TW202038918A - Pharmaceutical composition - Google Patents

Abstract

Provided is a pharmaceutical composition that has an improved stability of bardoxolone methyl or a pharmaceutically acceptable salt thereof. Use is made of a pharmaceutical composition provided with a coating film, said pharmaceutical composition comprising bardoxolone methyl or a pharmaceutically acceptable salt thereof, a disintegrating agent and a binder.

Description

Pharmaceutical composition

The present invention relates to a pharmaceutical composition, and more specifically to a pharmaceutical composition containing Bardoxolone methyl or a pharmaceutically acceptable salt thereof.

As synthetic terpenoids, bardoxolone methyl represented by the following formula (methyl 2-cyano-3,12-dioxo oleanorane-1,9(11)-diene -28-ester (Methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate) (hereinafter sometimes referred to as "compound A") (refer to Patent Document 1), and It is known that this bardoxolone methyl has a polymorphic form (refer to Patent Document 2). [化1]

It is known that bardoxolone methyl is a low-molecular compound that activates the transcription factor Nrf2, which plays a central role in the stress defense response in the body. It has a wide range of anti-oxidative stress and anti-inflammatory effects. It is used in preclinical research and human clinical trials. It has effective anti-inflammatory and anti-tumor effects in the test. It is also known that bardoxolone methyl exhibits significant anti-cancer activity especially for patients with advanced cancer, and it can improve kidney function, insulin resistance, and blood sugar control in patients with chronic kidney disease caused by type 2 diabetes. Value and capacity for systemic circulatory system diseases (refer to Patent Document 3). In addition, clinical trials have shown that the eGFR (Estimated glomerular filtration rate) value (an indicator of renal function) (an indicator of renal function) is significantly improved by the administration of bardoxolone methyl (see Non-Patent Document 1, Non-Patent Document 2 and Non-Patent Document 3).

The industry has conducted researches to design a suitable pharmaceutical composition for bardoxolone methyl (refer to Patent Document 4), but it is required to further stabilize bardoxolone methyl. [Prior Technical Literature] [Patent Literature]

[Patent Document 1] WO1999/65478 Publication [Patent Document 2] WO2009/023232 Publication [Patent Document 3] WO2009/089545 Publication [Patent Document 4] WO2010/093944 Publication [Non-Patent Literature]

[Non-Patent Document 1] N Engl J Med, 2013, 369, p2492-2503 [Non-Patent Document 2] AM J Nephrol, 2011, 33, p469-476 [Non-Patent Document 3] N Engl J Med, 2011, p327-336

[The problem to be solved by the invention]

The present invention provides a pharmaceutical composition that contains bardoxolone methyl or its pharmacologically acceptable salt, and can be tolerated as a stable pharmaceutical composition. [Technical means to solve the problem]

The present invention relates to the following (1) to (26). (1) A pharmaceutical composition comprising bardoxolone methyl or its pharmaceutically acceptable salt, disintegrating agent and binding agent, and having a coating film. (2) The pharmaceutical composition according to (1), wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, One or more of the group consisting of calcium carboxymethyl cellulose, sodium carboxymethyl starch, partially gelatinized starch and starch. (3) The pharmaceutical composition according to (2), wherein the disintegrant is one selected from the group consisting of crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose More than species. (4) The pharmaceutical composition according to any one of (1) to (3), which contains 0.1 to 20 parts by weight of a disintegrant relative to 100 parts by weight of the pharmaceutical composition. (5) The pharmaceutical composition according to any one of (1) to (4), wherein the binding agent is selected from the group consisting of 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, poly A group consisting of vinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol, starch, gelatin, dextrin, pullulan, agar, and gum arabic One or more of them. (6) The pharmaceutical composition according to (5), wherein the binding agent is one or more 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), which contains 0.1-30 parts by weight of the binding agent relative to 100 parts by weight of the pharmaceutical composition. (8) The pharmaceutical composition according to any one of (1) to (7), which further contains 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) The pharmaceutical composition according to any one of (1) to (10), wherein the coating film comprises a water-soluble polymer, lactose, sugar, mannitol, titanium oxide, talc, calcium carbonate, and triglyceride. One or more coating agents in the group consisting of acetate. (12) The pharmaceutical composition according to (11), wherein the water-soluble polymer is selected from polyethylene glycol, polyvinyl alcohol polyethylene glycol graft copolymer, polyvinylpyrrolidone, hypromellose, One or more of the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and polyvinyl alcohol acrylic acid methyl methacrylate copolymer. (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 coloring agent contains one or more selected from the group consisting of yellow ferric oxide, iron oxide, and titanium oxide. (15) The pharmaceutical composition according to any one of (1) to (14), which contains 0.1 to 100 parts by weight of the coating agent relative to 100 parts by weight of the coating film. (16) The pharmaceutical composition according to any one of (1) to (15), which further contains a gloss agent. (17) The pharmaceutical composition according to (16), wherein the gloss agent is carnauba wax and/or magnesium stearate. (18) A pharmaceutical composition, which is the pharmaceutical composition described in any one of (1) to (17), With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of bardoxolone methyl or its pharmaceutically acceptable salt, Relative to 100 parts by weight of the pharmaceutical composition, containing 3-20 parts by weight of the binding agent, With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-15 parts by weight of the disintegrant, The coating agent contains 50 to 90 parts by weight with respect to 100 parts by weight of the coating film. (19) The pharmaceutical composition according to any one of (1) to (18), wherein bardoxolone methyl 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 lozenge. (22) A blister package product comprising the pharmaceutical composition described in any one of (1) to (21), and a film formed by laminating a polymer and an aluminum foil. (23) The blister package product described in (22), wherein the film formed by laminating the polymer is selected from polypropylene, polyvinyl chloride, polyvinylidene chloride and polychlorotrifluoroethylene. A film made by laminating more than one polymer. (24) A pharmaceutical packaged product, which is formed by enclosing the blister packaged product as described in (22) or (23) in the package body. (25) The medical packaging product described in (24), wherein the packaging body is an aluminum bag. (26) The pharmaceutical package according to (24) or (25), wherein a deoxidizer and/or a desiccant are further enclosed in the package.

According to the present invention, by preparing a pharmaceutical composition containing bardoxolone methyl or its pharmacologically acceptable salt, disintegrant and binding agent and having a coating film, it can increase the or Its pharmacologically acceptable salt stability.

The pharmaceutical composition of the present invention is a pharmaceutical composition containing bardoxolone methyl (hereinafter sometimes referred to as "compound A") or its pharmaceutically acceptable salt, binding agent and disintegrant and having a coating film . 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 based thereon.

In the present invention, the so-called "pharmaceutically acceptable" means generally safe and non-toxic, and can be used to prepare pharmaceutical compositions that are not undesirable in terms of biology or other aspects, and include acceptable use For human-oriented medical use and veterinary use.

In the present invention, the so-called "pharmaceutically acceptable salt" means the salt defined above that is pharmaceutically acceptable and has the required pharmacological activity. Examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as maleic acid, methanesulfonic acid, and oxalic acid. As a pharmaceutically acceptable salt, there can also be cited base addition salts that may be formed when the existing acidic protons can react with inorganic or organic bases. Examples of pharmaceutically acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Examples of pharmaceutically acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

Examples of the pharmaceutically acceptable salts 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 alkali salts such as amine salt. The compound A of the present invention or a pharmaceutically acceptable salt thereof includes any of its intramolecular salts or adducts, and these solvates or hydrates.

Compound A or its pharmaceutically acceptable salts also include geometric isomers, optical isomers and other stereoisomers, tautomers, etc. The present invention includes all possible differences including these. Structures and mixtures of these.

Part or all of each atom in Compound A or its pharmaceutically acceptable salt may be substituted by corresponding isotope atoms. The present invention also includes these derivatives substituted by isotope atoms.

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

The content of compound A or its pharmaceutically acceptable salt in the pharmaceutical composition of the present invention is not particularly limited, and is preferably 0.1-20 parts by weight, more preferably 1-20 parts by weight relative to 100 parts by weight of the pharmaceutical composition Parts, more preferably 2-15 parts by weight, particularly preferably 2-10 parts by weight.

Compound A can take any form of crystalline (form A), amorphous (form B) or a mixture of these. According to a preferred aspect of the present invention, compound A is mainly amorphous (form B), as opposed to 100 parts by weight of compound A preferably contains 50 parts by weight to 100 parts by weight of amorphous (form B), more preferably contains 80 parts by weight to 99.9 parts by weight, and more preferably contains 95 parts by weight to 99 parts by weight. According to a more preferable aspect of the present invention, compound A is an amorphous solid dispersion in a vitreous matrix, for example, a solution or suspension of a mixture of compound A and methacrylic acid copolymer is spray-dried to obtain the product Things. Such a solid dispersion can preferably include a mixture of compound A and a methacrylic acid copolymer in a weight ratio of 4:6, and can more preferably include a mixture of compound A and a methacrylic acid copolymer. The product obtained by spray drying.

