, but preferably one or more selected from the group consisting of water-soluble polymers, lactose, sucrose, mannitol, titanium oxide, talc, calcium carbonate, and triacetin. It contains a coating agent, and more preferably contains triacetin.
  • the water-soluble polymer is not particularly limited as long as it is used as a medicine, but preferably polyethylene glycol, polyvinyl alcohol polyethylene glycol graft copolymer, polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, and polyvinyl alcohol methacrylic acid acrylate. It is one or more selected from the group consisting of acid methyl copolymers.
  • the coating film of the pharmaceutical composition of the present invention preferably further contains a coloring agent, and the coloring agent contains one or more selected from the group consisting of yellow ferric oxide, iron oxide, and titanium oxide. It is more preferable that it contains.
  • the coating agent in the coating film is not particularly limited, but is preferably 0.1 part by weight to 100 parts by weight, more preferably 1 part by weight to 95 parts by weight, and more preferably 50 parts by weight with respect to 100 parts by weight of the coating film. It is more preferable to include from 90 parts by weight to 90 parts by weight.
  • the amount of the coating liquid used in the coating treatment is not particularly limited as long as it is an amount capable of imparting photostability and the like to the pharmaceutical composition. Is preferably 0.01 part by weight to 50 parts by weight, more preferably 0.05 parts by weight to 30 parts by weight, and further preferably 0.1 parts by weight to 20 parts by weight. preferable.
  • the pharmaceutical composition of the present invention preferably further comprises a brightening agent, more preferably carnauba wax and/or magnesium stearate as the brightening agent.
  • the pharmaceutical composition of the present invention is preferably an oral preparation, and flavoring agents and the like can be further added.
  • the shape of the pharmaceutical composition of the present invention is not particularly limited, but it is preferably a solid preparation, more preferably a tablet, a powder, a fine granule, a granule, a capsule or a dry syrup, and a tablet. More preferably.
  • a tablet By forming the pharmaceutical composition of the present invention into a tablet, it has the advantages that it is easy to take, has sufficient physical strength, and is less likely to be crushed than a capsule.
  • the production method includes granulating a mixture containing bardoxolone methyl or a pharmaceutically acceptable salt thereof as an active ingredient, a disintegrating agent, and a binder, It is manufactured through tableting and a film coating process.
  • the method for producing the pharmaceutical composition of the present invention is not particularly limited, but it can be produced by a method generally used in the technical field of pharmaceutics such as compression molding, for example, direct compression method. Or dry granule compression method (roller compression molding method, slag tableting method, etc.) and the like.
  • a method of mixing the compound A or a pharmaceutically acceptable salt thereof, and additives such as a disintegrant and a binder, and granulating and sizing as necessary is preferable. Then, for example, when a tablet is prepared, the obtained dried granulation product is used to form a tablet using a compression tableting machine.
  • the tableting pressure can be appropriately selected from the range of 300 to 3000 kg/cm 2 , for example.
  • the tablet size is not particularly limited, but it is preferable that the weight per tablet is 20 to 3000 mg and the tablet diameter is 5 to 15 mm.
  • the uncoated tablet thus obtained can be coated with a solution/dispersion solution in which a coating agent is dissolved/dispersed to form a coating.
  • the solvent that dissolves/disperses the coating agent include water, ethanol, isopropyl alcohol, and a mixed solvent thereof. Among these, water is preferable.
  • the coating is performed using, for example, a conventional pan-type coating machine, an aeration type coating machine, a fluidized bed type coating apparatus, a rolling fluid type coating apparatus and the like.
  • 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included in 100 parts by weight of the pharmaceutical composition
  • 0.1 to 30 parts by weight of a binder preferably hypromellose
  • a disintegrating agent preferably low-substituted hydroxypropylcellulose
  • a coating agent preferably, the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin
  • 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included in 100 parts by weight of the pharmaceutical composition
  • 0.1 to 30 parts by weight of a binder preferably hypromellose
  • a disintegrating agent preferably low-substituted hydroxypropylcellulose
  • a brightening agent preferably carnauba wax and/or magnesium stearate
  • a coating agent preferably, the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin
  • 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included in 100 parts by weight of the pharmaceutical composition
  • 0.1 to 30 parts by weight of a binder preferably hypromellose
  • a disintegrating agent preferably low-substituted hydroxypropylcellulose
  • 0.01 to 30 parts by weight of a stabilizer preferably an organic acid, more preferably fumaric acid
  • a brightening agent preferably carnauba wax and/or magnesium stearate
  • 0.1 to 100 parts by weight of a coating agent preferably, the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin
  • composition of the present invention 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included in 100 parts by weight of the pharmaceutical composition,
  • a binder preferably hypromellose
  • a disintegrant preferably low-substituted hydroxypropylcellulose
  • a coating agent preferably, the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin
  • a composition preferably a tablet).
