Pharmaceutical composition containing dihydropyridone derivative

Abstract

Provided is a pharmaceutical composition comprising a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate of these.　A pharmaceutical composition containing the compound represented by formula (I) or the like and having excellent compound dissolution concentration by containing a polymer is provided. By using an encapsulated formulation containing a compound represented by formula (I) or the like, an encapsulated formulation that is stable under acidic conditions is provided.

Description

Pharmaceutical compositions containing dihydropyridinone derivatives

[0001] The present invention relates to a compound of formula (I): The present invention relates to a pharmaceutical composition containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof (hereinafter referred to as a compound represented by formula (I), etc.). More specifically, the present invention relates to a pharmaceutical composition containing a polymer.

[0002] Patent Documents 1 and 2 disclose that compounds represented by formula (I) and the like have inhibitory activity against monoacylglycerol acyltransferase 2 (hereinafter also referred to as MGAT2) and are useful for treating diseases and disorders such as obesity. Three isoforms of MGAT have been identified: MGAT1, MGAT2, and MGAT3. Of these, MGAT2 and MGAT3 are highly expressed in the small intestine and are thought to be involved in fat absorption in the small intestine. Experiments using wild-type mice have reported that high-fat diet loading increases MGAT2 expression in the small intestine and increases MGAT activity (Non-Patent Document 1). Furthermore, MGAT2 knockout mice have been shown to suppress high-fat diet-induced weight gain, insulin resistance, elevated blood cholesterol levels, and fatty liver formation, as well as increased energy consumption (Non-Patent Document 2).

[0003] Furthermore, Patent Document 3 describes crystals of the compound represented by formula (I) and the like.

[0004] Furthermore, Patent Document 4 discloses a preparation containing hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, D-mannitol, and magnesium stearate as additives and cefcapene pivoxil hydrochloride as an active ingredient, but none of the cited documents discloses the preparation of the present invention.

[0005] WO2019 / 013311WO2019 / 013312WO2023 / 243616JP 2009-249377

[0006] Journal of Biological Chemistry (2004), 279, 18878-18886Nature Medicine (2009), 15, (4), 442-446

[0007] An object of the present invention is to provide a pharmaceutical composition containing a compound represented by formula (I) and the like.

[0008] The present inventors have found that the use of a polymer in the production of a pharmaceutical composition containing the compound represented by formula (I) or the like allows the production of a pharmaceutical composition with an excellent dissolution concentration of the compound represented by formula (I) or the like, and have completed the pharmaceutical composition of the present invention containing the compound represented by formula (I) or the like and the polymer. Furthermore, the present inventors have found that the compound represented by formula (I) or the like is unstable under acidic, neutral, and weakly alkaline conditions, and have completed a capsule containing the compound represented by formula (I) or the like.

