KR20210096162A - pharmaceutical composition - Google Patents

Abstract

A pharmaceutical composition with improved stability of bardoxolonemethyl or a pharmaceutically acceptable salt thereof is provided. A pharmaceutical composition having a coating film containing bardoxolonemethyl or a pharmaceutically acceptable salt thereof, a disintegrant and a binder is used.

Description

pharmaceutical composition

Reference to related applications

This patent application is accompanied by a claim of priority based on Japanese Patent Application No. 2018-221650, which is a Japanese application filed on November 27, 2018, and the entire disclosure of this Japanese application is incorporated herein by reference. content].

The present invention relates to a pharmaceutical composition, and more particularly, to a pharmaceutical composition containing bardoxolonemethyl or a pharmaceutically acceptable salt thereof.

As a synthetic terpenoid, bardoxolonemethyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)-diene-28-oate) represented by the following formula (hereinafter "Compound A") ') is known (see Patent Document 1), and it is known that the bardoxolone methyl has 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 response in the body, has a wide range of antioxidant stress and anti-inflammatory actions, and is an effective anti-inflammatory in all clinical studies and human clinical trials. It has been found to have action and antitumor action. In particular, bardoxolone methyl exhibits significant anticancer activity in patients with advanced cancer, and also measures renal function, insulin resistance, blood glucose control and systemic circulatory disease in patients with chronic kidney disease caused by type 2 diabetes. It is also known that it has the ability to improve (refer patent document 3). Moreover, in a clinical trial, it has been shown that the eGFR value (index of renal function) is remarkably improved by administration of bardoxolone methyl (refer nonpatent literature 1, nonpatent literature 2, and nonpatent literature 3).

Although research for designing an appropriate pharmaceutical composition for bardoxolone methyl is being conducted (refer to Patent Document 4), further stabilization of bardoxolone methyl is required.

Publication WO1999/65478 Publication WO2009/023232 Publication WO2009/089545 WO2010/093944 Publication

N Engl J Med, 2013, 369, p2492-2503 AM J Nephrol, 2011, 33, p469-476 N Engl J Med, 2011, p327-336

The present invention provides a stable pharmaceutical composition containing bardoxolone methyl or a pharmacologically acceptable salt thereof and acceptable as a pharmaceutical.

The present invention relates to the following (1) to (26).

(1) A pharmaceutical composition having a coating film comprising bardoxolonemethyl or a pharmaceutically acceptable salt thereof, a disintegrant, and a binder.

(2) the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, partially α-starch and starch 1 The pharmaceutical composition as described in (1) which is more than a species.

(3) The pharmaceutical composition according to (2), wherein the disintegrant is at least one selected from the group consisting of crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose.

(4) The pharmaceutical composition according to any one of (1) to (3), wherein 0.1 to 20 parts by weight of a disintegrant is contained with respect to 100 parts by weight of the pharmaceutical composition.

(5) The binder is hydroxypropyl cellulose, methyl cellulose, hypromellose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxy With propyl starch, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol, starch, gelatin, dextrin, pullulan, agar and gum arabic The pharmaceutical composition according to any one of (1) to (4), which is at least one selected from the group consisting of.

(6) The pharmaceutical composition according to (5), wherein the binder is at least one selected from the group consisting of hydroxypropyl cellulose, hypromellose, polyvinyl alcohol and polyvinylpyrrolidone.

(7) The pharmaceutical composition according to any one of (1) to (6), wherein 0.1 to 30 parts by weight of a binder is contained with respect to 100 parts by weight of the pharmaceutical composition.

(8) The pharmaceutical composition according to any one of (1) to (7), further comprising a stabilizer.

(9) The pharmaceutical composition according to (8), wherein the stabilizer is an organic acid.

(10) The pharmaceutical composition according to (9), wherein the organic acid is fumaric acid and/or malic acid.

(11) In any one of (1) to (10), wherein the coating film contains at least one coating agent selected from the group consisting of water-soluble polymer, lactose, sucrose, mannitol, titanium oxide, talc, calcium carbonate and triacetin. A described pharmaceutical composition.

(12) the water-soluble polymer consists of polyethylene glycol, polyvinyl alcohol, polyethylene glycol graft copolymer, polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol and polyvinyl alcohol methyl methacrylate copolymer The pharmaceutical composition as described in (11) which is 1 or more types selected from the group.

(13) The pharmaceutical composition according to (11) or (12), wherein the coating film further contains a colorant.

(14) The pharmaceutical composition according to (13), wherein the colorant contains at least one selected from the group consisting of yellow ferric trioxide, iron oxide and titanium oxide.

(15) The pharmaceutical composition according to any one of (1) to (14), wherein 0.1 to 100 parts by weight of the coating agent is contained with respect to 100 parts by weight of the coating film.

(16) The pharmaceutical composition according to any one of (1) to (15), further comprising a brightening agent.

(17) The pharmaceutical composition according to (16), wherein the glazing agent is carnauba wax and/or magnesium stearate.

(18) The pharmaceutical composition according to any one of (1) to (17),

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of bardoxolone methyl or a pharmaceutically acceptable salt thereof is included,

Based on 100 parts by weight of the pharmaceutical composition, 3 to 20 parts by weight of a binder is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 15 parts by weight of a disintegrant is included,

Based on 100 parts by weight of the coating film, 50 to 90 parts by weight of the coating agent are included.

pharmaceutical composition.

(19) The pharmaceutical composition according to any one of (1) to (18), wherein bardoxolonemethyl is amorphous.

(20) The pharmaceutical composition according to any one of (1) to (19), which is a solid preparation.

(21) The pharmaceutical composition according to (20), wherein the solid preparation is a tablet.

(22) A blister packaged product comprising the pharmaceutical composition according to any one of (1) to (21), a film laminated with a polymer, and an aluminum foil.

(23) The blister packaged product according to (22), wherein the film on which the polymer is laminated is a film laminated with at least one polymer selected from polypropylene, polyvinyl chloride, polyvinylidene chloride and polytrifluoroethylene chloride.

(24) A pharmaceutical packaged product according to (22) or (23), wherein the blister packaged product is enclosed in a package.

(25) The pharmaceutical packaging product according to (24), wherein the packaging body is an aluminum bag.

(26) The pharmaceutical packaging product according to (24) or (25), wherein an oxygen scavenger and/or a desiccant is also enclosed in the package.

According to the present invention, by providing a pharmaceutical composition having a coating film containing bardoxolonemethyl or a pharmaceutically acceptable salt thereof, a disintegrant, and a binder, the stability of bardoxolonemethyl or a pharmacologically acceptable salt thereof can improve

1 is a comparison of the dissolution rate (%) over time of a predetermined 4 before (at start), 1 month (1 month), 2 months (2 months), and 3 months (3 months) after storage. It is a graph. The vertical axis represents the dissolution rate (%), and the horizontal axis represents time (minutes).
Fig. 2 is a graph comparing the dissolution rate (%) over time of a predetermined 5 before storage (at the time of initiation), 1 month (1 month), 2 months (2 months), and 3 months (3 months). The vertical axis represents the dissolution rate (%), and the horizontal axis represents time (minutes).
3 is a graph comparing the dissolution rate (%) over time of a predetermined 6 before storage (at the time of initiation), 1 month (1 month), 2 months (2 months), and 3 months (3 months). The vertical axis represents the dissolution rate (%), and the horizontal axis represents time (minutes).
4 is a graph comparing the dissolution rate (%) of a predetermined 7 over time before storage (at the time of initiation), after 1 month (1 month), after 2 months (2 months), and after 3 months (3 months). The vertical axis represents the dissolution rate (%), and the horizontal axis represents time (minutes).

The pharmaceutical composition of the present invention is a pharmaceutical composition having a coating film containing bardoxolonemethyl (hereinafter, sometimes referred to as "Compound A") or a pharmaceutically acceptable salt thereof, a binder, and a disintegrant. . The chemical structure of the compound A is as described above, and it can manufacture by the method disclosed in International Publication No. 1999/65478 (patent document 1), or the method according to this.