  • compositions of the present invention are: 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included in 100 parts by weight of the pharmaceutical composition,
  • a binder preferably hypromellose
  • a disintegrant preferably low-substituted hydroxypropylcellulose
  • a brightening agent preferably carnauba wax and/or magnesium stearate
  • a coating agent preferably, the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin
  • composition of the present invention is: 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included in 100 parts by weight of the pharmaceutical composition,
  • a binder preferably hypromellose
  • a disintegrant preferably low-substituted hydroxypropylcellulose
  • a stabilizer preferably an organic acid, more preferably fumaric acid
  • a brightening agent preferably carnauba wax and/or magnesium stearate
  • 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included in 100 parts by weight of the pharmaceutical composition
  • 3 to 20 parts by weight of a binder is included in 100 parts by weight of the pharmaceutical composition
  • 0.1 to 15 parts by weight of a disintegrant is included per 100 parts by weight of the pharmaceutical composition
  • 50 to 90 parts by weight of a coating agent preferably, the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin
  • a composition preferably a tablet).
  • composition of the present invention is: 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included in 100 parts by weight of the pharmaceutical composition, 3 to 20 parts by weight of a binder (preferably hypromellose) is included in 100 parts by weight of the pharmaceutical composition, 0.1 to 15 parts by weight of a disintegrant (preferably a low-substituted hydroxypropylcellulose) is included per 100 parts by weight of the pharmaceutical composition, 0.01 to 1 part by weight of a brightening agent (preferably carnauba wax and/or magnesium stearate) per 100 parts by weight of the pharmaceutical composition, 50 to 90 parts by weight of a coating agent (preferably, the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) based on 100 parts by weight of the coating film. It is a composition (preferably a tablet).
  • composition of the present invention is: 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included in 100 parts by weight of the pharmaceutical composition, 3 to 20 parts by weight of a binder (preferably hypromellose) is included in 100 parts by weight of the pharmaceutical composition, 0.1 to 15 parts by weight of a disintegrant (preferably a low-substituted hydroxypropylcellulose) is included per 100 parts by weight of the pharmaceutical composition, A stabilizer (preferably an organic acid, more preferably fumaric acid) is contained in an amount of 0.1 to 5 parts by weight based on 100 parts by weight of the pharmaceutical composition, 0.01 to 1 part by weight of a brightening agent (preferably carnauba wax and/or magnesium stearate) per 100 parts by weight of the pharmaceutical composition, 50 to 90 parts by weight of a coating agent (preferably, the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) based on 100 parts by weight of the pharmaceutical composition, 3
  • bardoxolone methyl or a pharmaceutically acceptable salt thereof is added with a disintegrating agent and a binder, and coating coating treatment is performed. Methods for improving the stability of pharmaceutically acceptable salts are provided. Further, according to another preferred embodiment of the present invention, bardoxolone is characterized in that a disintegrating agent and a binder are added to bardoxolone methyl or a pharmaceutically acceptable salt thereof and a coating film treatment is carried out. Provided is a method for reducing the total amount of related substances of methyl or a pharmaceutically acceptable salt thereof.
  • additives used as pharmaceuticals may be added in the same manner as the above-mentioned pharmaceutical composition of the present invention.
  • One or more additives selected from the group consisting of stabilizers, excipients, lubricants, colorants, superplasticizers and brighteners used may be added.
  • the pharmaceutical composition of the present invention can be provided in an airtight container such as bottle packaging, blister packaging, and aluminum bag.
  • the material of the airtight container is not particularly limited as long as it can suppress the invasion of moisture from the outside, and a material used for the purpose of preventing moisture in contents sensitive to moisture in the field of pharmaceuticals can be used. Of these, blister-packed products are particularly preferable.
  • the blister packaged product of the present invention comprises a pharmaceutical composition containing the compound A, etc., and a film laminated with a polymer and an aluminum foil.
  • the film laminated with the polymer is not particularly limited as long as it is generally used for blister packaging, but polypropylene, polyvinyl chloride, polyvinylidene chloride, trifluoroethylene chloride (Aclar (trademark)), etc.
  • a film laminated with the above polymer is preferable, and polypropylene or hard vinyl chloride is more preferable.
  • the aluminum foil is not particularly limited as long as it is used for blister packaging, and may be a general-purpose general-purpose aluminum foil, but an aluminum foil having a reduced amount of melamine resin in the adhesive is preferable. ..