[0009] The present inventors have discovered a pharmaceutical composition containing a compound represented by formula (I) or the like and a polymer as shown below. The present inventors have also discovered a capsule containing a compound represented by formula (I) or the like and a polymer. (1) Formula (I): a pharmaceutical composition comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a polymer. (2) The pharmaceutical composition according to (1) above, wherein the polymer is one or more selected from the group consisting of a cellulose-based polymer, a vinyl-based polymer, an acrylic acid-based polymer, and a polyether-based polymer. (3) The pharmaceutical composition according to (2) above, wherein the polymer is a cellulose-based polymer or a vinyl-based polymer. (4) The pharmaceutical composition according to (3) above, wherein the polymer is a cellulose-based polymer and the cellulose-based polymer is one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxyethyl methylcellulose, hydroxyethyl cellulose, carmellose sodium, carmellose calcium, cellulose acetate phthalate, methylhydroxyethyl cellulose, ethyl cellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose-carmellose sodium, carmellose, powdered cellulose, low-substituted hydroxypropyl cellulose, and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose. (5) The pharmaceutical composition according to (4) above, wherein the cellulose polymer is hydroxypropyl cellulose or hydroxypropyl methylcellulose. (6) The pharmaceutical composition according to (3) above, wherein the polymer is a vinyl polymer, and the vinyl polymer is one or more selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpolypyrrolidone, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl acetal diethylaminoacetate, a mixture of fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, crospovidone, carboxyvinyl polymer, and polyvinyl alcohol copolymer. (7) The pharmaceutical composition according to (6) above, wherein the vinyl polymer is polyvinylpyrrolidone.(8) The pharmaceutical composition according to (1) above, wherein the polymer is a polymer that, when 1 μL of water is dropped onto a flat tablet consisting of the compound represented by formula (I), its pharmaceutically acceptable salt, or a solvate thereof, and the polymer, the contact angle is 85° or less. (9) The pharmaceutical composition according to (8) above, wherein the flat tablet is a tablet consisting of 50 mg of the compound represented by formula (I), its pharmaceutically acceptable salt, or a solvate thereof, and 10 mg of the polymer, and has a diameter of 7.5 mm. (10) The pharmaceutical composition according to any of (1) to (9) above, further comprising an excipient, a disintegrant, and a lubricant. (11) The pharmaceutical composition according to (10) above, comprising D-mannitol, low-substituted hydroxypropyl cellulose, and magnesium stearate. (12) The pharmaceutical composition according to any of (1) to (11) above, comprising a hydrate of the compound represented by formula (I). (13) The pharmaceutical composition according to any of (1) to (12) above, in the form of a capsule. (14) Formula (I): (15) A capsule containing a compound represented by formula (II): (16) The capsule according to (14) or (15) above, wherein the capsule base is a capsule base other than an enteric base. (17) The capsule according to any one of (14) to (16) above, wherein the capsule base is hydroxypropyl methylcellulose.

[0010] The present invention provides a pharmaceutical composition containing a compound represented by formula (I), etc., which has an excellent dissolution concentration of the compound represented by formula (I), etc. The present invention also provides a capsule as a pharmaceutical composition having excellent dissolution properties and high stability.

[0011] 1 is a chromatogram obtained by liquid chromatography of the compound represented by formula (I). It also shows the results of dissolution tests of the capsules of Example 11 and Reference Example 4. The vertical axis represents dissolution rate (unit: %), and the horizontal axis represents time (unit: minutes).

[0012] The present invention will be described in detail below.

[0013] The present invention relates to a pharmaceutical composition containing a compound represented by formula (I) or the like. One embodiment of the present invention is a pharmaceutical composition containing a compound represented by formula (I) or the like and a polymer. Particularly preferred is a pharmaceutical composition containing a water-soluble polymer as the polymer. Another embodiment of the present invention is the above pharmaceutical composition containing one or more polymers selected from the group consisting of cellulose-based polymers, vinyl-based polymers, acrylic acid-based polymers, and polyether-based polymers. Particularly preferred is a water-soluble cellulose-based polymer or a water-soluble vinyl-based polymer.

[0014] The cellulose-based polymer is preferably one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose (hereinafter also referred to as hypromellose), hydroxypropyl methylcellulose phthalate, methylcellulose, carboxymethylethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxyethyl methylcellulose, hydroxyethyl cellulose, carmellose sodium, carmellose calcium, cellulose acetate phthalate, methylhydroxyethyl cellulose, ethylcellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose-carmellose sodium, carmellose, powdered cellulose, low-substituted hydroxypropyl cellulose, and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose. Water-soluble cellulose-based polymers are preferred, and hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, and crystalline cellulose-carmellose sodium are preferred. Hydroxypropyl cellulose or hydroxypropyl methylcellulose is particularly preferred, with hydroxypropyl cellulose being even more preferred. The vinyl polymer is preferably one or more selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpolypyrrolidone, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl acetal diethylaminoacetate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, crospovidone, carboxyvinyl polymer, and polyvinyl alcohol copolymer. Water-soluble vinyl polymers are preferred, and polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl acetal diethylaminoacetate, carboxyvinyl polymer, and polyvinyl alcohol copolymer are particularly preferred. Polyvinylpyrrolidone is particularly preferred.The acrylic acid-based polymer is preferably one or more selected from the group consisting of aminoalkyl methacrylate copolymer, ethyl acrylate-methyl methacrylate copolymer dispersion, methacrylic acid copolymer, 2-methyl-5-vinylpyridine methyl acrylate-methacrylic acid copolymer, dry methacrylic acid copolymer, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, polyvinyl acetal diethylamino acetate, and aminoalkyl acrylate copolymer E. Water-soluble acrylic acid-based polymers are preferred, and methacrylic acid copolymer, 2-methyl-5-vinylpyridine methyl acrylate-methacrylic acid copolymer, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, polyvinyl acetal diethylamino acetate, and aminoalkyl acrylate copolymer E are preferred. Aminoalkyl methacrylate copolymers are particularly preferred. Polyether-based polymers are preferably polyethylene glycol and propylene oxide-ethylene oxide block copolymers. Water-soluble polyether-based polymers are preferred, and polyethylene glycol and propylene oxide-ethylene oxide block copolymers are preferred. The polymer can be used in an amount of 0.5 to 40% by weight, based on the total weight of the pharmaceutical composition. Preferably, it is 0.5 to 30% by weight. Particularly preferably, it is 0.5 to 10% by weight. Furthermore, it is 0.5 to 5% by weight. When the pharmaceutical composition is a capsule, the polymer can be used in an amount of 0.5 to 40% by weight, based on the total weight of the pharmaceutical composition to be filled in the capsule, excluding the capsule. Preferably, it is 0.5 to 30% by weight. Particularly preferably, it is 0.5 to 10% by weight. Furthermore, it is 0.5 to 5% by weight.