"Pharmaceutically acceptable" in the present invention means that it is useful for preparing a pharmaceutical composition that is generally safe, non-toxic, and is not undesirable in terms of biological and other points, and is also safe for humans. includes those permitted for medicinal as well as veterinary use.

In the present invention, "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable as defined above and has a desired pharmacological activity. Examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; Alternatively, for example, an acid addition salt formed with an organic acid such as maleic acid, methanesulfonic acid, or oxalic acid may be mentioned. Pharmaceutically acceptable salts also include base addition salts which may be formed when the acidic protons present are capable of reacting with an inorganic base or an organic base. Examples of the pharmaceutically acceptable inorganic base include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Examples of the pharmaceutically acceptable organic base include ethanolamine, diethanolamine, triethanolamine, tromethamine and N-methylglucamine.

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. Compound A of the present invention or a pharmaceutically acceptable salt thereof includes all of its intramolecular salts, adducts, solvates, and hydrates thereof.

Among Compound A or its pharmaceutically acceptable salt, stereoisomers such as geometric isomers and optical isomers, tautomers, etc. may exist, but the present invention includes all possible isomers and mixtures thereof, including these.

Part or all of each atom in Compound A or a pharmaceutically acceptable salt thereof may be substituted with the corresponding isotope atom, and the present invention also includes derivatives substituted with these isotope atoms.

Compound A of the present invention or a pharmaceutically acceptable salt thereof also includes an active metabolite of Compound A (the active metabolite includes, for example, various conjugates) or a pharmaceutically acceptable salt thereof.

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 parts by weight, more preferably 1 to 20 parts by weight with respect to 100 parts by weight of the pharmaceutical composition. It is a weight part, More preferably, it is 2-15 weight part, Especially preferably, it is 2-10 weight part.

Compound A may be either 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 100 parts by weight of Compound A It is preferable to include 50 parts by weight to 100 parts by weight of the amorphous (form B), more preferably 80 parts by weight to 99.9 parts by weight, and still more preferably to include 95 parts by weight to 99 parts by weight. According to a more preferred embodiment of the present invention, compound A is an amorphous solid dispersion in a glassy matrix, for example a product obtained by spray drying a solution or suspension of a mixture of compound A and a methacrylic acid copolymer. This solid dispersion is preferably a mixture of compound A and methacrylic acid copolymer in a weight ratio of 4:6, more preferably a product obtained by spray drying the corresponding mixture of compound A and methacrylic acid copolymer can be heard

To obtain an amorphous solid dispersion of Compound A, it can be prepared using various preparative techniques. Suitable methods for producing a solid dispersion of amorphous Compound A include various conventional thermal methods (eg, hot melt extrusion), solvent methods and thermal/solvent methods (eg, spray drying or flow immersion of granules). can be heard

Regarding the preparation method of the solid dispersion, according to "The Forefront of Oral Formulation Technology for Poorly Water-soluble Drugs" (CMC Publishing, 2016) (Reference 1), from the viewpoint of stability of the amorphous drug in the solid dispersion, As for the glass transition point, the higher one is preferable. Further, from the viewpoint of manufacturing, it is described that the exhaust temperature at the time of spray drying is preferably below the glass transition point of the solid dispersion (refer to page 195 of Reference Document 1). In addition, water, methanol, ethanol, acetone, dichloromethane, etc. are mentioned as a typical solvent used for the solid dispersion by the spray drying method, From these, an appropriate solvent is selected according to a drug and a carrier. It is described that the drug concentration of the spray solution is preferably 50 mg/mL or more because the drug and carrier dissolved at a high concentration can improve the production efficiency (see page 196 of Reference Document 1).

The pharmaceutical composition of the present invention typically contains a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. Here, the "therapeutically effective" amount is an amount that obtains a desired pharmacological effect when the pharmaceutical composition of the present invention is administered to a patient. In general, a therapeutically effective amount can be determined empirically by reference to the clinical parameters of the patient.

Although it will not specifically limit if the disintegrating agent contained in the pharmaceutical composition of this invention is used as a pharmaceutical, For example, PVP-type disintegrants, such as crospovidone; cellulose-based disintegrants such as croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, and carboxymethyl cellulose calcium; and starch-based disintegrants such as sodium carboxymethyl starch, partially α-starch and starch, and preferably crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, and carboxymethyl. At least one selected from the group consisting of calcium cellulose, sodium carboxymethyl starch, partially α-starch and starch, and more preferably at least one selected from the group consisting of a PVP-based disintegrant and a cellulose-based disintegrant. , more preferably at least one selected from the group consisting of crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose, more preferably croscarmellose sodium or low-substituted hydroxypropyl cellulose. , particularly preferably low-substituted hydroxypropyl cellulose. Here, the low-substituted hydroxypropyl cellulose is a low-substituted hydroxypropyl ether of cellulose, and the dried low-substituted hydroxypropyl cellulose is a hydroxypropoxy group (-OC ₃ H ₆ OH : 75.09) 5.0 to 16.0%.

Although the content of the disintegrant in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a medicament, it is preferable to include 0.1 parts by weight to 20 parts by weight, and 0.1 parts by weight to 18 parts by weight with respect to 100 parts by weight of the pharmaceutical composition. It is more preferable to include part by weight, and it is still more preferable to include 0.1 part by weight 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 medicament, Preferably, hydroxypropyl cellulose, hypromellose (hydroxypropylmethyl cellulose), methyl cellulose, carboxymethyl cellulose, carboxymethyl Ethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropyl starch, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, It is at least one selected from the group consisting of polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol, starch (more preferably corn starch, potato starch), gelatin, dextrin, pullulan, agar and gum arabic, and more Preferably, it is at least one selected from the group consisting of hydroxypropyl cellulose, hypromellose, polyvinyl alcohol and polyvinyl pyrrolidone, more preferably hydroxypropyl cellulose or hypromellose, especially Preferably it is hypromellose.

The content of the binder in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a medicament, and it is preferable to include 0.1 to 30 parts by weight, and 0.5 to 25 parts by weight, based on 100 parts by weight of the pharmaceutical composition. It is more preferable to include, and it is still more preferable to include 3 to 20 parts by weight.

The pharmaceutical composition of the present invention may contain other additives used as pharmaceuticals in addition to Compound A, a disintegrant and a binder, for example, a stabilizer, an excipient, a lubricant, a colorant, a glidant, and a glossing agent used in pharmaceutical formulations. It may contain 1 or more types of additives selected from the group which consists of. Stabilizers, excipients, lubricants, colorants, fluidizing agents, and brightening agents in the present specification are not limited to the uses (functions) described respectively, and can be used for other uses (functions) (for example, the use of a binder as an excipient, the use of an excipient as a binder, etc.).

Although it will not specifically limit if the stabilizer contained in the pharmaceutical composition of this invention is used as a pharmaceutical, For example, an organic acid, calcium carbonate, etc. are mentioned, Preferably it is an organic acid. 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, maleic acid, etc., preferably fumaric acid and/or malic acid and more preferably fumaric acid. By containing fumaric acid and/or malic acid in the pharmaceutical composition of the present invention, it is possible to obtain a good formulation with a small total amount of analogs and high stability.

The content of the stabilizer (preferably an organic acid) in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicament, but contains 0.01 to 30 parts by weight of the stabilizer with respect to 100 parts by weight of the pharmaceutical composition. It is preferable to do it, and it is more preferable to contain 0.05 to 10 weight part, It is more preferable to contain 0.1 to 5 weight part.

The excipient contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a pharmaceutical, and examples thereof include sugar, sugar alcohol, crystalline cellulose, silicic acid-treated crystalline cellulose (silicified crystalline cellulose), and inorganic salts. and preferably lactose, sucrose, maltose, sucrose, mannitol, sorbitol, erythritol, maltitol, xylitol, glucose, crystalline cellulose, silicic acid-treated crystalline cellulose, monohydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate , calcium phosphate, and two or more of these excipients may be used in combination, more preferably lactose (preferably lactose hydrate), mannitol, and silicic acid-treated crystalline cellulose, and two or more of these excipients may be used in combination. .