  • the method for producing the blister packaged product of the present invention is not particularly limited, but a pocket is formed in the film laminated with the polymer using a commonly used blister packaging machine, a tablet is charged, and aluminum is used. It is obtained by sealing the foil with heat or the like.
  • the pharmaceutical packaged product of the present invention is obtained by enclosing the blister packaged product in a package.
  • the package is not particularly limited as long as it is generally used for pharmaceutical packaging, but an aluminum bag or the like is preferable.
  • the medicinal packaged product may be simultaneously encapsulated with a general medicinal packaged product, and it is preferable to enclose an oxygen absorber and/or a desiccant together with the blister packaged product.
  • the pharmaceutical packaged product of the present invention can be produced by enclosing the blister packaged product produced as described above in a package such as an aluminum bag and sealing the package using a heat sealing machine or the like.
  • the coating agent mixture was dispersed in water to prepare a coating liquid having a solid content concentration of 10% by weight (the composition of the coating agent mixture is shown in Table 2 below).
  • a tablet coating machine PRC-7, manufactured by Paulec Co., Ltd.
  • coating was performed by spraying the coating liquid on 100 parts by weight of the plain tablets so that the coating was 5 parts by weight in a dry state. .. Carnauba wax in an amount of 0.03% by weight with respect to the uncoated tablets was sprinkled on the uncoated tablets to give a desired tablet.
  • Prescription example 2 500.0 g of a solid dispersion containing 40% by weight of Compound A (bardoxolone methyl) (manufactured by a spray-drying method, the following "solid dispersion” was manufactured in the same manner), crystalline silica treated with silicic acid (Prosolv, JRS Pharma).
  • This mixture was subjected to dry granulation and sizing with a roller compactor (CCS-220, manufactured by Paulec Co., Ltd.). An amount of 0.38% by weight of magnesium stearate was added to the obtained sized product and mixed to obtain a tableting mixture. Tablets (weight: 130 mg, tablet shape: circular shape (7 mm diameter)) were manufactured using a rotary tableting machine (HT-AP15, Hata Tekko Co., Ltd.) to prepare a plain tablet containing 5 mg of Compound A (Formulation Example 2). ) (See Table 3).
  • the coating agent mixture was dispersed in water to prepare a coating liquid having a solid content concentration of 10% by weight (the composition of the coating agent mixture is shown in Table 4 below).
  • a tablet coating machine PRC-7, manufactured by Paulec Co., Ltd.
  • coating was performed by spraying the coating liquid on 100 parts by weight of the plain tablets so that the coating was 5 parts by weight in a dry state. .. Carnauba wax in an amount of 0.03% by weight with respect to the uncoated tablets was sprinkled on the uncoated tablets to give a desired tablet.
  • Prescription example 3 A mixed product was prepared in the same manner as in 5 mg tablet formulation example 2 and tableted (weight: 260 mg, tablet shape: circular shape (9 mm diameter)) using a rotary tableting machine (HT-AP15, Hata Tekko Co., Ltd.). By doing so, a plain tablet containing 10 mg of Compound A (Formulation Example 3) (see Table 3) was obtained.
  • the coating agent mixture was dispersed in water to prepare a coating liquid having a solid content concentration of 15% by weight (the composition of the coating agent mixture is shown in Table 4 below).
  • Coating of 200 g of uncoated tablets is performed by using a tablet coating machine (DRC-200, manufactured by Paulec Co., Ltd.) to spray 100 parts by weight of uncoated tablets with a coating solution so that the coating is 4 parts by weight in a dry state. It was Carnauba wax in an amount of 0.03% by weight with respect to the uncoated tablets was sprinkled on the uncoated tablets to give a desired tablet.
  • DRC-200 tablet coating machine
  • Prescription example 4 A mixed product was prepared in the same manner as in 5 mg tablet prescription example 2, and was tableted using a rotary tableting machine (HT-AP15, Hata Tekko Co., Ltd.) (weight: 390 mg, tablet shape: oval shape (major axis 13.5 mm). , Short diameter 7 mm)) to obtain a plain tablet containing 15 mg of Compound A (Formulation Example 4) (see Table 3).
  • the coating agent mixture was dispersed in water to prepare a coating liquid having a solid content concentration of 15% by weight (the composition of the coating agent mixture is shown in Table 4 below).
  • a tablet coating machine PRC-7, manufactured by Paulec Co., Ltd.
  • 100 parts by weight of uncoated tablets were sprayed with a coating liquid so that the coating was 3.5 parts by weight in a dry state, thereby performing coating.
  • Carnauba wax in an amount of 0.03% by weight with respect to the uncoated tablets was sprinkled on the uncoated tablets to give a desired tablet.