In order to obtain an amorphous solid dispersion of Compound A, various fractionation techniques can be used to produce it. As a suitable method for producing a solid dispersion of amorphous compound A, various previous thermal methods (such as hot melt extrusion), solvent methods, and thermal/solvent methods (such as spray drying or fluidizing of granules) can be cited. Dipping method). Regarding the preparation method of solid dispersions, according to the "Forefront of Oral Preparation Technology for Poorly Water-soluble Drugs" (CMC Publication, 2016) (Reference 1), the stability of amorphous drugs in solid dispersions From a viewpoint, it is more desirable that the glass transition point of the solid dispersion is higher. Further, it is described that from the viewpoint of manufacturing, it is preferable to set the exhaust gas temperature during spray drying to be equal to or lower than the glass transition point of the solid dispersion (see page 195 of Reference 1). In addition, as representative solvents used in the production of solid dispersions by the spray drying method, water, methanol, ethanol, acetone, dichloromethane, etc. can be cited. A suitable solvent can be selected from among these according to the drug and the carrier. It is described that the drug and the carrier are dissolved at a high concentration to improve the production efficiency. Therefore, it is preferable to set the drug concentration of the spray solution to 50 mg/mL or more (refer to page 196 of Reference 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" refers to the amount that can obtain the desired pharmacological effect when the pharmaceutical composition of the present invention is administered to a patient. Generally speaking, the therapeutically effective amount can be determined empirically by referring to the clinical parameters of the patient.

The disintegrant contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medical user, and examples include PVP-based disintegrants such as crospovidone; croscarmellose sodium, Cellulose disintegrants such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, and calcium carboxymethyl cellulose; starch disintegrants such as sodium carboxymethyl starch, partially gelatinized starch, starch, etc.; preferably It is selected from crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, partially gelatinized starch One or more of the group consisting of starch and starch, more preferably one or more selected from the group consisting of PVP-based disintegrant and cellulose-based disintegrant, and more preferably selected from crospovidone One or more of the group consisting of croscarmellose sodium and low-substituted hydroxypropyl cellulose, more preferably croscarmellose sodium or low-substituted hydroxypropyl cellulose, Particularly preferred is hydroxypropyl cellulose with a low degree of substitution. Here, the low-substituted hydroxypropyl ether of low-substituted hydroxypropyl cellulose-based cellulose, which is obtained by drying low-substituted hydroxypropyl cellulose, contains hydroxypropoxy (-OC ₃ H ₆ OH: 75.09) 5.0 to 16.0%.

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. It is preferably 0.1 to 20 parts by weight relative to 100 parts by weight of the pharmaceutical composition. Preferably, it contains 0.1 to 18 parts by weight, and more preferably contains 0.1 to 15 parts by weight.

The binding agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medical user, and is preferably selected from hydroxypropyl cellulose, hypromellose (hydroxypropyl methyl cellulose), Methyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxy Propyl starch, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol, starch (more preferably corn starch, Potato starch), gelatin, dextrin, amylopectin, agar, and gum arabic are more than one kind, more preferably selected from hydroxypropyl cellulose, hypromellose, polyvinyl alcohol and polyethylene One or more of the group consisting of pyrrolidone is more preferably hydroxypropyl cellulose or hypromellose, particularly preferably hypromellose.

The content of the binding agent in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine. Relative to 100 parts by weight of the pharmaceutical composition, it preferably contains 0.1 to 30 parts by weight, more preferably The content is 0.5 to 25 parts by weight, and more preferably 3 to 20 parts by weight.

The pharmaceutical composition of the present invention may also contain compound A, disintegrating agent, and other additives used as medicine other than the binding agent. For example, it may contain stabilizers, excipients, lubricants, and coloring agents used in pharmaceutical preparations. , One or more additives in the group consisting of fluidizing agent and gloss agent. The stabilizers, excipients, lubricants, colorants, fluidizing agents, and glossing agents in this specification are not limited to their respective uses (functions), and can also be used for other uses (functions) (for example, the binding agent is used as Use of excipients, use of excipients as binding agents, etc.).

The stabilizer contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medical user, and examples include organic acids, calcium carbonate, etc., and organic acids are preferred. As the organic acid contained in the pharmaceutical composition of the present invention, for example, fumaric acid, malic acid, citric acid, citric acid hydrate, citric anhydride, succinic acid, adipic acid, tartaric acid, maleic acid The acid etc. are preferably fumaric acid and/or malic acid, and more preferably fumaric acid. By making the pharmaceutical composition of the present invention contain fumaric acid and/or malic acid, it is possible to produce a good preparation with less total amount of related substances and higher 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 medicine. Relative to 100 parts by weight of the pharmaceutical composition, the stabilizer preferably contains 0.01 Parts by weight to 30 parts by weight, more preferably 0.05 parts by weight to 10 parts by weight, and still more preferably 0.1 parts by weight to 5 parts by weight.

The excipients contained in the pharmaceutical composition of the present invention are not particularly limited as long as they are used by medical users. Examples include sugars, sugar alcohols, crystalline cellulose, and silicic acid-treated crystalline cellulose (silicated crystalline cellulose). ), inorganic salts, etc., preferably lactose, white sugar, maltose, sucrose, mannitol, sorbitol, erythritol, maltitol, xylitol, glucose, crystalline cellulose, silica-treated crystalline cellulose, phosphoric acid Calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, calcium phosphate, two or more of these excipients can be used in combination, more preferably lactose (preferably lactose hydrate), mannitol, silicic acid treated crystal For cellulose, two or more of these excipients can 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 medicine. Relative to 100 parts by weight of the pharmaceutical composition, it preferably contains 0.1 to 99.9 parts by weight of the excipient Parts, more preferably 1 part by weight to 95 parts by weight, and still more preferably 10 parts by weight 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 medical user. For example, magnesium stearate, calcium stearate, sodium lauryl sulfate, talc, and glycerol monostearate are preferred. Ester, light silicic anhydride, sodium stearyl fumarate, sucrose fatty acid esters (such as sucrose stearate, sucrose palmitate, sucrose oleate, sucrose laurate, etc.), can be 2 kinds The above lubricants are 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. Relative to 100 parts by weight of the pharmaceutical composition, it preferably contains 0.05 parts by weight to 10 parts by weight, more preferably The content is from 0.1 parts by weight to 5 parts by weight, and more preferably from 0.5 parts by weight 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 medical user, and preferably contains selected from yellow ferric oxide, titanium oxide, talc, ferric oxide, black iron oxide, Iron oxide, copper chlorophyll, sodium copper chlorophyllin, carbon black, medicinal carbon, food coloring, licorice extract, green tea powder, riboflavin, riboflavin butyrate, riboflavin sodium phosphate and octyl myristate One or more types in the group consisting of dialkyl esters, and more preferably one or more types selected from the group consisting of yellow ferric oxide, iron oxide, and titanium oxide.

The content of the coloring agent in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine. For example, it may contain 0.01 to 5 parts by weight relative to 100 parts by weight of the pharmaceutical composition.

The fluidizing agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medical user. Examples include: hydrous silica, light silicic anhydride, synthetic aluminum silicate, synthetic hydromagnesium carbonate, dry Aluminum hydroxide gel, kaolin, calcium silicate, aluminum magnesium silicate, talc, etc., can be used in combination of two or more of these fluidizing agents.

The content of the fluidizing agent in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine. For example, it may contain 0.01 to 5 parts by weight relative to 100 parts by weight of the pharmaceutical composition.

The gloss agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is used as a medical user. For example, carnauba wax, shellac, beeswax, hydrogenated oil, magnesium stearate, etc. can be used. The above glossing agents are used in combination, preferably carnauba wax and/or magnesium stearate.

The content of the gloss agent contained in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a medicine. It is preferably 0.0001 to 100 parts by weight relative to 100 parts by weight of the pharmaceutical composition, and more It is preferably 0.001 to 10 parts by weight, and more preferably 0.01 to 1 part by weight.

The pharmaceutical composition of the present invention has a coating film. The coating film can be provided, for example, by coating a naked preparation (for example, a naked tablet) containing Compound A or a pharmaceutically acceptable salt thereof, a disintegrant, and a binding agent. This coating treatment can be performed, for example, by spraying a coating solution containing a coating agent on a naked preparation (for example, a naked tablet) containing Compound A by a spray coating method. The coating agent is used by dissolving, suspending, or dispersing in a coating liquid, and as a solvent constituting the coating liquid, for example, water, alcohols such as methanol or ethanol, etc., are more preferably water.

The coating film of the pharmaceutical composition of the present invention is not particularly limited, and preferably comprises a group selected from the group consisting of water-soluble polymers, lactose, sugar, mannitol, titanium oxide, talc, calcium carbonate and triacetin One or more of the coating agents, more preferably contains glycerol triacetate.

The water-soluble polymer is not particularly limited as long as it is used by medical users, and is preferably selected from polyethylene glycol, polyvinyl alcohol polyethylene glycol graft copolymer, polyvinylpyrrolidone, and hypromellose , Hydroxypropyl cellulose, polyvinyl alcohol, and polyvinyl alcohol acrylic acid methyl methacrylate copolymer.

The coating film of the pharmaceutical composition of the present invention preferably further contains a coloring agent, and the coloring agent is more preferably one or more selected from the group consisting of yellow ferric oxide, iron oxide, and titanium oxide.

The coating agent in the coating film is not particularly limited. Relative to 100 parts by weight of the coating film, it preferably contains 0.1 to 100 parts by weight, more preferably 1 to 95 parts by weight, and more preferably Contains 50 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 light stability and the like to the pharmaceutical composition. With respect to 100 parts by weight of the naked preparation, the coating film (coating ) It is preferably 0.01 parts by weight to 50 parts by weight in a dry state, more preferably 0.05 parts by weight to 30 parts by weight, and still more preferably 0.1 parts by weight to 20 parts by weight.