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 medicament, but it is preferable to contain 0.1 to 99.9 parts by weight of the excipient with respect to 100 parts by weight of the pharmaceutical composition, and 1 part by weight to It is more preferable to contain 95 weight part, and it is still more preferable to contain 10 weight part - 90 weight part.

The lubricant contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a pharmaceutical, and for example, magnesium stearate, calcium stearate, sodium lauryl sulfate, talc, glycerin monostearate, light anhydrous silicic acid, fumarate stearate. Aryl sodium and sucrose fatty acid esters (for example, sucrose stearate, sucrose palmitate, sucrose oleate, sucrose lauric acid ester, etc.) are preferable, and these two or more types of 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 is an amount usable as a medicament, but it is preferably contained in an amount of 0.05 to 10 parts by weight, and 0.1 to 5 parts by weight based on 100 parts by weight of the pharmaceutical composition. It is more preferable to include part by weight, and it is still more preferable to include 0.5 to 3 parts by weight.

The coloring agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medicament, but yellow ferric trioxide, titanium oxide, talc, ferric trioxide, black iron oxide, iron oxide, copper chlorophyll, copper chlorophyllin sodium, carbon black, medicinal use It is preferable to include at least one selected from the group consisting of burnt, food coloring, licorice extract, green tea matcha, riboflavin, butyrate riboflavin, sodium riboflavin phosphate and octyldodecyl myristate, and yellow ferric trioxide, iron oxide and titanium oxide. It is more preferable to include at least one selected from the group consisting of.

The content of the colorant in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a medicament, and may include, for example, 0.01 parts by weight to 5 parts by weight with respect to 100 parts by weight of the pharmaceutical composition.

The glidant contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a pharmaceutical, and for example, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, synthetic hydrotalcite, dry aluminum hydroxide gel, kaolin, silicic acid. Calcium, magnesium metasilicate aluminate, talc, etc. are mentioned, You may use combining these 2 or more types of fluidizing agents.

The content of the fluidizing agent in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a medicament, and may be included, for example, from 0.01 parts by weight to 5 parts by weight with respect to 100 parts by weight of the pharmaceutical composition.

The glazing agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medicament, and examples thereof include carnauba wax, shellac, beeswax, hydrogenated oil, magnesium stearate, and the like. A combination of agents may be used, and carnauba wax and/or magnesium stearate are preferable.

The content of the brightening agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a medicament, but it is preferable to include 0.0001 parts by weight to 100 parts by weight with respect to 100 parts by weight of the pharmaceutical composition, and 0.001 parts by weight to It is more preferable to contain 10 weight part, and it is more preferable to contain 0.01 weight part - 1 weight part.

The pharmaceutical composition of this invention has a coating film. This coating film can be provided by, for example, coating a small preparation (eg, predetermined) containing Compound A or a pharmaceutically acceptable salt thereof, a disintegrant, and a binder. The said coating process can be performed by spraying the coating liquid containing a coating agent to the cleaning agent (for example, predetermined|prescribed) containing compound A by the spray coating method etc., for example. The coating agent is used by dissolving, suspending, or dispersing in the coating solution. Examples of the solvent constituting the coating solution include water, alcohols such as methanol and ethanol, and the like, but water is more preferable.

The coating film of the pharmaceutical composition of the present invention is not particularly limited, but preferably contains at least one coating agent selected from the group consisting of a water-soluble polymer, lactose, sucrose, mannitol, titanium oxide, talc, calcium carbonate and triacetin. and, more preferably, triacetin.

The water-soluble polymer is not particularly limited as long as it is used as a pharmaceutical, but preferably polyethylene glycol, polyvinyl alcohol, polyethylene glycol graft copolymer, polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol and poly It is at least one selected from the group consisting of vinyl alcohol acrylate methyl methacrylate copolymer.

The coating film of the pharmaceutical composition of the present invention preferably further contains a colorant, more preferably if the colorant contains at least one selected from the group consisting of yellow ferric trioxide, iron oxide and titanium oxide.

Although the coating agent in a coating film is not specifically limited, It is preferable to contain 0.1 weight part - 100 weight part with respect to 100 weight part of coating films, It is more preferable to contain 1 weight part - 95 weight part, 50 weight part - 90 weight part It is more preferable to include parts by weight.

The amount of the coating solution used for the coating treatment is not particularly limited as long as it is an amount capable of imparting photostability to the pharmaceutical composition, but with respect to 100 parts by weight of the cleaning agent, the coating film (coating) is 0.01 parts by weight to in a dry state. It is preferable that it is 50 weight part, It is more preferable that it is 0.05 weight part - 30 weight part, It is more preferable that it is 0.1 weight part - 20 weight part.

It is preferable that the pharmaceutical composition of the present invention further contains a varnishing agent, and it is more preferable that carnauba wax and/or magnesium stearate are included as varnishing agents.

The pharmaceutical composition of the present invention is preferably an oral preparation, and a corrosive agent and the like may be further added.

Although the shape of the pharmaceutical composition of the present invention is not particularly limited, it is preferably a solid preparation, more preferably in the form of a tablet, powder, fine granule, granule, capsule or dry syrup, and still more preferably a tablet. By making the shape of the pharmaceutical composition of the present invention into a tablet, it is easy to take, has a physically sufficient strength, and has the advantage of being less crushable than a capsule.

As a manufacturing method when the pharmaceutical composition of the present invention is a tablet, a mixture containing bardoxolone methyl or a pharmaceutically acceptable salt thereof as an active ingredient, a disintegrant, and a binder is granulated and tableted, followed by a film coating process. manufactured through

Although the manufacturing method of the pharmaceutical composition of this invention is not specifically limited, For example, it can manufacture by the method generally used in the technical field of pharmaceuticals, such as compression molding, For example, a direct compression method or dry granulation. It can manufacture by a compression method (a roller compression molding method, a slag tableting method, etc.) etc. In either case, for example, it is preferable to use a method of mixing Compound A or a pharmaceutically acceptable salt thereof and additives such as a disintegrant or binder, and granulating and sizing as necessary. Next, when manufacturing a tablet, for example, forming a tablet with the obtained dry granulated material using a compression tableting machine is mentioned. The tableting pressure can be appropriately selected from, for example, the range of 300 to 3000 kg/cm ^{2 .} Although the tablet size is not particularly limited, it is preferable that the weight per tablet is 20 to 3000 mg and the diameter of the tablet is 5 to 15 mm. When a predetermined coating treatment is performed, the obtained tablet may be coated with a solution/dispersion in which a coating agent is dissolved/dispersed to form a skin. Examples of the solvent for dissolving/dispersing the coating agent include water, ethanol, isopropyl alcohol, and a mixed solvent thereof. Among these, water is preferable. Coating is performed using, for example, a conventional fan-type coater, a vented coater, a fluidized-bed coater, a motor-driven fluidized coater, or the like.

As a preferable aspect of the pharmaceutical composition of this invention,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 30 parts by weight of a binder (preferably hypromellose) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) is included,

Based on 100 parts by weight of the coating film, 0.1 to 100 parts by weight of a coating agent (preferably, the coating film includes at least one coating agent selected from the group consisting of hypromellose, lactose and triacetin) is included in a pharmaceutical composition (preferably) is purified).

As another preferable aspect of the pharmaceutical composition of this invention,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 30 parts by weight of a binder (preferably hypromellose) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.0001 to 10 parts by weight of a brightening agent (preferably carnauba wax and/or magnesium stearate) is included,

Based on 100 parts by weight of the coating film, 0.1 to 100 parts by weight of a coating agent (preferably, the coating film includes at least one coating agent selected from the group consisting of hypromellose, lactose and triacetin) is included in a pharmaceutical composition (preferably) is purified).