  • the intended tablet can also be obtained by polishing with magnesium stearate instead of carnauba wax as a brightening agent.
  • the mixture was mixed 200 times inside to obtain a mixture (I) containing the compound A.
  • 631.9 g of crystalline cellulose treated with silicic acid and 11.9 g of light anhydrous silicic acid were mixed 200 times in a plastic bag to obtain a mixture (II).
  • Example 1 Preparation method of uncoated tablet 1 215.0 g of the above mixture (I), 210.5 g of lactose hydrate, 19.5 g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Soda Co., Ltd.), croscarmellose 32.5 g of sodium (Ac-Di-Sol, manufactured by FMC Biopolymer) was mixed 200 times in a plastic bag, and further 2.5 g of magnesium stearate (Parteck LUB, Merck) was added and further mixed 50 times. The obtained mixture was dry granulated by a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.).
  • TF-Labo dry granulator
  • the obtained dry granulated product was sized by a sizing machine (Comill, manufactured by Paulec Co., Ltd.).
  • the obtained sized product 443.1 g, the mixed product (II) 124.6 g and croscarmellose sodium (Ac-Di-Sol, manufactured by FMC Biopolymer) 30.0 g were mixed 200 times in a plastic bag, and further mixed.
  • 2.3 g of magnesium stearate was added and mixed 50 times to obtain a tableting mixture.
  • Uncoated tablet 1 was obtained by tableting (weight 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).
  • Example 2 Preparation method of uncoated tablet 2 148.9 g of the above-mentioned mixture (I), 145.7 g of lactose hydrate, 13.5 g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Soda Co., Ltd.), low substitution degree 22.5 g of hydroxypropyl cellulose (L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed 200 times in a plastic bag, and further 1.7 g of magnesium stearate (Parteck LUB, Merck) was added and further mixed 50 times. The obtained mixture was dry granulated by a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.).
  • TF-Labo dry granulator
  • the obtained dry granulated product was sized by a sizing machine (Comill, Powrex Co., Ltd.).
  • the obtained sized product 295.4 g, the mixed product (II) 83.1 g and low-substituted hydroxypropyl cellulose (L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) 20.0 g were mixed 200 times in a plastic bag.
  • 1.5 g of magnesium stearate was further added and mixed 50 times to obtain a mixture for tableting.
  • Uncoated tablet 2 was obtained by tableting (weight 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).
  • Example 3 Preparation method of uncoated tablet 3 148.9 g of the above-mentioned mixture (I), 145.7 g of lactose hydrate, 13.5 g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Soda Co., Ltd.), starch glycolic acid 22.5 g of sodium (Primogel, DFE Pharma) was mixed 200 times in a plastic bag, and further 1.7 g of magnesium stearate (Partec LUB, Merck) was added and further mixed 50 times. The obtained mixture was dry granulated by a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.).
  • TF-Labo dry granulator
  • the obtained dry granulated product was sized by a sizing machine (Comill, manufactured by Paulec Co., Ltd.).
  • the obtained sized product 295.4 g, the mixed product (II) 83.1 g and sodium starch glycolate (Primogel, DFE Pharma) 20.0 g were mixed 200 times in a plastic bag, and magnesium stearate 1. 5 g was added and mixed 50 times to obtain a mixture for tableting.
  • a plain tablet 3 was obtained by tableting (weight 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, manufactured by Kikusui Seisakusho).
  • Test Example 1 Comparative test of stability of plain tablets 1 to 3 obtained in Examples 1, 2 and 3, bardoxolone methyl analogues were measured by liquid chromatography under the following conditions. did. As a column for liquid chromatography, ACQUITY UPLC HSS C18, particle size 1.8 ⁇ m, 2.1 mm ⁇ 50 mm (manufactured by Waters) or its equivalent was used, and the column temperature was maintained at 40° C.
  • the mobile phase A was 20 mmol/L sodium dihydrogen phosphate/citrate buffer (pH 4.5), and the mobile phase B was acetonitrile.
  • the sample solution was diluted with 65% by weight of acetonitrile so that the concentration of bardoxolone methyl was 100 ⁇ g/mL.
  • the related substances were measured with an ultraviolet absorptiometer (measuring wavelength: 242 nm) at a flow rate of 0.6 mL/min, and the total amount (%) of each related substance with respect to the indicated amount of bardoxolone methyl was determined.
  • the stability test was conducted under the following conditions. Storage conditions: 30° C., 75% RH, 1 month Storage form: Put plain tablets 1 to 3 in a brown bottle with an open lid.