The pharmaceutical composition of the present invention preferably further contains a gloss agent, and more preferably contains carnauba wax and/or magnesium stearate as a gloss agent.

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

The shape of the pharmaceutical composition of the present invention is not particularly limited. It is preferably a solid preparation, more preferably a tablet, powder, fine granule, granule, capsule or dry syrup, and more preferably a lozenge. . By setting the shape of the pharmaceutical composition of the present invention as a lozenge, it has the advantages of being easy to take, having sufficient physical strength, and not easy to collapse compared with capsules.

As a manufacturing method when the pharmaceutical composition of the present invention is a tablet, a mixture containing bardoxolone methyl or its pharmaceutically acceptable salt, disintegrant and binding agent as an active ingredient is granulated, Tablets are manufactured through a film coating step.

The manufacturing method of the pharmaceutical composition of the present invention is not particularly limited. For example, it can be manufactured by a method generally used in the technical field of pharmaceutics such as compression molding, such as a direct compression method or a dry granule compression method (roller compression molding method, Standard Chartered ingot method, etc.). In each case, it is preferable to mix the compound A or its pharmaceutically acceptable salt, and additives such as a disintegrant or binding agent, and perform granulation and sizing as necessary. Then, for example, when preparing a tablet, it is possible to use a compression tablet machine to form the obtained dry granulated product into a tablet. The ingot pressure can be appropriately selected within the range of, for example, 300 to 3000 kg/cm ² . The size of the tablet is not particularly limited, and it is preferable that the weight of one tablet is 20 to 3000 mg, and the diameter of the tablet is 5 to 15 mm. In the case of coating the naked tablets, a solution/dispersion solution in which the coating agent is dissolved/dispersed can be used to coat the obtained naked tablets to form a coating. Examples of the solvent for dissolving/dispersing the coating agent include water, ethanol, isopropanol, mixed solvents of these, and the like. Among these, water is preferred. The coating is performed using, for example, a conventional pan-type coating machine, a vent-type coating machine, a fluidized layer coating device, a rotating fluidized coating device, and the like.

As a preferred aspect of the pharmaceutical composition of the present invention, a pharmaceutical composition (preferably a lozenge), wherein With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of compound A or a pharmaceutically acceptable salt thereof, With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-30 parts by weight of a binding agent (preferably hypromellose), With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose), A coating agent is contained relative to 100 parts by weight of the coating film (it is preferable that the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) 0.1-100 parts by weight.

As another preferred aspect of the pharmaceutical composition of the present invention, a pharmaceutical composition (preferably a lozenge), wherein With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of compound A or a pharmaceutically acceptable salt thereof, With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-30 parts by weight of a binding agent (preferably hypromellose), With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose), With respect to 100 parts by weight of the pharmaceutical composition, it contains a gloss agent (preferably carnauba wax and/or magnesium stearate) 0.0001 to 10 parts by weight, A coating agent is contained relative to 100 parts by weight of the coating film (it is preferable that the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) 0.1-100 parts by weight.

As another preferred aspect of the pharmaceutical composition of the present invention, a pharmaceutical composition (preferably a lozenge), wherein With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of compound A or a pharmaceutically acceptable salt thereof, With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-30 parts by weight of a binding agent (preferably hypromellose), With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose), Relative to 100 parts by weight of the pharmaceutical composition, it contains 0.01-30 parts by weight of a stabilizer (preferably an organic acid, more preferably fumaric acid), With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.001 to 10 parts by weight of a gloss agent (preferably carnauba wax and/or magnesium stearate), A coating agent is contained relative to 100 parts by weight of the coating film (it is preferable that the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) 0.1-100 parts by weight.

As a more preferable aspect of the pharmaceutical composition of the present invention, a pharmaceutical composition (preferably a lozenge), wherein With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of compound A or a pharmaceutically acceptable salt thereof, With respect to 100 parts by weight of the pharmaceutical composition, 0.5-25 parts by weight of a binding agent (preferably hypromellose) is contained, With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-18 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose), A coating agent is contained relative to 100 parts by weight of the coating film (it is preferable that the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) 1 to 95 parts by weight.

As another more preferable aspect of the pharmaceutical composition of the present invention, a pharmaceutical composition (preferably a lozenge), wherein With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of compound A or a pharmaceutically acceptable salt thereof, With respect to 100 parts by weight of the pharmaceutical composition, 0.5-25 parts by weight of a binding agent (preferably hypromellose) is contained, With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-18 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose), With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.001 to 10 parts by weight of a gloss agent (preferably carnauba wax and/or magnesium stearate), A coating agent is contained relative to 100 parts by weight of the coating film (it is preferable that the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) 1 to 95 parts by weight.

As another more preferable aspect of the pharmaceutical composition of the present invention, a pharmaceutical composition (preferably a lozenge), wherein With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of compound A or a pharmaceutically acceptable salt thereof, With respect to 100 parts by weight of the pharmaceutical composition, 0.5-25 parts by weight of a binding agent (preferably hypromellose) is contained, With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-18 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose), Relative to 100 parts by weight of the pharmaceutical composition, it contains a stabilizer (preferably an organic acid, more preferably fumaric acid) 0.05-10 parts by weight, With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.001 to 10 parts by weight of a gloss agent (preferably carnauba wax and/or magnesium stearate), A coating agent is contained relative to 100 parts by weight of the coating film (it is preferable that the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) 1 to 95 parts by weight.

As a further preferred aspect of the pharmaceutical composition of the present invention, a pharmaceutical composition (preferably a lozenge), wherein With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of compound A or a pharmaceutically acceptable salt thereof, With respect to 100 parts by weight of the pharmaceutical composition, containing 3-20 parts by weight of a binding agent (preferably hypromellose), With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-15 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose), A coating agent is contained relative to 100 parts by weight of the coating film (it is preferable that the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) 50 to 90 parts by weight.

As yet another preferred aspect of the pharmaceutical composition of the present invention, a pharmaceutical composition (preferably a lozenge), wherein With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of compound A or a pharmaceutically acceptable salt thereof, With respect to 100 parts by weight of the pharmaceutical composition, containing 3-20 parts by weight of a binding agent (preferably hypromellose), With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-15 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose), With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.01 to 1 part by weight of a gloss agent (preferably carnauba wax and/or magnesium stearate), A coating agent is contained relative to 100 parts by weight of the coating film (it is preferable that the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) 50 to 90 parts by weight.

As yet another preferred aspect of the pharmaceutical composition of the present invention, a pharmaceutical composition (preferably a lozenge), wherein With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of compound A or a pharmaceutically acceptable salt thereof, With respect to 100 parts by weight of the pharmaceutical composition, containing 3-20 parts by weight of a binding agent (preferably hypromellose), With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-15 parts by weight of a disintegrant (preferably low-substituted hydroxypropyl cellulose), Relative to 100 parts by weight of the pharmaceutical composition, it contains a stabilizer (preferably an organic acid, more preferably fumaric acid) 0.1 to 5 parts by weight, With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.01 to 1 part by weight of a gloss agent (preferably carnauba wax and/or magnesium stearate), A coating agent is contained relative to 100 parts by weight of the coating film (it is preferable that the coating film contains one or more coating agents selected from the group consisting of hypromellose, lactose, and triacetin) 50 to 90 parts by weight.

According to another aspect of the present invention, there is provided a method for improving the stability of bardoxolone methyl or a pharmaceutically acceptable salt thereof, characterized in that: bardoxolone methyl or a pharmaceutically acceptable salt thereof Add disintegrant and binder, and carry out coating treatment. In addition, according to another preferred aspect of the present invention, there is provided a method for reducing the total amount of related substances such as bardoxolone methyl or its pharmaceutically acceptable salt, which is characterized in that: Or its pharmaceutically acceptable salt is added with a disintegrant and a binding agent, and the coating is processed. In this method, similar to the above-mentioned pharmaceutical composition of the present invention, other additives used as medicines other than compound A, disintegrating agent, and binding agent can also be added. For example, it can be added to pharmaceutical preparations. Stabilizers, excipients, lubricants, colorants, fluidizers, and gloss agents are one or more additives.

The pharmaceutical composition of the present invention can be provided by being stored in airtight containers such as bottle packaging, blister packaging, and aluminum bags. As the raw material of the airtight container, there is no particular limitation as long as it can inhibit the penetration of external moisture. The raw materials used in the pharmaceutical field for the purpose of preventing moisture intolerant contents can be used. Among them, the blister is particularly preferred. Packaging goods.

The blister package of the present invention includes the above-mentioned pharmaceutical composition containing compound A and the like, and a film and aluminum foil formed by laminating a polymer. The polymer laminated film is not particularly limited as long as it is generally used by blister packaging products. Preferably, polypropylene, polyvinyl chloride, polyvinylidene chloride, polychlorotrifluoroethylene ( Films formed by laminating polymers such as ACLAR (trademark), etc., are more preferably polypropylene or rigid vinyl chloride. The aluminum foil is not particularly limited as long as it can be used for blister packaging products, and it may be a general general-purpose aluminum foil, preferably an aluminum foil having a reduced amount of melamine resin in the adhesive. The manufacturing method of the blister packaging product of the present invention is not particularly limited, and can be obtained by using a commonly used blister packaging machine to form pockets on the film formed by laminating polymers, After the tablet is put, the aluminum foil is sealed with heat or the like.