As another preferable aspect of the pharmaceutical composition of this invention,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 30 parts by weight of a binder (preferably hypromellose) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.01 to 30 parts by weight of a stabilizer (preferably an organic acid, more preferably a fumaric acid) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.001 to 10 parts by weight of a brightening agent (preferably carnauba wax and/or magnesium stearate) is included,

Based on 100 parts by weight of the coating film, 0.1 to 100 parts by weight of a coating agent (preferably, the coating film includes at least one coating agent selected from the group consisting of hypromellose, lactose and triacetin) is included in a pharmaceutical composition (preferably) is purified).

As a more preferable aspect of the pharmaceutical composition of this invention,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.5 to 25 parts by weight of a binder (preferably hypromellose) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 18 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) is included,

Based on 100 parts by weight of the coating film, the coating agent (preferably the coating film includes at least one coating agent selected from the group consisting of hypromellose, lactose and triacetin) is contained in 1 to 95 parts by weight of a pharmaceutical composition (preferably is purified).

As another more preferable aspect of the pharmaceutical composition of this invention,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.5 to 25 parts by weight of a binder (preferably hypromellose) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 18 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.001 to 10 parts by weight of a brightening agent (preferably carnauba wax and/or magnesium stearate) is included,

Based on 100 parts by weight of the coating film, the coating agent (preferably the coating film includes at least one coating agent selected from the group consisting of hypromellose, lactose and triacetin) is contained in 1 to 95 parts by weight of a pharmaceutical composition (preferably is purified).

As another more preferable aspect of the pharmaceutical composition of this invention,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.5 to 25 parts by weight of a binder (preferably hypromellose) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 18 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.05 to 10 parts by weight of a stabilizer (preferably an organic acid, more preferably a fumaric acid) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.001 to 10 parts by weight of a brightening agent (preferably carnauba wax and/or magnesium stearate) is included,

Based on 100 parts by weight of the coating film, the coating agent (preferably the coating film includes at least one coating agent selected from the group consisting of hypromellose, lactose and triacetin) is contained in 1 to 95 parts by weight of a pharmaceutical composition (preferably is purified).

As a more preferable aspect of the pharmaceutical composition of this invention,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included,

Based on 100 parts by weight of the pharmaceutical composition, 3 to 20 parts by weight of a binder (preferably hypromellose) are included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 15 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) is included,

Based on 100 parts by weight of the coating film, 50 to 90 parts by weight of a coating agent (preferably, the coating film includes at least one coating agent selected from the group consisting of hypromellose, lactose and triacetin) is included in a pharmaceutical composition (preferably is purified).

As another more preferable aspect of the pharmaceutical composition of this invention,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included,

Based on 100 parts by weight of the pharmaceutical composition, 3 to 20 parts by weight of a binder (preferably hypromellose) are included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 15 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) is included,

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) is included,

Based on 100 parts by weight of the coating film, 50 to 90 parts by weight of a coating agent (preferably, the coating film includes at least one coating agent selected from the group consisting of hypromellose, lactose and triacetin) is included in a pharmaceutical composition (preferably is purified).

As another more preferable aspect of the pharmaceutical composition of this invention,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of Compound A or a pharmaceutically acceptable salt thereof is included,

Based on 100 parts by weight of the pharmaceutical composition, 3 to 20 parts by weight of a binder (preferably hypromellose) are included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 15 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose) is included,

Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 5 parts by weight of a stabilizer (preferably an organic acid, more preferably a fumaric acid) is included,

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) is included,

Based on 100 parts by weight of the coating film, 50 to 90 parts by weight of a coating agent (preferably, the coating film includes at least one coating agent selected from the group consisting of hypromellose, lactose and triacetin) is included in a pharmaceutical composition (preferably is purified).

According to another aspect of the present invention, bardoxolone methyl or a pharmaceutically acceptable salt thereof is characterized in that a disintegrant and a binder are added to bardoxolone methyl or a pharmaceutically acceptable salt thereof, and a coating film treatment is performed. A method for improving the stability of the salt to be used is provided. Further, according to another preferred embodiment of the present invention, bardoxolone methyl or a pharmaceutical thereof is characterized in that a disintegrant and a binder are added to bardoxolone methyl or a pharmaceutically acceptable salt thereof, and a coating film treatment is performed. There is provided a method for reducing the total amount of related substances of salts that are commercially acceptable. In this method, similarly to the pharmaceutical composition of the present invention, other additives used as pharmaceuticals may be added in addition to the compound A, disintegrant and binder, for example, stabilizers, excipients, lubricants, and coloring agents used in pharmaceutical formulations. , at least one additive selected from the group consisting of a glidant and a brightening agent may be added.

The pharmaceutical composition of the present invention can be provided by being accommodated in an airtight container such as bottle packaging, blister packaging, or an aluminum bag. The material of the airtight container is not particularly limited as long as it can suppress the ingress of moisture from the outside. In the pharmaceutical field, materials used for the purpose of moisture proofing of contents that are weak to moisture can be used, but among them, blister packaging Product is particularly preferred.

The blister packaged product of this invention contains the pharmaceutical composition containing the said compound A etc., and the film and aluminum foil which laminated|stacked the polymer. The film on which the polymer is laminated is not particularly limited as long as it is generally used for blister packaging, but polymers such as polypropylene, polyvinyl chloride, polyvinylidene chloride, polytrifluoroethylene (Accra (trademark)) A film on which is laminated is preferable, and polypropylene or rigid vinyl chloride is more preferable. It will not specifically limit as said aluminum foil, if it is used for a blister packaged product, Although a general general-purpose aluminum foil may be sufficient, it is preferable that it is the aluminum foil which reduced the amount of melamine resin in an adhesive agent. The manufacturing method of the blister packaged product of the present invention is not particularly limited, but using a generally used blister packaging machine, a pocket is formed in the film laminated with the polymer, the tablet is put, and the aluminum foil is heated by heat or the like. obtained by sealing.

The pharmaceutical packaging product of the present invention is one in which the blister packaging product is sealed in a packaging body. The package is not particularly limited as long as it is generally used for pharmaceutical packaging, and an aluminum bag or the like is preferable. In the said pharmaceutical packaging, water to be enclosed in a general pharmaceutical packaging may be sealed simultaneously, and it is preferable to encapsulate an oxygen scavenger and/or a desiccant simultaneously with the said blister packaged product. The pharmaceutical packaging product of the present invention can be manufactured by enclosing the blister packaged product or the like produced as described above in a package such as an aluminum bag, and sealing it using a heat sealer or the like.

Example

Hereinafter, the present invention will be described in more detail by way of examples, but the technical scope of the present invention is not limited to these examples.

Preparation example of film coated tablet

Prescription Example 1:

480.8 g of a solid dispersion containing 40% by weight of compound A (bardoxolonemethyl) (produced by a spray drying method, the following "solid dispersion" is also prepared), silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma) 1976.9 g, lactose hydrate (Japanese Pharmacopoeia) 1715.4 g, hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) 250.0 g, low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Corporation) 500.0 g of Kyoko Kogyo Co., Ltd.) and 38.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Sangyo Co., Ltd.) were mixed with a mixer (TBM-25, manufactured by Tokuju Kosakusho Co., Ltd.). To this mixture, 19.2 g of magnesium stearate was added and further mixed. This mixture was dry granulated and sized with a roller compactor (CCS-220, manufactured by Paurex, Ltd.). Magnesium stearate in an amount used as 0.38 wt% with respect to the obtained sized product was added and mixed to obtain a mixture for tableting. Tablets (prescription example 1) (see Table 1) were obtained by formulating (weight: 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tabletting machine (HT-AP15, manufactured by Hatadekko Co., Ltd.).

The coating agent mixture was dispersed in water to prepare a coating solution having a solid content concentration of 10% by weight (the composition of the coating agent mixture is shown in Table 2 below). Using a prescribed tablet coating machine (PRC-7, manufactured by Paurex Co., Ltd.), coating was performed by spraying the coating solution so that the coating solution was 5 parts by weight in a dry state with respect to 100 parts by weight. The target tablet was obtained by spraying carnauba wax in an amount of 0.03% by weight with respect to the predetermined amount and performing polishing.

The compositions of the obtained tablets and tablets are shown in Tables 1 and 2 below.