  • Example 4 Preparation method of uncoated tablet 4 Compound A 44.2 g, silicic acid-treated crystalline cellulose 110.4 g, light anhydrous silicic acid 1.8 g, lactose hydrate 176.9 g, hypromellose (TC-5E, Shin-Etsu Chemical Co., Ltd.) (Manufactured by Mitsui Chemicals Co., Ltd.) was mixed 200 times in a plastic bag, 1.8 g of magnesium stearate (Parteck LUB, Merck) was further added and the mixture was further mixed 50 times. The obtained mixture was dry granulated by a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.).
  • TF-Labo dry granulator
  • the obtained dry granulated product was sized by a sizing machine (Comill, manufactured by Paulec Co., Ltd.). 295.4 g of sized product, 81.5 g of crystalline silica treated with silicic acid, 1.5 g of light anhydrous silicic acid, and 20 g of croscarmellose sodium (Ac-Di-Sol, FMC biopolymer) were mixed 200 times in a plastic bag. Then, 1.5 g of magnesium stearate was further added and mixed 50 times to obtain a mixture for tableting.
  • a plain tablet 4 was obtained by tableting (weight 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).
  • Example 5 Method for preparing uncoated tablet 5
  • Compound A 44.2 g, silicic acid-treated crystalline cellulose 90.9 g, light silicic acid 1.8 g, lactose hydrate 159.6 g, hypromellose (TC-5E, Shin-Etsu Chemical Co., Ltd.) 41.4 g) were mixed 200 times in a plastic bag, 1.8 g of magnesium stearate (Parteck LUB, Merck) was further added, and the mixture was further mixed 50 times.
  • the obtained mixture was dry granulated by a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.).
  • the obtained dry granulated product was sized by a sizing machine (Comill, manufactured by Paulec Co., Ltd.). 295.4 g of sized product, 81.5 g of crystalline cellulose treated with silicic acid, 1.5 g of light anhydrous silicic acid, and 20.0 g of croscarmellose sodium (Ac-Di-Sol, FMC biopolymer) 200 times in a plastic bag. After mixing, 1.5 g of magnesium stearate was further added and mixed 50 times to obtain a mixture for tableting.
  • a plain tablet 5 was obtained by tableting (weight 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).
  • Example 6 Method for preparing plain tablet 6
  • TF-Labo dry granulator
  • the obtained dry granulated product was sized by a sizing machine (Comill, manufactured by Paulec Co., Ltd.). 275.4 g of sized product, 81.5 g of silicic acid-treated crystalline cellulose, 1.5 g of light anhydrous silicic acid, and 40.0 g of low-substituted hydroxypropyl cellulose (L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) in a plastic bag. The mixture was mixed 200 times, 1.5 g of magnesium stearate was further added and mixed 50 times to obtain a mixture for tableting.
  • a plain tablet 6 was obtained by tableting (weight 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).
  • Example 7 Method for preparing uncoated tablet 7
  • Compound A 44.2 g, silicic acid-treated crystalline cellulose 78.2 g, light silicic acid 1.8 g, lactose hydrate 149.3 g, hypromellose (TC-5E, Shin-Etsu Chemical Co., Ltd.) 41.4 g) were mixed 200 times in a plastic bag, 1.8 g of magnesium stearate (Parteck LUB, Merck) was further added, and the mixture was further mixed 50 times.
  • the obtained mixture was dry granulated by a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.).
  • the obtained dry granulated product was sized by a sizing machine (Comill, Powrex Co., Ltd.). 275.4 g of sized product, 81.5 g of silicic acid-treated crystalline cellulose, 1.5 g of light anhydrous silicic acid, and 40.0 g of low-substituted hydroxypropyl cellulose (L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) in a plastic bag. The mixture was mixed 200 times, 1.5 g of magnesium stearate was further added and mixed 50 times to obtain a mixture for tableting.
  • a plain tablet 7 was obtained by tableting (weight 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).
  • composition of the disintegrant and the binder in the plain tablets 4 to 7 is as follows.
  • Test Example 2 Comparative test of dissolution of uncoated tablets 4 to 7 obtained in Example 4, Example 5, Example 6 and Example 7 The uncoated tablets 4 to 7 obtained were put in a brown glass bottle and were not stoppered. The sample was stored at a temperature of 30° C. and a relative humidity of 75% before storage (at the start) for 1 month, 2 months, and 3 months.
  • the dissolution test was carried out according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method, 50 rpm).
  • test solution 900 mL of the second solution of the Japanese Pharmacopoeia dissolution test containing 0.15% by weight of sodium lauryl sulfate was used, and the compound A at the start of the test was tested at 5, 10, 15, 30, 45, 60, 90, 120, and 135 minutes.