The pharmaceutical packaging product of the present invention is obtained by enclosing the above-mentioned blister packaging product in a packaging body. The packaging body is not particularly limited as long as it is a general user of medical packaging products, and an aluminum bag or the like is preferable. It is possible to simultaneously enclose what is contained in a general pharmaceutical package in the pharmaceutical package, and it is preferable to enclose the deoxidizer and/or desiccant together with the above-mentioned blister package. The medical packaging product of the present invention can be manufactured by enclosing the blister package product manufactured in the above manner into a package such as an aluminum bag, and sealing it using a heat sealer or the like. [Example]

Hereinafter, the present invention will be explained more specifically with examples, but the technical scope of the present invention is not limited to these examples.

Manufacturing example of film-coated tablets Formulation example 1 : Using a mixer (TBM-25, manufactured by Deshou Works Co., Ltd.), a solid dispersion containing 40% by weight of compound A (bardoxolone methyl) (by Manufactured by spray drying method, the following "solid dispersions" are also manufactured in the same way) 480.8 g, 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, manufactured by Shin-Etsu Chemical Co., Ltd.) 500.0 g, and light silicic anhydride (Adsuride 101 , Freund Corporation Co., Ltd.) 38.5 g was mixed. 19.2 g of magnesium stearate was added to the mixture, and the mixture was further mixed. Using a roller press (CCS-220, manufactured by Powrex Co., Ltd.), the mixture was subjected to dry granulation and granulation. Magnesium stearate was added in an amount of 0.38% by weight with respect to the obtained whole grain product and mixed to obtain a mixed product for tableting. Using a rotary tablet machine (HT-AP15, manufactured by Hata Iron Works Co., Ltd.) to make a tablet (weight: 130 mg, tablet shape: round (diameter 7 mm)) to obtain a bare tablet (Formulation Example 1) ) (Refer to Table 1).

The coating agent mixture was dispersed in water to prepare a coating solution with a solid content 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 Powrex Co., Ltd.) was used to coat the naked tablet by spraying the coating solution so that the coating becomes 5 parts by weight relative to 100 parts by weight of the naked tablet in a dry state. Carnauba wax in an amount of 0.03% by weight with respect to the bare ingot was dispersed for polishing, thereby obtaining the target lozenge.

The compositions of the obtained bare tablets and tablets are shown in Tables 1 and 2 below. [Table 1] Table 1: (bare ingot) of Formulation Example 1 Formulation ingredient In 1 tablet (mg) Content rate (wt%) Compound A 5.0 3.85 Methacrylic acid copolymer 7.5 5.77 Silicic acid treated crystalline cellulose 51.4 39.5 Light Silicic Anhydride 1 0.8 Lactose hydrate 44.6 34.3 Hypromellose 6.5 5 Low-substituted hydroxypropyl cellulose (L-HPC) 13 10 Magnesium stearate 1 0.8 total 130 100

[Table 2] Table 2 : Film coating formula of formula example 1 ( bare tablets ) ingredient In 1 tablet (mg) Content rate (wt%) Hypromellose 3.90 60.0 Titanium Oxide 1.46 22.4 Lactose hydrate 0.65 10.0 Triacetin 0.39 6.0 Yellow ferric oxide 0.10 1.5 Iron oxide 0.01 0.1 total 6.50 100.0

Formulation Example 2 Using a mixer (TBM-25, manufactured by Tokusu Works Co., Ltd.), a solid dispersion containing 40% by weight of compound A (bardoxolone methyl) (manufactured by spray drying method, the following "Solid dispersion" is also produced in the same way) 500.0 g, silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma) 2068.0 g, lactose hydrate (Japanese Pharmacopoeia) 1796.0 g, hypromellose (TC-5E, Shin-Etsu Chemical) Industrial Co., Ltd. manufacturing) 236.1 g, low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Chemical Co., Ltd. manufacturing) 520.0 g, and light silicic anhydride (Adsuride 101, Freund Corporation manufacturing) ) 40.0 g for mixing. 20.0 g of magnesium stearate was added to this mixture and further mixed. Using a roller press (CCS-220, manufactured by Powrex Co., Ltd.), the mixture was subjected to dry granulation and granulation. Magnesium stearate was added in an amount of 0.38% by weight with respect to the obtained whole grain product and mixed to obtain a mixed product for tableting. A rotary tablet machine (HT-AP15, manufactured by Hata Iron Works Co., Ltd.) was used for tableting (weight: 130 mg, tablet shape: round (diameter 7 mm)) to obtain a tablet containing 5 mg of compound A Bare ingot (Formulation example 2) (refer to Table 3).

The coating agent mixture was dispersed in water to prepare a coating liquid with a solid content 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 Powrex Co., Ltd.) was used to coat the naked tablet by spraying the coating solution so that the coating becomes 5 parts by weight relative to 100 parts by weight of the naked tablet in a dry state. Carnauba wax in an amount of 0.03% by weight with respect to the bare ingot was dispersed for polishing, thereby obtaining the target lozenge.

Formulation example 3 is the same as formulation example 2 for 5 mg tablets, and the mixture is prepared using a rotary tablet machine (HT-AP15, manufactured by Hata Iron Works Co., Ltd.) to make tablets (weight: 260 mg, tablet shape: round) (Diameter 9 mm)), thereby obtaining bare tablets containing 10 mg of compound A (Formulation Example 3) (refer to Table 3).

The coating agent mixture was dispersed in water to prepare a coating liquid with a solid content of 15% by weight (the composition of the coating agent mixture is shown in Table 4 below). Using a tablet coating machine (DRC-200, manufactured by Powrex Co., Ltd.), 200 g of the naked tablet was coated with a spray coating solution so that the coating in a dry state became 4 parts by weight relative to 100 parts by weight of the naked tablet. clothes. Carnauba wax in an amount of 0.03% by weight with respect to the bare ingot was dispersed for polishing, thereby obtaining the target lozenge.

Formulation example 4 is the same as formulation example 2 for 5 mg tablets, and the mixture is prepared using a rotary tablet machine (HT-AP15, manufactured by Hata Iron Works Co., Ltd.) for tableting (weight: 390 mg, tablet shape: oval) (Long diameter 13.5 mm, short diameter 7 mm)), thereby obtaining a bare tablet containing 15 mg of compound A (Formulation Example 4) (refer to Table 3).

The coating agent mixture was dispersed in water to prepare a coating liquid with a solid content 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 Powrex Co., Ltd.), the coating solution was sprayed and coated in a dry state so that the coating was 3.5 parts by weight relative to 100 parts by weight of the bare tablet. Carnauba wax in an amount of 0.03% by weight with respect to the bare ingot was dispersed for polishing, thereby obtaining the target lozenge.

The compositions of the obtained bare tablets and tablets are shown in Tables 3 and 4 below. [table 3] Table 3: (bare ingot) Formulation of Formulation Examples 2 to 4 ingredient 5 mg tablets (Formulation example 2) 10 mg tablets (Formulation Example 3) 15 mg tablets (Formulation Example 4) In 1 tablet (mg) Content rate (wt%) In 1 tablet (mg) Content rate (wt%) In 1 tablet (mg) Content rate (wt%) Compound A 5.0 3.85 10.0 3.85 15.0 3.85 Methacrylic acid copolymer 7.5 5.77 15.0 5.77 22.5 5.77 Silicic acid treated crystalline cellulose 51.7 39.8 103.4 39.8 155.1 39.8 Lactose hydrate 44.9 34.5 89.8 34.5 134.7 34.5 Low-substituted hydroxypropyl cellulose (L-HPC) 13.0 10.0 26.0 10.0 39.0 10.0 Hypromellose 5.9 4.5 11.8 4.5 17.7 4.5 Light Silicic Anhydride 1.0 0.8 2.0 0.8 3.0 0.8 Magnesium stearate 1.0 0.8 2.0 0.8 3.0 0.8 total 130 100 260 100 390 100

[Table 4] Table 4 : The formula used to coat the film coating of formula examples 2 to 4 ( bare tablets ) and add gloss agent ingredient 5 mg tablets 10 mg tablets 15 mg tablets In 1 tablet (mg) Content rate (wt%) In 1 tablet (mg) Content rate (wt%) In 1 tablet (mg) Content rate (wt%) Hypromellose 3.90 59.6 6.19 59.6 8.12 59.6 Titanium Oxide 1.46 22.3 2.31 22.3 3.03 22.3 Lactose hydrate 0.65 9.9 1.03 9.9 1.35 9.9 Triacetin 0.39 6.0 0.62 6.0 0.81 6.0 Yellow ferric oxide 0.10 1.5 0.15 1.5 0.20 1.5 Iron oxide 0.01 0.2 0.01 0.2 0.01 0.2 Carnauba wax 0.03 0.5 0.07 0.5 0.10 0.5 total 6.54 100 10.39 100 13.63 100 *Carnauba wax is used as a gloss agent, and other ingredients are used for coating film coating. Furthermore, in Table 4 above, by using magnesium stearate instead of carnauba wax as a gloss agent for polishing, the target lozenges can also be obtained.

The mixing of the common mixture of bare ingots 1 to 3 will include 336.5 g of solid dispersion of 40% by weight compound A, 807.7 g of silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma), and 13.5 g of light silicic anhydride in polyethylene Mix 200 times in the bag to obtain a mixture (I) containing compound A. In addition, 631.9 g of silicic acid-treated crystalline cellulose and 11.9 g of light silicic anhydride were mixed 200 times in a polyethylene bag to obtain a mixture (II).