Prescription Example 2

500.0 g of a solid dispersion containing 40 wt% of Compound A (bardoxolone methyl) (manufactured by a spray drying method, the following “solid dispersion” is also prepared in the same manner), silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma) 2068.0 g, lactose hydrate (Japanese Pharmacopoeia) 1796.0 g, hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) 236.1 g, low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Corporation) 520.0 g of Kyoko Kogyo Co., Ltd.) and 40.0 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Sangyo Co., Ltd.) were mixed with a mixer (TBM-25, manufactured by Tokuju Kosakusho) with a mixer. To this mixture, 20.0 g of magnesium stearate was added and further mixed. This mixture was dry granulated and sized with a roller compactor (CCS-220, manufactured by Paurex, Ltd.). Magnesium stearate in an amount used as 0.38 wt% with respect to the obtained sized product was added and mixed to obtain a mixture for tableting. A tablet containing 5 mg of Compound A by formulating (weight: 130 mg, shape of tablet: circular shape (7 mm diameter)) using a rotary tabletting machine (HT-AP15, Hatadekko Co., Ltd.) (Prescription Example 2) (Table 3) was obtained.

The coating agent mixture was dispersed in water to prepare a coating solution having a solid content concentration of 10% by weight (the composition of the coating agent mixture is shown in Table 4 below). Using a prescribed tablet coating machine (PRC-7, manufactured by Paurex Co., Ltd.), coating was performed by spraying the coating solution so that the coating solution was 5 parts by weight in a dry state with respect to 100 parts by weight. The target tablet was obtained by spraying carnauba wax in an amount of 0.03% by weight with respect to the predetermined amount and performing polishing.

Prescription Example 3

5 mg tablet A compound by preparing a mixture in the same manner as in Formulation Example 2, and formulating (weight: 260 mg, tablet shape: circular shape (9 mm diameter)) using a rotary tabletting machine (HT-AP15, manufactured by Hatadekko Co., Ltd.) A tablet containing 10 mg of A (Formulation Example 3) (see Table 3) was obtained.

The coating agent mixture was dispersed in water to prepare a coating solution having a solid content concentration of 15% by weight (the composition of the coating agent mixture is shown in Table 4 below). For a predetermined 200 g, using a tablet coating machine (DRC-200, manufactured by Paurex Co., Ltd.), coating was performed by spraying the coating solution so that the coating solution was 4 parts by weight in a dry state with respect to 100 parts by weight of the predetermined. The target tablet was obtained by spraying carnauba wax in an amount of 0.03% by weight with respect to the predetermined amount and performing polishing.

Prescription Example 4

A 5 mg tablet mixture was prepared in the same manner as in Formulation Example 2, and formulated using a rotary tabletting machine (HT-AP15, manufactured by Hatadekko Co., Ltd.) (weight: 390 mg, tablet shape: oval shape (long diameter 13.5 mm, short 7 mm in diameter)) to obtain a 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 solution having a solid content concentration of 15% by weight (the composition of the coating agent mixture is shown in Table 4 below). Using a tablet coating machine (PRC-7, manufactured by Paurex Co., Ltd.), coating was performed by spraying the coating solution so that the coating solution was 3.5 parts by weight in a dry state with respect to 100 parts by weight. The target tablet was obtained by spraying carnauba wax in an amount of 0.03% by weight with respect to the predetermined amount and performing polishing.

The compositions of the obtained tablets and tablets are shown in Tables 3 and 4 below.

In Table 4, the target tablet can also be obtained by polishing using magnesium stearate instead of carnauba wax as a polishing agent.

Mixing of predetermined 1 to 3 common mixtures

336.5 g of a solid dispersion containing 40% by weight of Compound A, 807.7 g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), and 13.5 g of light anhydrous silicic acid were mixed 200 times in a polyethylene bag, and a mixture containing Compound A ( I) was obtained. Separately, 631.9 g of silicic acid-treated crystalline cellulose and 11.9 g of light anhydrous silicic acid were mixed 200 times in a polyethylene bag to obtain a mixture (II).

Example 1: Preparation method of predetermined 1

The mixture (I) 215.0 g, lactose hydrate 210.5 g, hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Soda Co., Ltd.) 19.5 g, croscarmellose sodium (Ac-Di-Sol, FMC biopolymer) 1) 32.5 g was mixed 200 times in a polyethylene bag, 2.5 g of magnesium stearate (Patech LUB, Merck) was added, and further mixed 50 times. The obtained mixture was dry granulated with a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.). The obtained dry granulated product was sized with a sizing machine (Comil, manufactured by Paurex, Ltd.). 443.1 g of the obtained sized product, 124.6 g of the mixture (II) and 30.0 g of sodium croscarmellose (Ac-Di-Sol, manufactured by FMC Biopolymer) were mixed 200 times in a polyethylene bag, and further, 2.3 g of magnesium stearate was added and mixed 50 times to obtain a mixture for tableting. Predetermined 1 was obtained by formulating (weight 130 mg, shape of tablet: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).

Example 2: Preparation method of predetermined 2

The above mixture (I) 148.9 g, lactose hydrate 145.7 g, hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Soda Co., Ltd.) 13.5 g, low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu) 22.5 g of Chemical Industries, Ltd.) was mixed 200 times in a polyethylene bag, further, 1.7 g of magnesium stearate (Patech LUB, Merck) was put, and it mixed 50 times. The obtained mixture was dry granulated with a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.). The obtained dry granulated product was sized with a sizing machine (Comil, Paurex, Ltd.). 295.4 g of the obtained sized product, 83.1 g of the mixture (II) and 20.0 g of low-substituted hydroxypropyl cellulose (L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed 200 times in a polyethylene bag, Further, 1.5 g of magnesium stearate was added and mixed 50 times to obtain a mixture for tableting. Predetermined 2 was obtained by formulation (weight 130 mg, shape of tablet: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).

Example 3: Preparation method of predetermined 3

The mixture (I) 148.9 g, lactose hydrate 145.7 g, hydroxypropyl cellulose (HPC-SSL-SFP, Nippon Soda Co., Ltd.) 13.5 g, sodium starch glycolate (Primogel, DFE Pharma) 22.5 g polyethylene After mixing 200 times in the bag, 1.7 g of magnesium stearate (Patech LUB, Merck) was added, and further mixed 50 times. The obtained mixture was dry granulated with a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.). The obtained dry granulated product was sized with a sizing machine (Comil, manufactured by Paurex, Ltd.). 295.4 g of the obtained sized product, 83.1 g of the mixture (II), and 20.0 g of sodium starch glycolate (Primogel, DFE Pharma) were mixed 200 times in a polyethylene bag, and 1.5 g of magnesium stearate was added and mixed 50 times. and a mixture for tableting was obtained. Prescribed 3 was obtained by enacting (weight 130 mg, shape of tablet: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, manufactured by Kikusui Seisakusho).

Test Example 1: Comparative test of stability in Examples 1 to 3 obtained in Examples 1, 2 and 3

The measurement of the analog of bardoxolone methyl was measured by performing a test by liquid chromatography under the following conditions. As a column for liquid chromatography, ACQUITY UPLC HSS C18, a particle diameter of 1.8 µm, 2.1 mm x 50 mm (manufactured by Waters) or an equivalent thereof was used, and the column temperature was maintained at 40°C. 20 mmol/L sodium dihydrogen phosphate/citrate buffer (pH 4.5) was used as mobile phase A, and acetonitrile was used as mobile phase B. The sample solution diluted with acetonitrile of 65% by weight was used so that the concentration of bardoxolonemethyl was 100 µg/mL. Analogs were measured with a flow rate of 0.6 mL/min and an ultraviolet absorptiometer (measurement wavelength: 242 nm) to determine the total amount (%) of each analog with respect to the indicated amount of bardoxolonemethyl.

The stability test was performed under the following conditions.

Storage conditions: 30℃, 75%RH, 1 month

Preservation form: Predetermined 1 to 3 were put into a brown bottle with an open lid.