[0015] Another aspect of the present invention is a pharmaceutical composition containing a polymer that forms a contact angle of 85 degrees or less when 1 μL of water is dropped onto a flat tablet made of a compound represented by formula (I) or the like and a polymer. A hydrate of the compound represented by formula (I) can be used as the compound represented by formula (I) or the like used in the flat tablet. Contact angle measurements can be performed according to the method described in the wettability evaluation in Test Example 2. Therefore, those skilled in the art can select a polymer to be used in the pharmaceutical composition of the present invention. That is, those skilled in the art can select a polymer that forms a contact angle of 85 degrees or less when 1 μL of water is dropped onto a flat tablet made of a compound represented by formula (I) or the like and a polymer. Examples of such polymers include water-soluble cellulose-based polymers and water-soluble vinyl-based polymers. In the case of hydroxypropyl cellulose, the contact angle is 77 to 82 degrees; in the case of hydroxypropyl methylcellulose, the contact angle is 80 to 85 degrees; and in the case of polyvinylpyrrolidone, the contact angle is 77 to 82 degrees. When the above polymers that form a contact angle of 85 degrees or less were used, particularly good dissolution concentrations were observed, as described in Example 1.

[0016] As a flat tablet comprising a compound represented by formula (I) or the like and a polymer, a flat tablet comprising 50 mg of a compound represented by formula (I) or the like and 10 mg of a polymer can be used. The diameter of the tablet is not particularly limited, but a flat tablet with a diameter of 7.5 mm can be used. A flat tablet refers to a tablet with flat top and bottom surfaces. The contact angle refers to the angle between the liquid surface and the solid surface (the angle inside the liquid) at the point where the free surface of a stationary liquid contacts a solid wall, and is listed in a chemical dictionary.

[0017] The pharmaceutical composition of the present invention may further contain an excipient, a disintegrant, and a lubricant. Examples of excipients that can be used include mannitol, microcrystalline cellulose, crystalline cellulose, lactose, corn starch, and bailecho starch. Mannitol (e.g., D-mannitol), crystalline cellulose, and microcrystalline cellulose are particularly preferred. D-mannitol is even more preferred. Examples of disintegrants include carmellose, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crystalline cellulose, powdered cellulose, partially pregelatinized starch, potato starch, corn starch, hydroxypropyl starch, sodium carboxymethyl starch, low-substituted sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, starch, crospovidone, and polyvinyl alcohol. Low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone are preferred, and low-substituted hydroxypropyl cellulose is even more preferred. Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, polyoxyl 40 stearate, sodium stearyl fumarate, talc, light anhydrous silicic acid, hydrated silicon dioxide, magnesium carbonate, precipitated calcium carbonate, dried aluminum hydroxide gel, magnesium aluminometasilicate, magnesium silicate, synthetic aluminum silicate, magnesium oxide, magnesium sulfate, glycerin fatty acid esters, hydrogenated oils, white beeswax, hydrogenated soybean oil, beeswax, cetanol, sodium laurate, sucrose fatty acid esters, polyethylene glycol (macrogol), etc. Preferred are magnesium stearate, sodium stearyl fumarate, and sucrose fatty acid esters, and even more preferred is magnesium stearate. When the pharmaceutical composition of the present invention contains an excipient, a disintegrant, and a lubricant, the amounts can be appropriately selected according to the knowledge and experience of a person skilled in the art.