Example 1 : Preparation method of bare ingot 1 The above-mentioned mixture (I) 215.0 g, lactose hydrate 210.5 g, hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Soda Co., Ltd.) 19.5 g, and cross-linked 32.5 g of sodium carboxymethyl cellulose (Ac-Di-Sol, manufactured by FMC BioPolymer) was mixed 200 times in a polyethylene bag, 2.5 g of magnesium stearate (Parteck LUB, Merck) was added, and further mixed 50 times. Using a dry granulator (TF-Labo, manufactured by Freund Corporation), the obtained mixture was subjected to dry granulation. A granulator (COMIL, manufactured by Powrex Co., Ltd.) was used to granulate the obtained dry granulated product. 443.1 g of the obtained whole product, 124.6 g of the above-mentioned mixed product (II), and 30.0 g of croscarmellose sodium (Ac-Di-Sol, manufactured by FMC BioPolymer) were mixed 200 times in a polyethylene bag, Furthermore, 2.3 g of magnesium stearate was added and mixed 50 times to obtain a tablet mixture. A rotary tablet machine (VIRGO, manufactured by Kikusui Manufacturing Co., Ltd.) was used to make a tablet (weight 130 mg, tablet shape: round (diameter 7 mm)) to obtain a bare tablet 1.

Example 2 : Preparation method of bare ingot 2 The above-mentioned mixture (I) 148.9 g, lactose hydrate 145.7 g, hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Soda Co., Ltd.) 13.5 g, and low substitution 22.5 g of hydroxypropyl cellulose (L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) was mixed 200 times in a polyethylene bag, then 1.7 g of magnesium stearate (Parteck LUB, Merck) was added, and further mixed 50 times . Using a dry granulator (TF-Labo, manufactured by Freund Corporation), the obtained mixture was subjected to dry granulation. A granulator (COMIL, manufactured by Powrex Co., Ltd.) was used to granulate the obtained dry granulated product. 295.4 g of the obtained whole product, 83.1 g of the above-mentioned mixed product (II), and 20.0 g of low-substituted hydroxypropyl cellulose (L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed in a polyethylene bag for 200 Then, 1.5 g of magnesium stearate was further added and mixed 50 times to obtain a tablet mixture. A rotary tablet machine (VIRGO, manufactured by Kikusui Manufacturing Co., Ltd.) was used to make a tablet (weight 130 mg, tablet shape: round (diameter 7 mm)) to obtain bare tablet 2.

Example 3 : Preparation method of bare tablet 3 The above mixture (I) 148.9 g, lactose hydrate 145.7 g, hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Soda Co., Ltd.) 13.5 g, and starch ethanol Sodium sulfate (Primojel, DFE Pharma) 22.5 g was mixed 200 times in a polyethylene bag, 1.7 g of magnesium stearate (Parteck LUB, Merck) was added, and further mixed 50 times. Using a dry granulator (TF-Labo, manufactured by Freund Corporation), the obtained mixture was subjected to dry granulation. A granulator (COMIL, manufactured by Powrex Co., Ltd.) was used to granulate the obtained dry granulated product. 295.4 g of the obtained whole product, 83.1 g of the above-mentioned mixed product (II), and 20.0 g of sodium starch glycolate (Primojel, DFE Pharma) were mixed in a polyethylene bag for 200 times, and 1.5 g of magnesium stearate was added. Mix 50 times to obtain a mixture for tableting. A rotary tablet machine (VIRGO, manufactured by Kikusui Manufacturing Co., Ltd.) was used to make a tablet (weight 130 mg, tablet shape: round (diameter 7 mm)) to obtain bare tablet 3.

Test Example 1 : Comparative test of the stability of bare ingots 1 to 3 obtained in Example 1 , Example 2, and Example 3. The determination of related substances such as bardoxolone methyl was carried out by liquid chromatography under the following conditions And determined. As a column for liquid chromatography, ACQUITY UPLC HSS C18 with a particle size of 1.8 μm, 2.1 mm×50 mm (manufactured by Waters) or its equivalent was used, and the column temperature was maintained at 40°C. As the mobile phase A, 20 mmol/L sodium dihydrogen phosphate-citric acid buffer (pH 4.5) was used, and as the mobile phase B, acetonitrile was used. The sample solution was diluted with 65% by weight of acetonitrile so that the concentration of bardoxolone methyl became 100 μg/mL. At a flow rate of 0.6 mL/min, use an ultraviolet absorbance photometer (measurement wavelength: 242 nm) to measure the related substances, and obtain the total amount (%) of various related substances relative to the indicated amount of bardoxolone methyl.

The stability test is carried out under the following conditions. Storage conditions: 30℃, 75%RH, 1 month Storage form: Put naked ingots 1～3 in the brown bottle with the lid open

[table 5] Table 5 : Comparison results of the stability of bare ingots 1 to 3 Bare Ingot 1 Bare Ingot 2 Bare Ingot 3 Disintegrant used Croscarmellose Sodium Low degree of substitution hydroxypropyl cellulose Sodium starch glycolate The total amount of related substances (%) 0.26 0.16 0.33

According to the results in Table 5 above, it can be seen that no matter what kind of disintegrant is added, it is a preparation with a small total amount of related substances and excellent stability (also, although the data is not shown, no matter where it is added In the case of a disintegrant, the total amount of similar substances is smaller than the initial increase). Comparing these three kinds of naked tablets, it can be seen that the naked tablets containing low-substituted hydroxypropyl cellulose as a disintegrant are the preparations with less total amount (and increase) of related substances and the most excellent overall stability. .

Example 4 : Preparation method of bare ingot 4 Compound A 44.2 g, silicic acid-treated crystalline cellulose 110.4 g, light silicic anhydride 1.8 g, lactose hydrate 176.9 g, and hypromellose (TC-5E, Shin-Etsu Chemical) Industrial Co., Ltd.) 4.6 g was mixed in a polyethylene bag 200 times, and 1.8 g of magnesium stearate (Parteck LUB, Merck) was added, and the mixture was further mixed 50 times. Using a dry granulator (TF-Labo, manufactured by Freund Corporation), the obtained mixture was subjected to dry granulation. A granulator (COMIL, manufactured by Powrex Co., Ltd.) was used to granulate the obtained dry granulated product. Put 295.4 g of the whole product, 81.5 g of silicic acid-treated crystalline cellulose, 1.5 g of light silicic anhydride, and 20 g of croscarmellose sodium (Ac-Di-Sol, manufactured by FMC BioPolymer) in a polyethylene bag After mixing 200 times, 1.5 g of magnesium stearate was further added, and the mixture was mixed 50 times to obtain a tablet mixture. A rotary tablet machine (VIRGO, manufactured by Kikusui Manufacturing Co., Ltd.) was used to make a tablet (weight 130 mg, tablet shape: round (diameter 7 mm)) to obtain bare tablet 4.

Example 5: Method of Preparation 5 ingot bare Compound A 44.2 g, crystalline cellulose, silicic acid treatment 90.9 g, light silica anhydride 1.8 g, Lactose monohydrate 159.6 g, and hypromellose (TC-5E, Shin-Etsu Chemical Industrial Co., Ltd.) 41.4 g was mixed 200 times in a polyethylene bag, and 1.8 g of magnesium stearate (Parteck LUB, Merck) was added, and further mixed 50 times. Using a dry granulator (TF-Labo, manufactured by Freund Corporation), the obtained mixture was subjected to dry granulation. A granulator (COMIL, manufactured by Powrex Co., Ltd.) was used to granulate the obtained dry granulated product. Put 295.4 g of the whole product, 81.5 g of silicic acid-treated crystalline cellulose, 1.5 g of light silicic anhydride, and 20.0 g of croscarmellose sodium (Ac-Di-Sol, manufactured by FMC BioPolymer) in a polyethylene bag After mixing 200 times, 1.5 g of magnesium stearate was further added, and the mixture was mixed 50 times to obtain a tablet mixture. A rotary tablet machine (VIRGO, manufactured by Kikusui Manufacturing Co., Ltd.) was used to make a tablet (weight 130 mg, tablet shape: round (diameter 7 mm)) to obtain bare tablet 5.

Example 6 : Preparation method of bare ingot 6 Compound A 44.2 g, silicic acid-treated crystalline cellulose 98.0 g, light silicic anhydride 1.8 g, lactose hydrate 166.3 g, and hypromellose (TC-5E, Shin-Etsu Chemical) Industrial Co., Ltd.) 4.6 g was mixed in a polyethylene bag 200 times, and 1.8 g of magnesium stearate (Parteck LUB, Merck) was added, and the mixture was further mixed 50 times. Using a dry granulator (TF-Labo, manufactured by Freund Corporation), the obtained mixture was subjected to dry granulation. A granulator (COMIL, manufactured by Powrex Co., Ltd.) was used to granulate the obtained dry granulated product. The whole product 275.4 g, silicic acid-treated crystalline cellulose 81.5 g, light silicic anhydride 1.5 g, and low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Chemical Co., Ltd.) 40.0 g were added to polyethylene The bag was mixed 200 times, and 1.5 g of magnesium stearate was further added and mixed 50 times to obtain a tablet mixture. A rotary tableting machine (VIRGO, manufactured by Kikusui Manufacturing Co., Ltd.) was used to make tablets (weight 130 mg, tablet shape: round (diameter 7 mm)), thereby obtaining bare tablets 6.