From the results in Table 5 above, even when any disintegrant was added, it was found that the total amount of analogs was small and the formulation was excellent in terms of stability (in addition, although data are not shown, the amount of increase in the total amount of analogs from the start In few cases, disintegrants were added). When these three tablets were compared, it was found that tablets containing low-substituted hydroxypropyl cellulose as a disintegrant had a small total amount (and increased amount) of related substances, and was overall the most excellent in stability.

Example 4: Preparation method of predetermined 4

44.2 g of compound A, 110.4 g of silicic acid-treated crystalline cellulose, 1.8 g of light anhydrous silicic acid, 176.9 g of lactose hydrate, and 4.6 g of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in a polyethylene bag After mixing 200 times, 1.8 g of magnesium stearate (Patech LUB, Merck) was added and further mixed 50 times. The obtained mixture was dry granulated with a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.). The obtained dry granulated product was sized with a sizing machine (Comil, manufactured by Paurex, Ltd.). 295.4 g of sized product, 81.5 g of silicic acid-treated crystalline cellulose, 1.5 g of light anhydrous silicic acid, and 20 g of sodium croscarmellose (Ac-Di-Sol, manufactured by FMC Biopolymer) were mixed 200 times in a polyethylene bag, and further magnesium stearate 1.5 g was added and mixed 50 times to obtain a mixture for tableting. Prescribed 4 was obtained by formulating (weight 130 mg, shape of tablet: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).

Example 5: Preparation method of predetermined 5

44.2 g of Compound A, 90.9 g of silicic acid-treated crystalline cellulose, 1.8 g of light anhydrous silicic acid, 159.6 g of lactose hydrate, 41.4 g of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in a polyethylene bag After mixing 200 times, 1.8 g of magnesium stearate (Patech LUB, Merck) was added and further mixed 50 times. The obtained mixture was dry granulated with a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.). The obtained dry granulated product was sized with a sizing machine (Comil, manufactured by Paurex, Ltd.). 295.4 g of sized product, 81.5 g of silicic acid-treated crystalline cellulose, 1.5 g of light anhydrous silicic acid, and 20.0 g of croscarmellose sodium (Ac-Di-Sol, manufactured by FMC Biopolymer) were mixed 200 times in a polyethylene bag, and further stearic acid 1.5 g of magnesium was added and mixed 50 times to obtain a mixture for tableting. Prescribed 5 was obtained by formulating (weight 130 mg, shape of tablet: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).

Example 6: Preparation method of predetermined 6

Compound A 44.2 g, silicic acid-treated crystalline cellulose 98.0 g, light anhydrous silicic acid 1.8 g, lactose hydrate 166.3 g, hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) 4.6 g in a polyethylene bag After mixing 200 times, 1.8 g of magnesium stearate (Patech LUB, Merck) was added and further mixed 50 times. The obtained mixture was dry granulated with a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.). The obtained dry granulated product was sized with a sizing machine (Comil, manufactured by Paurex, Ltd.). 275.4 g of sized product, 81.5 g of silicic acid-treated crystalline cellulose, 1.5 g of light anhydrous silicic acid, 40.0 g of low-substituted hydroxypropyl cellulose (L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) 200 times in a polyethylene bag After mixing, 1.5 g of magnesium stearate was added and mixed 50 times to obtain a mixture for tableting. Prescribed 6 was obtained by formulating (weight 130 mg, shape of tablet: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).

Example 7: Preparation method of predetermined 7

44.2 g of compound A, 78.2 g of silicic acid-treated crystalline cellulose, 1.8 g of light anhydrous silicic acid, 149.3 g of lactose hydrate, and 41.4 g of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in a polyethylene bag After mixing 200 times, 1.8 g of magnesium stearate (Patech LUB, Merck) was added and further mixed 50 times. The obtained mixture was dry granulated with a dry granulator (TF-Labo, manufactured by Freund Sangyo Co., Ltd.). The obtained dry granulated product was sized with a sizing machine (Comil, Paurex, Ltd.). 275.4 g of sized product, 81.5 g of silicic acid-treated crystalline cellulose, 1.5 g of light anhydrous silicic acid, 40.0 g of low-substituted hydroxypropyl cellulose (L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) 200 times in a polyethylene bag After mixing, 1.5 g of magnesium stearate was added and mixed 50 times to obtain a mixture for tableting. Predetermined 7 was obtained by formulation (weight 130 mg, shape of tablet: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho).

The compositions of the disintegrant and the binder in the predetermined 4 to 7 are as follows.

Test Example 2: Comparative test of dissolution properties of predetermined 4 to 7 obtained in Examples 4, 5, 6 and 7

The obtained predetermined 4 to 7 were placed in a brown glass bottle, and stored without a stopper at a temperature of 30° C. and a relative humidity of 75% before storage (at the time of initiation), for 1 month, for 2 months, and for 3 months.

A dissolution test was performed according to the second method of the Japanese Pharmacopoeia dissolution test (paddle method, 50 rpm). As the 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 dissolution rate of Compound A at 5, 10, 15, 30, 45, 60, 90, 120, and 135 minutes from the start of the test was evaluated by liquid chromatography. As a column, ACQUITY UPLC HSS C18, a particle diameter of 1.8 µm, 2.1 mm x 50 mm (manufactured by Waters) or an equivalent thereof was used, and the temperature was maintained at 40°C. 20 mmol/L sodium dihydrogen phosphate/citrate buffer (pH 4.5) was used as mobile phase A, and acetonitrile was used as mobile phase B. Measurement was performed with a flow rate of 0.6 mL/min and an ultraviolet absorptiometer (measurement wavelength: 242 nm).

The results of the dissolution rate (%) over time of predetermined 4 to 7 before (at the time of initiation), 1 month (1 month), 2 months (2 months), and 3 months (3 months) after storage are shown in Figs. shown in As a preparation excellent in that the dissolution rate fluctuates with a predetermined storage period is excellent, for Compound A, in the presence of a binder, either croscarmellose sodium or low-substituted hydroxypropyl cellulose (L-HPC) is used as a disintegrant. Even when it used, there was little fluctuation|variation in the dissolution rate, and it turned out that a favorable dissolution rate is obtained in any predetermined (predetermined 4-7).

In addition, when comparing these two disintegrants, low-substituted hydroxypropyl cellulose (L-HPC) has less fluctuation than croscarmellose sodium, and for compound A, low-substituted hydroxypropyl cellulose ( L-HPC) was found to be a more preferable 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), 564.2 g of lactose hydrate (Japanese Pharmacopoeia), and 5.8 g of light anhydrous silicic acid are mixed, containing compound A A mixture was obtained. 494.8 g of this mixture was mixed with 19.4 g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Soda Co., Ltd.) 200 revolutions in a polyethylene bag, and 2.7 g of magnesium stearate was further mixed 50 revolutions in a polyethylene bag mixed. This mixture was dry granulated with a roller compactor (TF-Labo, manufactured by Freund Sangyo Co., Ltd.). The obtained dry granulated product was sized with a sizing machine (Comil, manufactured by Paurex, Ltd.). 480 g of the obtained sized product, 132.5 g of silicic acid-treated crystalline cellulose, 2.5 g of light anhydrous silicic acid, and sodium croscarmellose (Ac-Di-Sol, manufactured by FMC Biopolymer) were mixed in a polyethylene bag. Furthermore, 2.5 g of magnesium stearate was added, and the mixture for tableting was obtained by 50 rotations mixing in a polyethylene bag. Tablets were obtained by formulating (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 each of the coating agent mixtures in water (the composition of the coating agent mixture and the solid content concentration of the coating solution are shown in Table 7 below). Using a tablet coating machine (DRC-200, manufactured by Paurex, Inc.) to a predetermined 200 g, the target tablet 1 by spraying each coating solution so that the coating is 5 parts by weight in a dry state with respect to 100 parts by weight of a predetermined target tablet 1 got