[0018] The pharmaceutical composition of the present invention may contain additives used in the pharmaceutical field other than excipients, disintegrants, and lubricants. For example, it may contain binders, flow agents, flavorings, and flavoring agents. Examples of binders that can be used include polyvinylpyrrolidone, crystalline cellulose, hydroxypropyl cellulose, hypromellose, and low-substituted hydroxypropyl cellulose. Hydroxypropyl cellulose is particularly preferred. Examples of flow agents that can be used include light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminum metasilicate, and talc. Light anhydrous silicic acid is particularly preferred. Specific examples of flavorings that are preferred include orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, spruce oil, pine oil, peppermint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, menthol, lemon powder, lemon oil, and rose oil. Specific examples of preferred flavoring agents include aspartame, sucralose, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and its salts, and anhydrous citric acid. When the pharmaceutical composition of the present invention contains a binder, a fluidizing agent, a flavoring, a flavoring, etc., the amounts to be added can be appropriately selected according to the knowledge and experience of those skilled in the art.

[0019] Pharmaceutically acceptable salts of the compound represented by formula (I) include, but are not limited to, hydrochloride, sulfate, nitrate, fumarate, etc. Solvates of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof include hydrates, ethanolates, dioxane solvates, etc. Preferred are hydrates, with the 0.25 hydrate being more preferred. A method for producing hydrates is described in Patent Document 3. Preferred examples of the compound represented by formula (I) or the like include hydrates of the compound represented by formula (I), with the 0.25 hydrate being more preferred. The pharmaceutical composition of the present invention may contain 1 to 50 mg, preferably 3 to 30 mg, of the compound represented by formula (I), etc. Particularly preferred are 3 mg, 10 mg, or 30 mg.

[0020] The pharmaceutical composition of the present invention is preferably a solid preparation, and examples of the solid preparation include capsules, tablets, powders, granules, pills, etc. Capsules are particularly preferred. In the case of capsules, the capsule size is preferably 000 to 5 capsules. More preferably, 2 to 4 capsules are preferred. Particularly preferred are 2 or 4 capsules.

[0021] Another aspect of the present invention is a capsule containing a compound represented by formula (I). Examples of such capsules include those in which the compound represented by formula (II) is not detected when a dissolution test is performed in 0.1 N aqueous hydrochloric acid (e.g., 50 mL of 0.1 N aqueous hydrochloric acid) at 37°C with a paddle at 50 rpm for 5 minutes. Preferred examples include capsules in which the compound represented by formula (II) is not detected when a 10-minute dissolution test is performed. More preferred examples include capsules in which the compound represented by formula (II) is not detected when a 15-minute dissolution test is performed. Measurement of formula (II) can be performed according to the method described in Test Example 3.

[0022] Examples of capsule bases used in capsules include hypromellose, gelatin, pullulan, and carboxymethylethylcellulose. Preferred are hypromellose and gelatin, and particularly preferred is hypromellose. Furthermore, capsule bases other than enteric bases can be used in capsules. Examples include hypromellose, gelatin, and pullulan. Preferred are hypromellose and gelatin, and particularly preferred is hypromellose.

[0023] The total weight of the pharmaceutical composition of the present invention is, but is not limited to, 40 to 250 mg, more preferably 88 to 210 mg, and particularly preferably 88 mg or 210 mg. The total weight of the capsule of the present invention is, but is not limited to, 40 to 250 mg, more preferably 88 to 210 mg, and particularly preferably 88 mg or 210 mg.