  • the elution rate was evaluated by liquid chromatography.
  • ACQUITY UPLC HSS C18, particle diameter 1.8 ⁇ m, 2.1 mm ⁇ 50 mm manufactured by Waters
  • the mobile phase A 20 mmol/L sodium dihydrogen phosphate/citrate buffer (pH 4.5) was used, and as the mobile phase B, acetonitrile was used. The measurement was performed with an ultraviolet absorptiometer (measuring wavelength: 242 nm) at a flow rate of 0.6 mL/min.
  • the low-substituted hydroxypropyl cellulose has less variation than croscarmellose sodium, and the low-substituted hydroxypropyl cellulose is lower than that of the compound A. It has been found that cellulose (L-HPC) is the more preferred disintegrant.
  • Example 8 Method for preparing tablet 1 144.2 g of a solid dispersion containing 40% by weight of compound A, 346.2 g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), lactose hydrate (JP) 564.2 g and light weight. 5.8 g of silicic acid anhydride was mixed to obtain a mixed product containing the compound A. 494.8 g of this mixed product was mixed with 19.4 g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Soda Co., Ltd.) for 200 revolutions in a plastic bag, and further 2.7 g of magnesium stearate was added in a plastic bag for 50 times. Spin mixed.
  • HPC-SSL-SFP hydroxypropyl cellulose
  • This mixture was dry-granulated with a roller compactor (TF-Labo, manufactured by Freund Sangyo Co., Ltd.).
  • the obtained dry granulated product was sized by a sizing machine (Comill, manufactured by Paulec Co., Ltd.).
  • the obtained sized product (480 g), silicic acid-treated crystalline cellulose (132.5 g), light anhydrous silicic acid (2.5 g) and croscarmellose sodium (Ac-Di-Sol, manufactured by FMC Biopolymer) were mixed in a plastic bag. Further, 2.5 g of magnesium stearate was added and mixed 50 times in a plastic bag to obtain a tableting mixture.
  • Uncoated tablets were obtained by tableting (weight: 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).
  • a coating solution was prepared by dispersing the coating agent mixture in water (the composition of the coating agent mixture and the solid content concentration of the coating solution are shown in Table 7 below).
  • a tablet coating machine DRC-200, manufactured by Paulec Co., Ltd.
  • 200 g of uncoated tablets were sprayed with each coating solution so that the coating was 5 parts by weight in a dry state with respect to 100 parts by weight of uncoated tablets.
  • the target tablet 1 was obtained.
  • Example 9 Method for preparing tablet 2 144.2 g of a solid dispersion containing 40% by weight of compound A, 346.2 g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), lactose hydrate (JP) 564.2 g and light weight. 5.8 g of silicic acid anhydride was mixed to obtain a mixed product containing the compound A. 494.8 g of this mixed product was mixed with 19.4 g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Soda Co., Ltd.) for 200 revolutions in a plastic bag, and further 2.7 g of magnesium stearate was added in a plastic bag for 50 times. Spin mixed.
  • HPC-SSL-SFP hydroxypropyl cellulose
  • This mixture was dry-granulated with a roller compactor (TF-Labo, manufactured by Freund Sangyo Co., Ltd.).
  • the obtained dry granulated product was sized by a sizing machine (Comill, manufactured by Paulec Co., Ltd.).
  • the obtained sized product (480 g), silicic acid-treated crystalline cellulose (132.5 g), light anhydrous silicic acid (2.5 g) and croscarmellose sodium (Ac-Di-Sol, manufactured by FMC Biopolymer) were mixed in a plastic bag. Further, 2.5 g of magnesium stearate was added and mixed 50 times in a plastic bag to obtain a tableting mixture.
  • Uncoated tablets were obtained by tableting (weight: 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).
  • a coating solution was prepared by dispersing the coating agent mixture in water (the composition of the coating agent mixture and the solid content concentration of the coating solution are shown in Table 7 below).
  • a tablet coating machine DRC-200, manufactured by Paulec Co., Ltd.
  • 200 g of uncoated tablets were sprayed with each coating solution so that the coating was 5 parts by weight in a dry state with respect to 100 parts by weight of uncoated tablets. By doing so, the target tablet 2 was obtained.
  • Test Example 3 Comparison of the stability of the film-coated tablets obtained in Examples 8 and 9 Bardoxolone methyl analogues were measured by liquid chromatography under the following conditions.
  • As a column ACQUITY UPLC HSS C18, particle size 1.8 ⁇ m, 2.1 mm ⁇ 50 mm (manufactured by Waters) or its equivalent was used and maintained at 40° C.