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), 564.2 g of lactose hydrate (Japanese Pharmacopoeia), and 5.8 g of light anhydrous silicic acid are mixed, containing compound A A mixture was obtained. 494.8 g of this mixture was mixed with 19.4 g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Nippon Soda Co., Ltd.) 200 revolutions in a polyethylene bag, and 2.7 g of magnesium stearate was further mixed 50 revolutions in a polyethylene bag mixed. This mixture was dry granulated with a roller compactor (TF-Labo, manufactured by Freund Sangyo Co., Ltd.). The obtained dry granulated product was sized with a sizing machine (Comil, manufactured by Paurex, Ltd.). 480 g of the obtained sized product, 132.5 g of silicic acid-treated crystalline cellulose, 2.5 g of light anhydrous silicic acid, and sodium croscarmellose (Ac-Di-Sol, manufactured by FMC Biopolymer) were mixed in a polyethylene bag. Furthermore, 2.5 g of magnesium stearate was added, and the mixture for tableting was obtained by 50 rotations mixing in a polyethylene bag. Tablets were obtained by formulating (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 each of the coating agent mixtures in water (the composition of the coating agent mixture and the solid content concentration of the coating solution are shown in Table 7 below). Using a tablet coating machine (DRC-200, manufactured by Paurex, Ltd.) to a predetermined 200 g, the target tablet 2 by spraying each coating solution so that the coating is 5 parts by weight in a dry state with respect to 100 parts by weight of a predetermined target tablet 2 got

Test Example 3: Comparison of the stability of the film-coated tablets obtained in Examples 8 and 9

The measurement of the analog of bardoxolone methyl was tested by liquid chromatography under the following conditions. ACQUITY UPLC HSS C18, a particle diameter of 1.8 µm, 2.1 mm x 50 mm (manufactured by Waters) or an equivalent thereof was used as the column, and maintained at 40°C. 20 mmol/L sodium dihydrogen phosphate/citrate buffer (pH 4.5) was used as mobile phase A, and acetonitrile was used as mobile phase B. As a sample solution, what was diluted with 65 weight% acetonitrile so that the density|concentration of a compound might become 100 micrograms/mL was used. Analogs were measured with a flow rate of 0.6 mL/min and an ultraviolet absorptiometer (measurement wavelength: 242 nm) to determine the total amount (%) of each analog with respect to the indicated amount of bardoxolonemethyl.

The stability test was performed under the following conditions.

Storage conditions: 30℃, 75%RH, 1 month

Preservation form: Tablets 1 and 2 were placed in an open brown bottle.

From the results in Table 8, it was found that even when any film coating formulation was used, a tablet having a coating film containing Compound A, a disintegrant, and a binder was a good formulation with a small total amount of related substances and high stability. .

In particular, by incorporating triacetin into the film coating formulation, it was found that the total amount of analogs decreased and a good formulation with high stability could be obtained.

Example 10: Preparation method of prescription example 2 and prescribed 8

19.2 g of solid dispersion containing 40% by weight of compound A, 79.5 g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), 69.1 g of lactose hydrate, hypromellose (TC-5E, Shin-Etsu Chemical Co.) 9.1 g, 20 g of low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Chemical Co.) and 1.5 g of light anhydrous silicic acid (Adsolider 101, Freund Sangyo) were mixed in a polyethylene bag, and further magnesium stearate 0.8 g (Perteck LUB MST, Merck) was added and further mixed to obtain a mixture of Formulation Example 2 as described above.

19.2 g of a solid dispersion containing 40% by weight of compound A, 78.5 g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), 68.2 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.) 20.0 g, light anhydrous silicic acid (Adsolider 101, Freund Sangyo) 1.5 g, organic acid (stabilizer) 2.0 g in a polyethylene bag In addition, 0.8 g of magnesium stearate (Perteck LUB MST, Merck) was added and mixed further, and the mixture containing 1 weight% of organic acids was obtained.

The obtained mixture was dry granulated with a dry granulator (TF-Labo, Freund Sangyo). The obtained dry granulated product was sized with a sizing machine (Comil, Paurex). Magnesium stearate (Perteck LUB MST, Merck) was added to the obtained sized product in an amount of 0.38% by weight, and mixed 50 times in a polyethylene bag to obtain a mixture for tableting. Tablet 8 (including organic acid) was obtained by formulating (weight 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tableting machine (VIRGO, Kikusui Seisakusho). The composition of the predetermined 8 is shown in Table 9 below. Also, for reference, the composition of Formulation Example 2 is also republished.

Test Example 4: Comparative test of stability with or without addition of organic acid in Formulation Example 2 (prescribed) obtained in Example 10 and prescribed 8

The measurement of the analog of bardoxolone methyl was measured by performing a test by liquid chromatography under the following conditions. Specifically, ACQUITY UPLC HSS C18, a particle diameter of 1.8 µm, 2.1 mm x 50 mm (manufactured by Waters) or an equivalent thereof was used as a column and maintained at 40°C. 10 mmol/L phosphate buffer (pH 2.5) was used as mobile phase A and acetonitrile was used as mobile phase B. The sample solution was diluted with a moving layer A: acetonitrile mixture (4:6) so that the concentration of the compound was 400 µg/mL. Analogs were measured with a flow rate of 0.3 mL/min and an ultraviolet absorptiometer (measurement wavelength: 242 nm) to determine the total amount (%) of each analog with respect to the indicated amount of bardoxolonemethyl.

The stability test was performed under the following conditions.

Storage conditions: 40℃, 75%RH, 1 month or 2 months

Preservation form: Prescription example 2 (prescribed) and prescribed 8 (five types) were put in an open brown bottle]

From the results in Table 10, it was found that when a certain organic acid was added (prescribed 8), the increase in the total amount of analogs was small compared with the case where no organic acid was added (prescription example 2). In addition, it was found that among these organic acids, the formulations containing fumaric acid and malic acid were particularly small in both the total amount of related substances and their increase (1 month and 2 months).

Production of aluminum pouch packaging articles 1 to 3

Tablets were produced by the same procedure as in Formulation Example 2. Specifically, it is as follows.

500.0 g of a solid dispersion containing 40 wt% of Compound A (bardoxolone methyl) (manufactured by a spray drying method, the following “solid dispersion” is also prepared in the same manner), silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma) 2068.0 g, lactose hydrate (Japanese Pharmacopoeia) 1796.0 g, hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) 236.0 g, low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Corporation) 520.0 g of Kyoko Kogyo Co., Ltd.) and 40.0 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Sangyo Co., Ltd.) were mixed with a mixer (TBM-25, manufactured by Tokuju Kosakusho) with a mixer. To this mixture, 20.0 g of magnesium stearate was added and further mixed. This mixture was dry granulated and sized with a roller compactor (CCS-220, manufactured by Paurex, Ltd.). Magnesium stearate in an amount used as 0.38 wt% with respect to the obtained sized product was added and mixed to obtain a mixture for tableting. Formulated (weight: 130 mg, tablet shape: circular shape (7 mm diameter)) using a rotary tabletting machine (HT-AP15, manufactured by Hatadekko Co., Ltd.) to obtain predetermined X containing 5 mg of compound A. The obtained predetermined X was polished by spraying film coating and carnauba wax in the same manner as in Formulation Example 2 to obtain the target tablet X.

The compositions of the obtained predetermined 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 treated with Accra (trademark) film (Sumilite (trademark) FCL-1122, manufactured by Sumitomo Bakelite Co., Ltd.) (hereinafter also referred to as "Accra") or light chloride. Vinyl film (Sumilite (trademark) VSS, manufactured by Sumitomo Bakelite Co., Ltd.) (hereinafter also referred to as “hard vinyl chloride”) or polypropylene film (TAS2230V, manufactured by Daisei Chemicals Co., Ltd.) (hereinafter “polypropylene”) ') and aluminum foil (manufactured by Tokai Toyo Aluminum Hanbai Co., Ltd. or UACJ Seihaku Co., Ltd.) and PTP packaging machine (PFD-100 type, manufactured by Maruho Hatsujo Kogyo Co., Ltd.) in blister packaging. 1 to 3 were obtained. The obtained blister packaged product 3 sheets and desiccant (MS-Ceram-W3G, Tokai Chemical Kogyo Sho) were put in an aluminum bag and sealed with a heat sealer (V-301-10W, manufactured by Fuji Impulse Co., Ltd.) for the purpose of Aluminum bag packaging products 1 to 3 were obtained.