Example 7 : Preparation method of bare ingot 7 Compound A 44.2 g, silicic acid-treated crystalline cellulose 78.2 g, light silicic anhydride 1.8 g, lactose hydrate 149.3 g, and hypromellose (TC-5E, Shin-Etsu Chemical) Industrial Co., Ltd.) 41.4 g was mixed 200 times in a polyethylene bag, and 1.8 g of magnesium stearate (Parteck LUB, Merck) was added, and further mixed 50 times. Using a dry granulator (TF-Labo, manufactured by Freund Corporation), the obtained mixture was subjected to dry granulation. A granulator (COMIL, manufactured by Powrex Co., Ltd.) was used to granulate the obtained dry granulated product. The whole product 275.4 g, silicic acid-treated crystalline cellulose 81.5 g, light silicic anhydride 1.5 g, and low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Chemical Co., Ltd.) 40.0 g were added to polyethylene The bag was mixed 200 times, and 1.5 g of magnesium stearate was further added and mixed 50 times to obtain a tablet mixture. A rotary tablet machine (VIRGO, manufactured by Kikusui Manufacturing Co., Ltd.) was used to make a tablet (weight 130 mg, tablet shape: round (diameter 7 mm)) to obtain a bare tablet 7.

The composition of the disintegrant and binding agent in the above bare tablets 4-7 is as follows. [Table 6] Composition Bare 4-7 lozenges per one (1 3 0 mg) of disintegrant and binding agents in the Table 6: ingredient Bare Ingot 4 Bare Ingot 5 Bare Ingot 6 Bare Ingot 7 Disintegrant Sodium Croscarmellose (mg) 6.5 6.5 - - Low-substituted hydroxypropyl cellulose (L-HPC) (mg) - - 13 13 Binding agent Hypromellose (mg) 1.3 11.7 1.3 11.7

Test Example 2: Example 4, Example 5, the bare bare ingot of the ingot obtained in Example 6 and Example 7 Comparative test of dissolution of the 4 to 7 of the 4-7 obtained into the brown glass bottle, without plug in cover In the same state, in an environment with a temperature of 30°C and a relative humidity of 75%, store it before (at the beginning), 1 month, 2 months and 3 months.

The dissolution test was carried out in accordance with the second method of the Japanese Pharmacopoeia dissolution test (paddle method, 50 rpm). The test solution used 900 mL of Japanese Pharmacopoeia dissolution test second solution containing 0.15% by weight of sodium lauryl sulfate, and was evaluated by liquid chromatography at 5, 10, 15, 30, 45, 60, 90, 120 and The dissolution rate of compound A in 135 minutes. As the column, ACQUITY UPLC HSS C18 with a particle size of 1.8 μm, 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 measurement was performed with an ultraviolet absorbance photometer (measurement wavelength: 242 nm) at a flow rate of 0.6 mL/min.

The dissolution rate (%) of bare tablets 4-7 before storage (at the beginning), after 1 month (1 month), 2 months (2 months) and 3 months (3 months) ) The results are shown in Figures 1 to 4. Bare tablets are excellent formulations with little variation in the dissolution rate during each storage period. As a result, it can be seen that for compound A, in the presence of a binding agent, regardless of the use of croscarmellose sodium and low-substituted hydroxypropyl cellulose ( When L-HPC) is used as a disintegrant, the deviation of the dissolution rate is small, and each bare ingot (bare ingot 4-7) has a good dissolution rate.

In addition, comparing the two disintegrants, low-substituted hydroxypropyl cellulose (L-HPC) has a smaller deviation compared with croscarmellose sodium. It can be seen that for compound A, low-substituted hydroxypropyl cellulose (L-HPC) Base cellulose (L-HPC) is a better disintegrant.

Example 8 : The preparation method of tablet 1 consists of 144.2 g of 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 light 5.8 g of silicic anhydride was mixed to obtain a mixed product containing compound A. 494.8 g of the mixed product and 19.4 g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Soda Co., Ltd.) were rotated and mixed 200 times in a polyethylene bag, and then 2.7 g of magnesium stearate was placed in the polyethylene bag. Spin and mix 50 times. The mixture was subjected to dry granulation using a rolling press (TF-Labo, manufactured by Freund Corporation). A granulator (COMIL, manufactured by Powrex Co., Ltd.) was used to granulate the obtained dry granulated product. Put 480 g of the obtained whole product, 132.5 g of silicic acid-treated crystalline cellulose, 2.5 g of light silicic anhydride, and croscarmellose sodium (Ac-Di-Sol, manufactured by FMC BioPolymer) in a polyethylene bag Mix inside. Furthermore, 2.5 g of magnesium stearate was added, and the mixture was rotated and mixed 50 times in a polyethylene bag to obtain a tablet mixture. A rotary tablet machine (VIRGO, manufactured by Kikusui Manufacturing Co., Ltd.) was used to make tablets (weight: 130 mg, tablet shape: round (diameter 7 mm)) to obtain bare tablets.

The coating agent mixture was separately dispersed in water to prepare a coating liquid (the composition of the coating agent mixture and the solid content concentration of the coating liquid are shown in Table 7 below). Using a tablet coating machine (DRC-200, manufactured by Powrex Co., Ltd.), each coating solution was sprayed on 200 g of the naked tablet so that the coating was 5 parts by weight relative to 100 parts by weight of the naked tablet in a dry state. Coating, thereby obtaining the target tablet 1.

Example 9 : The preparation method of tablet 2 consists of 144.2 g of 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 light 5.8 g of silicic anhydride was mixed to obtain a mixed product containing compound A. 494.8 g of the mixed product and 19.4 g of hydroxypropyl cellulose (HPC-SSL-SFP, manufactured by Soda Co., Ltd.) were rotated and mixed 200 times in a polyethylene bag, and then 2.7 g of magnesium stearate was placed in the polyethylene bag. Spin and mix 50 times. The mixture was subjected to dry granulation using a rolling press (TF-Labo, manufactured by Freund Corporation). A granulator (COMIL, manufactured by Powrex Co., Ltd.) was used to granulate the obtained dry granulated product. Put 480 g of the obtained whole product, 132.5 g of silicic acid-treated crystalline cellulose, 2.5 g of light silicic anhydride, and croscarmellose sodium (Ac-Di-Sol, manufactured by FMC BioPolymer) in a polyethylene bag Mix inside. Furthermore, 2.5 g of magnesium stearate was added, and the mixture was rotated and mixed 50 times in a polyethylene bag to obtain a tablet mixture. A rotary tablet machine (VIRGO, manufactured by Kikusui Manufacturing Co., Ltd.) was used to make tablets (weight: 130 mg, tablet shape: round (diameter 7 mm)) to obtain bare tablets.

The coating agent mixture was separately dispersed in water to prepare a coating liquid (the composition of the coating agent mixture and the solid content concentration of the coating liquid are shown in Table 7 below). Using a tablet coating machine (DRC-200, manufactured by Powrex Co., Ltd.), each coating solution was sprayed on 200 g of the naked tablet so that the coating was 5 parts by weight relative to 100 parts by weight of the naked tablet in a dry state. Coating, thereby obtaining the target lozenge 2.

[Table 7] Table 7 : Film coating formula Example 8 (lozenge 1) Example 9 (lozenge 2) Content rate (wt%) In 1 tablet (mg) Content rate (wt%) In 1 tablet (mg) Hypromellose 29.1 1.89 60 3.9 Titanium Oxide 20.1 1.31 22.4 1.46 Lactose hydrate 41.6 2.7 10 0.65 Triacetin 8.3 0.54 6.0 0.39 Yellow ferric oxide 0.5 0.03 1.5 0.1 Iron oxide 0.3 0.02 0.1 0.01 total 100 6.5 100 6.5

Test Example 3 : Comparison of the stability of the film-coated tablets obtained in Example 8 and Example 9. The determination of bardoxolone methyl and other related substances was tested by liquid chromatography under the following conditions. As the column, ACQUITY UPLC HSS C18 with a particle size of 1.8 μm, 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 was diluted with 65% by weight acetonitrile so that the concentration of the compound became 100 μg/mL. At a flow rate of 0.6 mL/min, use an ultraviolet absorbance photometer (measurement wavelength: 242 nm) to measure the related substances, and obtain the total amount (%) of various related substances relative to the indicated amount of bardoxolone methyl.

The stability test is carried out under the following conditions. Storage conditions: 30℃, 75%RH, 1 month Storage form: Put tablets 1 and 2 in a brown bottle with an open lid

[Table 8] Table 8 : Comparison of the stability of the film-coated tablets ( tablets 1 and 2) obtained in Example 8 and Example 9 Example 8 (lozenge 1) Example 9 (lozenge 2) Storage Conditions starting time Storage conditions: 30 ^o C, 75%RH, 1 month, open the lid starting time Storage conditions: 30 ^o C, 75%RH, 1 month, open the lid The total amount of related substances (%) 0 0.09 0 0.11

According to the results in Table 8 above, it can be seen that no matter what kind of film coating formulation is used, as long as it is a tablet containing compound A, disintegrant and binding agent and has a coating film, the total amount of similar substances is less , Good preparation with high stability.

It can be seen that especially by containing triacetin in the film coating formula, a good preparation with less total amount of related substances and higher stability can be obtained.