  • As the mobile phase A 20 mmol/L sodium dihydrogen phosphate/citrate buffer (pH 4.5) was used, and as the mobile phase B, acetonitrile was used.
  • the sample solution used was diluted with 65 wt% acetonitrile so that the concentration of the compound was 100 ⁇ g/mL.
  • the related substances were measured with an ultraviolet absorptiometer (measuring wavelength: 242 nm) at a flow rate of 0.6 mL/min, and the total amount (%) of each related substance with respect to the indicated amount of bardoxolone methyl was determined.
  • the stability test was conducted under the following conditions. Storage conditions: 30° C., 75% RH, 1 month Storage form: Put tablets 1 and 2 in a brown bottle with an open lid.
  • Example 10 Formulation example 2 and method for preparing uncoated tablet 8 19.2 g of a solid dispersion containing 40% by weight of Compound A, 79.5 g of silicic acid-treated crystalline cellulose (Prosolve, JRS Pharma), 69.1 g of lactose hydrate, Hypromellose (TC-5E, Shin-Etsu Chemical Co., Ltd.) 9.1 g, low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Chemical Co., Ltd.) 20 g, light anhydrous silicic acid (Adsolider 101, Freund Industries) 1.5 g in a plastic bag. After mixing, 0.8 g of magnesium stearate (Pertek LUB MST, Merck) was added and further mixed to obtain a mixed product of the same Formulation Example 2 as above.
  • silicic acid-treated crystalline cellulose Prosolve, JRS Pharma
  • Hypromellose TC-5E, Shin-Etsu Chemical Co., Ltd.
  • Solid dispersion containing 40% by weight of compound A 19.2 g, silicic acid-treated crystalline cellulose 78.5 g (Prosolve, JRS Pharma), lactose hydrate 68.2 g, hypromellose (TC-5E, Shin-Etsu Chemical Co., Ltd.) 9.1 g , Low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Chemical Co., Ltd.) 20.0 g, light anhydrous silicic acid (Adsolider 101, Freund industrial) 1.5 g, organic acid (stabilizer) 2.0 g in a plastic bag After mixing, 0.8 g of magnesium stearate (Pertek LUB MST, Merck) was added and further mixed to obtain a mixed product containing 1% by weight of organic acid.
  • the obtained mixture was dry granulated with a dry granulator (TF-Labo, Freund Industries).
  • the obtained dry granulated product was sized with a sizing machine (co-mill, Paulec).
  • Magnesium stearate (Pertek LUB MST, Merck) in an amount of 0.38% by weight was added to the obtained sized product and mixed 50 times in a plastic bag to obtain a mixture for tableting.
  • Uncoated tablets 8 (including organic acid) were obtained by tableting (weight 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).
  • the composition of the uncoated tablet 8 is shown in Table 9 below. Also, for reference, the composition of Formulation Example 2 is repeated.
  • Test Example 4 Comparative test of stability of Formulation Example 2 (plain tablet) and the plain tablet 8 obtained in Example 10 with or without addition of an organic acid.
  • the measurement of the related substance of bardoxolone methyl was a liquid under the following conditions.
  • the test was performed and measured by chromatography. Specifically, ACQUITY UPLC HSS C18, particle diameter 1.8 ⁇ m, 2.1 mm ⁇ 50 mm (manufactured by Waters) or its equivalent was used as a column and maintained at 40° C.
  • As the mobile phase A 10 mmol/L phosphate buffer (pH 2.5) was used, and as the mobile phase B, acetonitrile was used.
  • the sample solution used was diluted with the mobile phase A:acetonitrile mixed solution (4:6) so that the concentration of the compound was 400 ⁇ g/mL.
  • the related substances were measured with an ultraviolet absorptiometer (measuring wavelength: 242 nm) at a flow rate of 0.3 mL/min, and the total amount (%) of each related substance with respect to the indicated amount of bardoxolone methyl was determined.
  • Storage condition 40° C., 75% RH, 1 month or 2 months
  • Storage form Formulation example 2 (plain tablet) and plain tablet 8 (5 types) were put in a brown bottle with an open lid.
  • Uncoated tablets were produced by the same procedure as in Manufacturing Prescription Example 2 of the aluminum bag packaged products 1 to 3 . Specifically, it is as follows. 500.0 g of a solid dispersion containing 40% by weight of Compound A (bardoxolone methyl) (manufactured by a spray-drying method, the following "solid dispersion” was manufactured in the same manner), crystalline silica treated with silicic acid (Prosolv, JRS Pharma).
  • This mixture was subjected to dry granulation and sizing with a roller compactor (CCS-220, manufactured by Paulec Co., Ltd.). An amount of 0.38% by weight of magnesium stearate was added to the obtained sized product and mixed to obtain a tableting mixture.