Production of aluminum pouch packaging articles 4 to 6

Except for adding 12.0 g of organic acid (0.2 wt% of organic acid (fumaric acid) is included in the predetermined amount) together with Compound A (bardoxolone methyl), reducing silicic acid-treated crystalline cellulose to 2060.0 g and lactose hydrate to 1792.0 g, In the same procedure as the aluminum bag-packed products 1 to 3, predetermined Y, tablet Y, blister-packed products 4 to 6, and aluminum bag-packed products 4 to 6 were obtained.

Test Example 5: Comparative test of stability of aluminum pouch packaging products 1 to 6

For aluminum bag packaged products 1 to 6 (hereinafter also referred to as “packaged products 1 to 6”), the total amount of related substances ( %) (“at start” and “40° C., 75% RH, 1 month, open”) were measured. The results are shown in Table 13 below. The measurement of the analog of bardoxolone methyl was measured by performing a test by liquid chromatography under the same conditions as in Test Example 4.

From the results of Tables 10 and 13 and Table 14 below, it was found that the increase in the total amount (%) of analogs was suppressed and stability was improved by using an aluminum bag packaged product. In addition, from the results in Table 13 above, in the aluminum bag packaged product, by adding 0.2% by weight of organic acid (fumaric acid) based on the predetermined total weight, the increase in the total amount of related substances (%) is suppressed, and stability tends to increase. found out In addition, in aluminum bag packaging, the increase in the total amount of related substances (%) is suppressed in the case of using a hard vinyl chloride film or a polypropylene film, compared to the Accra (trademark) film (polychlorinated trifluoroethylene), and stability is improved. found it to rise

Test Example 6: Review of Stability of Aluminum Bag Packaging

For Tablet X and Blister Packaged Product 1 (using Accra) (not put in an aluminum bag) obtained in the manufacturing process of the aluminum bag packaging products 1 to 3, the same storage conditions as in Test Examples 4 and 5 (40° C.) , 75% RH, 1 month, open) and storage condition (Tablet X is placed in an uncovered brown glass bottle), the total amount of related substances (%) (“at start” and “40° C., 75% RH, 1 month, open”) was measured. The results are shown in Table 14 below. The measurement of the analog of bardoxolone methyl was measured by performing a test by liquid chromatography under the same conditions as in Test Example 4.

From the results in Tables 13 and 14 above, it was found that the total amount of related substances and the amount of increase thereof were both smaller in the blister packaged product 1 and the aluminum bag packaging product 1 of the tablet X compared to the tablet X (film-coated formulation). Moreover, compared with the blister-packed product 1, it turned out that the aluminum bag-packed product 1 side of tablet X has little little analog total amount and its increase amount. Therefore, it turned out that stability can be improved by making the film coating formulation of this invention into a blister packaged product, and also found that stability can further improve by making the film coating prescription of this invention into 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, and tablet Y-1 prepared to contain 1% by weight of fumaric acid instead of 0.2% by weight in tablet Y, and tablet Y instead of fumaric acid contained in tablet Y Tablet Z prepared to contain 1% by weight of malic acid was used in the following tests. Tablet X, Tablet Y-1 and Tablet Z are all film coated formulations. The total amount (%) of analogs was measured for the prepared tablets X, Y-1, and Z under the same storage conditions and liquid chromatography conditions as in Test Example 5 (data not shown). As a result, tablets Y-1 (containing fumaric acid) and tablet Z (containing malic acid) prepared by adding an organic acid (fumaric acid or malic acid) were compared with the tablet X prepared without adding an organic acid, the total amount of analogs (%) It turned out that an increase was suppressed and stability became high. In addition, it turned out that the tablet Y-1 produced by adding fumaric acid, and the tablet Z produced by adding malic acid have almost no difference in the increase amount of the total amount (%) of analogs from the start of both.

Claims (26)

A pharmaceutical composition having a coating film comprising bardoxolonemethyl or a pharmaceutically acceptable salt thereof, a disintegrant, and a binder. According to claim 1, wherein the disintegrant is crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, from the group consisting of partially α-starch and starch One or more selected pharmaceutical compositions. The pharmaceutical composition according to claim 2, wherein the disintegrant is at least one selected from the group consisting of crospovidone, croscarmellose sodium, and low-substituted hydroxypropyl cellulose. The pharmaceutical composition according to any one of claims 1 to 3, wherein 0.1 to 20 parts by weight of a disintegrant is included with respect to 100 parts by weight of the pharmaceutical composition. The binder according to any one of claims 1 to 4, wherein the binder is hydroxypropyl cellulose, methyl cellulose, hypromellose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose acetate succinate. Nate, hydroxypropylmethylcellulose phthalate, hydroxypropyl starch, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol, starch, gelatin , dextrin, pullulan, agar, and at least one pharmaceutical composition selected from the group consisting of gum arabic. The pharmaceutical composition according to claim 5, wherein the binder is at least one selected from the group consisting of hydroxypropyl cellulose, hypromellose, polyvinyl alcohol and polyvinylpyrrolidone. The pharmaceutical composition according to any one of claims 1 to 6, wherein 0.1 to 30 parts by weight of the binder is included with respect to 100 parts by weight of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 7, further comprising a stabilizer. The pharmaceutical composition according to claim 8, wherein the stabilizing agent is an organic acid. The pharmaceutical composition according to claim 9, wherein the organic acid is fumaric acid and/or malic acid. The pharmaceutical composition according to any one of claims 1 to 10, wherein the coating film comprises at least one coating agent selected from the group consisting of water-soluble polymer, lactose, sucrose, mannitol, titanium oxide, talc, calcium carbonate and triacetin. . 12. The method of claim 11, wherein the water-soluble polymer is polyethylene glycol, polyvinyl alcohol polyethylene glycol graft copolymer, polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol and polyvinyl alcohol methyl methacrylate copolymer. At least one pharmaceutical composition selected from the group consisting of coalescing. The pharmaceutical composition according to claim 11 or 12, wherein the coating film further contains a colorant. The pharmaceutical composition according to claim 13, wherein the colorant comprises at least one selected from the group consisting of yellow ferric trioxide, iron oxide and titanium oxide. The pharmaceutical composition according to any one of claims 1 to 14, wherein the coating agent is contained in an amount of 0.1 to 100 parts by weight based on 100 parts by weight of the coating film. The pharmaceutical composition according to any one of claims 1 to 15, further comprising a brightening agent. The pharmaceutical composition according to claim 16, wherein the brightening agent is carnauba wax and/or magnesium stearate. The pharmaceutical composition according to any one of claims 1 to 17,
Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 20 parts by weight of bardoxolone methyl or a pharmaceutically acceptable salt thereof is included,
Based on 100 parts by weight of the pharmaceutical composition, 3 to 20 parts by weight of a binder is included,
Based on 100 parts by weight of the pharmaceutical composition, 0.1 to 15 parts by weight of a disintegrant is included,
Based on 100 parts by weight of the coating film, 50 to 90 parts by weight of the coating agent are included.
pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 18, wherein bardoxolonemethyl is amorphous. The pharmaceutical composition according to any one of claims 1 to 19, which is a solid preparation. The pharmaceutical composition according to claim 20, wherein the solid preparation is a tablet. A blister packaging product comprising the pharmaceutical composition according to any one of claims 1 to 21, a film laminated with a polymer, and an aluminum foil. The blister packaging product according to claim 22, wherein the polymer laminated film is a film laminated with at least one polymer selected from polypropylene, polyvinyl chloride, polyvinylidene chloride and polytrifluoroethylene chloride. A pharmaceutical packaging product, wherein the blister packaging product according to claim 22 or 23 is sealed in a packaging body. The pharmaceutical packaging article according to claim 24, wherein the packaging body is an aluminum bag. The pharmaceutical package according to claim 24 or 25, wherein a deoxidizer and/or a desiccant is also enclosed in the package.

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