Example 10 : The preparation method of formulation example 2 and bare tablet 8 will include 19.2 g of solid dispersion of 40% by weight of compound A, 79.5 g of silicic acid-treated crystalline cellulose (PROSOLV, JRS Pharma), 69.1 g of lactose hydrate, and hydroxypropyl Methylcellulose (TC-5E, Shin-Etsu Chemical Co., Ltd.) 9.1 g, low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Chemical Co., Ltd.) 20 g, and light silicic anhydride (Edsuraide 101, Freund Corporation) 1.5 g is mixed in a polyethylene bag, and 0.8 g of magnesium stearate (Perteck LUB MST, Merck) is added, and further mixed, to obtain the same mixed product of Formulation Example 2 as above.

A solid dispersion containing 40% by weight of compound A 19.2 g, silicic acid-treated crystalline cellulose 78.5 g (PROSOLV, JRS Pharma), lactose hydrate 68.2 g, hypromellose (TC-5E, Shin-Etsu Chemical Industry) 9.1 g. Low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Chemical Industry) 20.0 g, light silicic anhydride (Edsurid 101, Freund Corporation) 1.5 g, and organic acid (stabilizer) 2.0 g in polyethylene Mix in the bag, and then add 0.8 g of magnesium stearate (Perteck LUB MST, Merck), and further mix to obtain a mixed product containing 1% by weight of organic acid.

Using a dry granulator (TF-Labo, Freund Corporation), the obtained mixture was subjected to dry granulation. Use a granulator (COMIL, Powrex) to granulate the obtained dry granulated product. Magnesium stearate (Perteck LUB MST, Merck) was added to the obtained whole grain product in an amount of 0.38% by weight, and mixed in a polyethylene bag 50 times to obtain a tablet mixture. A rotary tablet machine (VIRGO, manufactured by Kikusui Manufacturing Co., Ltd.) was used for tableting (weight 130 mg, tablet shape: round (diameter 7 mm)), thereby obtaining bare tablet 8 (containing organic acid). The composition of the bare ingot 8 is shown in Table 9 below. In addition, the composition of Formulation Example 2 is also shown again for reference.

[Table 9] Table 9 : Composition of formula example 2 ( bare ingot ) and bare ingot 8 ingredient Formulation example 2 1 Dianzhong (mg) Bare tablets 8 in 1 tablet (mg) Compound A 5.0 5.0 Methacrylic acid copolymer 7.5 7.5 Silicic acid treated crystalline cellulose 51.7 51.0 Lactose hydrate 44.9 44.3 Hypromellose 5.9 5.9 Low degree of substitution hydroxypropyl cellulose 13.0 13.0 Organic acid* - 1.3 Light Silicic Anhydride 1.0 1.0 Magnesium stearate 1.0 1.0 total 130 130 *Organic acid is citric anhydride, succinic acid, adipic acid, fumaric acid or malic acid. Refer to Table 10 below.

Test Example 4 : Formulation Example 2 ( bare ingot ) obtained in Example 10 and comparative test of stability of bare ingot 8 based on the presence or absence of addition of organic acid. The determination of related substances such as bardoxolone methyl was performed under the following conditions. It is measured by liquid chromatography. Specifically, as a column, ACQUITY UPLC HSS C18 with a particle size of 1.8 μm, 2.1 mm × 50 mm (manufactured by Waters) or its equivalent was used, 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 was diluted with a fluidized bed A:acetonitrile mixture (4:6) so that the compound concentration became 400 μg/mL. At a flow rate of 0.3 mL/min, use an ultraviolet absorbance photometer (measurement wavelength: 242 nm) to measure the related substances, and obtain the total amount (%) of various related substances relative to the indicated amount of bardoxolone methyl.

The stability test is carried out under the following conditions. Storage conditions: 40℃, 75%RH, 1 month or 2 months Storage form: Put recipe example 2 (naked ingot) and bare ingot 8 (5 types) in a brown bottle with an open lid

[Table 10] Table 10 : Formulation Example 2 ( bare ingot ) obtained in Example 10 and the total amount of related substances in bare ingot 8 (%) Formulation example 2 Bare ingot 8 Organic acid No addition Citric anhydride Succinic acid Adipic acid Fumaric acid Malic acid starting time 0.24 0.28 0.28 0.29 0.30 0.29 Storage conditions: 40 ^o C, 75%RH, 1 month, open the lid 0.39 0.31 0.39 0.39 0.30 0.29 Increase* (1 month) 0.15 0.03 0.11 0.1 0 0 Storage conditions: 40 ^o C, 75%RH, 2 months, open the lid 0.49 0.33 0.37 0.44 0.31 0.29 Increase* (2 months) 0.25 0.05 0.09 0.15 0.01 0 *The increase represents the increase in the total amount of related substances (%) from the beginning.

According to the results of Table 10 above, it can be seen that when any organic acid is added (bare ingot 8), compared with the case without organic acid (formulation example 2), the increase in the total amount of the related substances is less. In addition, it can be seen that among these organic acids, especially the formulations with fumaric acid and malic acid added are less in the total amount of related substances and their increase (1 month and 2 months).

Manufacture of aluminum bag packaging products 1 to 3 The bare ingots were produced by the same procedure as the recipe example 2. The details are as follows. Using a mixer (TBM-25, manufactured by Tokushou Works Co., Ltd.), a solid dispersion containing 40% by weight of compound A (bardoxolone methyl) (manufactured by spray drying method, the following "solid dispersion Body" is also manufactured in the same way) 500.0 g, silicic acid-treated crystalline cellulose (Prosolv, JRS Pharma) 2068.0 g, lactose hydrate (Japanese Pharmacopoeia) 1796.0 g, hypromellose (TC-5E, Shin-Etsu Chemical Co., Ltd.) Company manufacture) 236.0 g, low-substituted hydroxypropyl cellulose (L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) 520.0 g, and light silicic anhydride (Adsoride 101, manufactured by Freund Corporation Co., Ltd.) 40.0 g Mix it. 20.0 g of magnesium stearate was added to this mixture and further mixed. Using a roller press (CCS-220, manufactured by Powrex Co., Ltd.), the mixture was subjected to dry granulation and granulation. Magnesium stearate in an amount of 0.38% by weight was added to the obtained whole grains, and mixed, to obtain a mixed product for tableting. A rotary tablet machine (HT-AP15, manufactured by Hata Iron Works Co., Ltd.) was used for tableting (weight: 130 mg, tablet shape: round (diameter 7 mm)) to obtain a tablet containing 5 mg of compound A Bare ingot X. In the same manner as in the formulation example 2, the film coating of the obtained bare tablet X and the spreading of carnauba wax were polished to obtain the target tablet X.

The compositions of the obtained bare tablets X and tablets X are shown in Tables 11 and 12 below. [Table 11] Table 11 : The formula of bare ingot X ingredient Bare Ingot X In 1 tablet (mg) Content rate (wt%) Compound A 5.0 3.85 Methacrylic acid copolymer 7.5 5.77 Silicic acid treated crystalline cellulose 51.7 39.8 Lactose hydrate 44.9 34.5 Low-substituted hydroxypropyl cellulose (L-HPC) 13.0 10.0 Hypromellose 5.9 4.5 Light Silicic Anhydride 1.0 0.8 Magnesium stearate 1.0 0.8 total 130 100

[Table 12] Table 12 : Formula used to coat naked tablets X with a gloss agent Lozenge X ingredient In 1 tablet (mg) Content rate (wt%) Hypromellose 3.9 59.6 Titanium Oxide 1.46 22.3 Lactose hydrate 0.65 9.9 Triacetin 0.39 6 Yellow ferric oxide 0.1 1.5 Iron oxide 0.01 0.2 Carnauba wax 0.03 0.5 total 6.54 100 *Carnauba wax is used as a gloss agent, and other ingredients are used for coating film coating.

For tablets X made according to the formulas in Tables 11 and 12 above, use ACLAR (trademark) film (SUMILITE (trademark) FCL-1122, manufactured by SUMITOMO BAKELITE Co., Ltd.) (hereinafter also referred to as "ACLAR") or hard chlorine 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 Dacheng Chemical Co., Ltd.) (hereinafter also referred to as "polypropylene" ) And aluminum foil (manufactured by Tokai Toyo Aluminium Hanbai Co., Ltd. or UACJ Foil Co., Ltd.), using a PTP packaging machine (Model PFD-100, manufactured by Maruho Hatsujyo Kogyo Co., Ltd.) to obtain blister packaging products 1 to 3. Put the blister packaging product and desiccant (MS-serum-W3G, Tokai Chemical Industry Co., Ltd.) obtained in version 3 into an aluminum bag, and use a heat sealer (V-301-10W, manufactured by FUJI IMPULSE Co., Ltd.) Seal, and obtain the target aluminum bag packaging products 1 to 3.

Manufacture of aluminum bag packaging products 4 to 6 together with compound A (bardoxolone methyl), add 12.0 g of organic acid (containing 0.2% by weight of organic acid (fumaric acid) in the bare ingot), and treat with silicic acid The crystalline cellulose was reduced to 2060.0 g, and the lactose hydrate was reduced to 1792.0 g. Other than that, the bare tablet Y, the tablet Y, and the blister packaged product 4~ were obtained by the same procedure as the aluminum bag packaged product 1~3 6 and aluminum bag packaging products 4~6.