  • a plain tablet X containing 5 mg of compound A was obtained by tableting (weight: 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (HT-AP15, manufactured by Hata Tekko Co., Ltd.). .. Film coating and carnauba wax were sprinkled on the obtained plain tablets X in the same manner as in Formulation Example 2 to give a desired tablet X by polishing.
  • compositions of the obtained plain tablet X and tablet X are shown in Tables 11 and 12 below.
  • Tablets X produced based on the formulations in Tables 11 and 12 above were prepared as Aclar (trademark) film (Sumilite (trademark) FCL-1122, manufactured by Sumitomo Bakelite Co., Ltd.) (hereinafter, also referred to as "Aclar") or hard vinyl chloride film ( Sumilite (trademark) VSS, manufactured by Sumitomo Bakelite Co., Ltd.
  • hard vinyl chloride or polypropylene film (TAS2230V, manufactured by Taisei Kako Co., Ltd.) (hereinafter also referred to as “polypropylene”) and aluminum foil (Tokai Toyo) Blister packaged products 1 to 3 were obtained using a PTP packaging machine (PFD-100 type, manufactured by Maruho Hatsujo Kogyo Co., Ltd.) using Aluminum Sales Co., Ltd. or UACJ Foil Co., Ltd.
  • PTP packaging machine PFD-100 type, manufactured by Maruho Hatsujo Kogyo Co., Ltd.
  • Test Example 5 Comparative test of stability of aluminum bag packaged products 1 to 6
  • For aluminum bag packaged products 1 to 6 (hereinafter, also referred to as “packaged products 1 to 6”), storage conditions similar to those of Test Example 4 above ( The total amount of related substances (%) (“starting time” and “40° C., 75% RH, 1 month, open”) was measured at 40° C., 75% RH, 1 month, open. The results are shown in Table 13 below. The measurement of the analogue of bardoxolone methyl was carried out by a liquid chromatography test under the same conditions as in Test Example 4.
  • Test Example 6 Examination of stability of aluminum bag packaged product Regarding tablet X and blister packaged product 1 (using Aclar) (not in aluminum bag) obtained in the manufacturing process of the above aluminum bag packaged products 1 to 3 The total amount of related substances (%) under the same storage conditions (40° C., 75% RH, 1 month, open) and storage conditions (tablet X is placed in a brown glass bottle with the lid removed) similar to those in Test Examples 4 and 5 above ( "At the start” and "40°C, 75% RH, 1 month, open") were measured. The results are shown in Table 14 below. The measurement of the analogue of bardoxolone methyl was carried out by a liquid chromatography test under the same conditions as in Test Example 4.
  • the blister packaged product 1 and the aluminum bag packaged product 1 of the tablet X may have a smaller total amount of related substances and an increased amount thereof as compared with the tablet X (film coating formulation). Do you get it. It was also found that the aluminum bag packaged product 1 of the tablet X had a slightly smaller total amount of related substances and its increased amount compared to the blister packaged product 1. Therefore, it was found that the stability can be improved by using the film coating formulation of the present invention as a blister packaging product, and further, the stability can be further improved by using the film coating formulation of the present invention as an aluminum bag packaging product. ..
  • Test Example 7 Comparative test of stability in film coating formulation
  • Tablet X used in the comparative test of Test Example 5 above and tablet Y contained 1% by weight of fumaric acid in plain tablets instead of 0.2% by weight.
  • Tablet Y-1 prepared so as to be contained, and tablet Z prepared so that 1% by weight of malic acid was contained in the plain tablet instead of fumaric acid contained in tablet Y were used in the following test. ..
  • Tablet X, tablet Y-1, and tablet Z are all film coating formulations. With respect to the produced tablets X, tablets Y-1, and Z, the total amount (%) of related substances was measured under the same storage conditions and liquid chromatography conditions as in Test Example 5 (data not shown).
  • tablets Y-1 (containing fumaric acid) and tablets Z (containing malic acid) prepared by adding an organic acid (fumaric acid or malic acid) were compared with tablets X-1 prepared without adding an organic acid.
  • an organic acid fluoride or malic acid

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Abstract

L'invention concerne une composition pharmaceutique présentant une stabilité améliorée de méthyle de bardoxolone ou d'un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également l'utilisation d'une composition pharmaceutique pourvue d'un film de revêtement, ladite composition contenant du méthyle de bardoxolone ou un sel pharmaceutiquement acceptable de celui-ci, un agent désintégrant et un liant.
PCT/JP2019/046268 2018-11-27 2019-11-27 Composition pharmaceutique WO2020111089A1 (fr)

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