Test Example 5: aluminum bag packaged product of Comparative Experiment 1-6 Stability of the aluminum bags for products 1 to 6 (hereinafter, also referred to as a "package of 1 to 6"), the same conditions are stored in the above Test Example 4 ( Measure the total amount of related substances (%) at 40°C, 75%RH, 1 month, opening the lid ("At the beginning" and "40°C, 75%RH, 1 month, opening the lid"). The results are shown in Table 13 below. The determination of the related substances such as bardoxolone methyl was carried out by liquid chromatography under the same conditions as in Test Example 4.

[Table 13] Table 13 : The total amount of related substances (%) of aluminum bag packaging products 1 ~ 6 after storage Package 1 Packaged goods 4 Packaged goods 2 Packaging goods 5 Package 3 Packing 6 Blister packaging film ACLAR ACLAR Rigid vinyl chloride Rigid vinyl chloride Polypropylene Polypropylene Addition of fumaric acid no Have no Have no Have starting time 0.24 0.24 0.28 0.24 0.28 0.24 Storage conditions: 40℃, 75%RH, 1 month, open lid 0.35 0.29 0.29 0.26 0.33 0.27 increments* 0.11 0.05 0.01 0.02 0.05 0.03 *The increase represents the increase in the total amount of related substances (%) from the beginning.

According to the results of the above-mentioned Tables 10 and 13 and the following Table 14, it can be seen that by making the aluminum bag packaging product, the increase in the total amount (%) of the related substances is suppressed and the stability is improved. In addition, according to the results of Table 13 above, it can be seen that in the aluminum bag packaged product, by adding 0.2% by weight of organic acid (fumaric acid) relative to the total weight of the bare ingot, the total amount of inhibitory related substances (% ) Increases the tendency to increase stability. Furthermore, it can be seen that in aluminum bag packaging products, compared with ACLAR (trademark) film (polychlorotrifluoroethylene), the use of rigid vinyl chloride film or polypropylene film can suppress the increase in the total amount of similar substances (%). Stability is improved.

Test Example 6 : Study on the stability of aluminum bag packaging products Aiming at the tablet X and blister packaging product 1 (using ACLAR) obtained during the manufacturing process of the above aluminum bag packaging products 1 to 3 (not packed in aluminum bags), The similar substances were measured under the same storage conditions (40°C, 75%RH, 1 month, open lid) and storage state (put the tablet X into a brown glass bottle with the lid open) as in the above test examples 4 and 5 Total amount (%) ("At the beginning" and "40℃, 75%RH, 1 month, open lid"). The results are shown in Table 14 below. The determination of the related substances such as bardoxolone methyl was carried out by liquid chromatography under the same conditions as in Test Example 4.

[Table 14] Table 14 : The total amount of related substances (%) of tablet X and blister package 1 after storage Lozenge X Blister Packed Product of Tablet X (Blister Packed Product 1) Addition of fumaric acid no no Save form Brown bottle with open lid Blister packaging products using ACLAR starting time 0.24 0.26 Storage conditions: 40℃, 75% RH, 1 month, open lid 0.42 0.38 increments* 0.18 0.12 *The increase represents the increase in the total amount of related substances (%) from the beginning.

According to the results of the above Tables 13 and 14, it can be seen that compared with the tablet X (film coating formula), the blister packaged product 1 and the aluminum bag packaged product 1 of the tablet X are both higher in the total amount of similar substances and their increased amount. less. In addition, it can be seen that compared with the blister packaged product 1, the aluminum bag packaged product 1 of the tablet X is less in the total amount of certain types of peripheral substances and the increase. Therefore, it can be seen that by making the film coating formula of the present invention into a blister package product, the stability can be improved, and it can be seen that by making the film coating formula of the present invention into an aluminum bag package product, the stability can be further improved.

Test Example 7 : The comparative test of the stability between film coating formulations was used in the following tests: the tablet X used in the comparative test of Test Example 5 above, and the bare tablet of tablet Y contained 1% by weight instead of Tablet Y-1 made with 0.2% by weight of fumaric acid, and tablet Z made by making the bare tablets of tablet Y contain 1% by weight of malic acid instead of fumaric acid. Tablet X, Tablet Y-1 and Tablet Z are all film coating formulations. For the prepared tablets X, Y-1 and Z, the total amount (%) of related substances was determined under the same storage conditions and liquid chromatography conditions as in Test Example 5 (data not shown). As a result, it can be seen that tablets Y-1 (containing fumaric acid) and tablets prepared by adding organic acid (fumaric acid or malic acid) are compared with tablets X prepared without organic acid. Z (containing malic acid) can inhibit the increase of the total amount of related substances (%) and improve the stability. In addition, it can be seen that both the tablet Y-1 made by adding fumaric acid and the tablet Z made by adding malic acid have almost no increase in the total amount (%) of the related substances from the beginning. [Reference to related applications]

This patent application claims priority based on Japanese Patent Application No. 2018-221650 filed on November 27, 2018, and the entire disclosure of the Japanese application is cited as part of the disclosure of the invention of this case.

Figure 1 compares the dissolution rate of bare ingot 4 before storage (at the beginning), after 1 month (1 month), after 2 months (2 months) and after 3 months (3 months). %) chart. The vertical axis represents the dissolution rate (%), and the horizontal axis represents time (minutes). Figure 2 compares the dissolution rate of bare ingot 5 before storage (at the beginning), after 1 month (1 month), after 2 months (2 months) and after 3 months (3 months). %) chart. The vertical axis represents the dissolution rate (%), and the horizontal axis represents time (minutes). Figure 3 compares the dissolution rate of bare ingot 6 before storage (at the beginning), after 1 month (1 month), after 2 months (2 months) and after 3 months (3 months). %) chart. The vertical axis represents the dissolution rate (%), and the horizontal axis represents time (minutes). Figure 4 compares the dissolution rate of bare ingot 7 before storage (at the beginning), after 1 month (1 month), after 2 months (2 months) and after 3 months (3 months). %) chart. The vertical axis represents the dissolution rate (%), and the horizontal axis represents time (minutes).

Claims (26)

A pharmaceutical composition containing bardoxolone methyl or its pharmaceutically acceptable salt, disintegrating agent and binding agent, and having a coating film. The pharmaceutical composition of claim 1, wherein the disintegrant is selected from crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose One or more of the group consisting of vegetarian calcium, sodium carboxymethyl starch, partially gelatinized starch and starch. The pharmaceutical composition according to claim 2, wherein the disintegrant is one or more 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, which contains 0.1 to 20 parts by weight of a disintegrant relative to 100 parts by weight of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 4, wherein the binding agent is selected from the group consisting of hydroxypropyl cellulose, methyl cellulose, hypromellose, carboxymethyl cellulose, and carboxymethyl ethyl cellulose Hydroxyethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl starch, carboxyvinyl polymer, polyvinylpyrrolidone, poly Vinylpyrrolidone vinyl acetate copolymer, polyvinyl alcohol, methacrylic acid copolymer, polyethylene glycol, starch, gelatin, dextrin, pullulan, agar, and acacia gum. The pharmaceutical composition according to claim 5, wherein the binding agent is one or more 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, which contains 0.1-30 parts by weight of the binding agent relative to 100 parts by weight of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 7, which further contains a stabilizer. The pharmaceutical composition according to claim 8, wherein the stabilizer 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 a water-soluble polymer, lactose, white sugar, mannitol, titanium oxide, talc, calcium carbonate, and triacetin One or more coating agents in the group. The pharmaceutical composition according to claim 11, wherein the water-soluble polymer is selected from polyethylene glycol, polyvinyl alcohol polyethylene glycol graft copolymer, polyvinylpyrrolidone, hypromellose, and hydroxypropyl fiber One or more of the group consisting of polyvinyl alcohol, polyvinyl alcohol and polyvinyl acrylate methyl methacrylate copolymer. 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 one or more selected from the group consisting of yellow ferric oxide, iron oxide, and titanium oxide. The pharmaceutical composition according to any one of claims 1 to 14, which comprises 0.1-100 parts by weight of the coating agent relative to 100 parts by weight of the coating film. The pharmaceutical composition according to any one of claims 1 to 15, which further contains a gloss agent. The pharmaceutical composition according to claim 16, wherein the gloss agent is carnauba wax and/or magnesium stearate. A pharmaceutical composition, which is the pharmaceutical composition according to any one of claims 1 to 17, With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-20 parts by weight of bardoxolone methyl or its pharmaceutically acceptable salt, Relative to 100 parts by weight of the pharmaceutical composition, containing 3-20 parts by weight of the binding agent, With respect to 100 parts by weight of the pharmaceutical composition, it contains 0.1-15 parts by weight of the disintegrant, The coating agent contains 50 to 90 parts by weight with respect to 100 parts by weight of the coating film. The pharmaceutical composition according to any one of claims 1 to 18, wherein the bardoxolone methyl 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 lozenge. A blister package product comprising the pharmaceutical composition according to any one of claims 1 to 21, and a film formed by laminating a polymer and an aluminum foil. For example, the blister package product of claim 22, wherein the film formed by laminating the polymer is a polymerization of one or more selected from polypropylene, polyvinyl chloride, polyvinylidene chloride and polychlorotrifluoroethylene Laminated film. A medical packaging product, which is formed by enclosing the blister packaging product of claim 22 or 23 in the packaging body. Such as the medical package of claim 24, where the package body is an aluminum bag. For example, the medical package of claim 24 or 25, wherein a deoxidizer and/or a desiccant is further enclosed in the package.

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