[0024] When the pharmaceutical composition of the present invention is a capsule, it can be prepared as follows, without any particular limitation. Specifically, a mixed powder is prepared by mixing the compound represented by formula (I) and additives such as a polymer, excipient, disintegrant, and lubricant, and the like, and then the mixed powder is filled into capsules to produce a capsule. When the pharmaceutical composition of the present invention is a granule, it can be prepared as follows, without any particular limitation. Specifically, a mixed powder is prepared as described above, and the mixed powder is granulated. The granulation step can be preferably carried out by a wet granulation method in which granulation is carried out by adding water, water containing a binder, or a solvent, or a dry granulation method or melt granulation method that does not use water. When the pharmaceutical composition of the present invention is a tablet, it can be prepared as follows, without any particular limitation. For example, granules can be prepared as described above and compressed into tablets using a tablet press. Alternatively, tablets can be produced by preparing a mixed powder as described above and compressing the mixed powder into tablets using a tablet press. Alternatively, tablets can be produced by mixing the compound represented by formula (I) with additives such as polymers to produce a mixed powder, granulating the mixed powder, mixing a disintegrant, a lubricant, etc., and tableting the mixture with a tablet press. When the pharmaceutical composition of the present invention is in the form of a powder, pills, etc., they can be produced according to the knowledge and experience normally possessed by a person skilled in the art.

[0025] For the pharmaceutical composition of the present invention, after the above-mentioned granules or tablets are produced, the granules or tablets may be coated with a coating layer. When forming a coating layer on the granules, a fluidized bed granulation coating machine, a fluidized bed tumbling coating machine, or the like may be used. When forming a coating layer on the tablets, a pan coating machine, an aerated coating machine, or the like may be used. While the granules or tablets are fluidized in the coating machine, the coating liquid is sprayed onto the granules or tablets, and then dried to form a coating layer.

[0026] As used herein, "D50" and "D90" refer to particle diameters at points where a cumulative curve is 50% and 90% when the total volume of a powder aggregate is taken as 100%, and can be measured by a dry method or a wet method.

[0027] The pharmaceutical composition of the present invention can be administered orally. Although not particularly limited, the compound represented by formula (I) can be administered at a dose of 3 to 30 mg / day. Particularly preferred doses are 3, 10, and 30 mg / day.

[0028] The pharmaceutical composition of the present invention can be used for the purposes described in Patent Documents 1 to 3. For example, it can be used to suppress weight gain caused by a high-fat diet, suppress the onset of insulin resistance, suppress increases in blood cholesterol, suppress fatty liver formation, and enhance or treat energy consumption. The pharmaceutical composition of the present invention can improve obesity and the like.

[0029] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples. Regarding the compound represented by formula (I), a compound having a particle size of D50 of 2.74 μm and D90 of 8.34 μm, and a compound having a particle size of D50 of 3.29 μm and D90 of 10.94 μm were used, with purities (quantitative values) of 99.4% and 99.6%, respectively. The compound having a particle size of D50 of 3.29 μm and D90 of 10.94 μm was measured using the liquid chromatography method shown in Measurement Method 1 with an injection volume of 2 μL. The chromatogram obtained is shown in Figure 1. The compound represented by formula (I) was detected with a purity (p%) of 99.4% at a retention time of 12,800 minutes.

[0030] Measurement method: 1 Detector: ultraviolet absorption photometer (measurement wavelength 267 nm) Column: YMC-Triart C18 ExRS, 3.0 × 100 mm, 1.9 μm Column temperature: constant temperature around 60°C Mobile phase A: diluted formic acid (1 → 1000), mobile phase B: acetonitrile Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the concentration gradient.

[0031] Test Example 1: Evaluation of Dissolution Concentration 30 mg of the compound of formula (I) and 300 mg of each of the water-soluble polymers shown in Examples 1 to 4 were added to a centrifuge tube, and 30 mL of pH 6.8 phosphate buffer was added. The tube was then shaken at 37°C and 100 rpm in a thermostatic shaker. After shaking for 2 hours, the sample was filtered through a 0.45 μm filter, and the concentration of the compound of formula (I) in the filtrate was measured using a 10 μL injection volume by the liquid chromatography method shown in Measurement Method 2. In Reference Example 1, a similar test was performed using only 30 mg of the compound of formula (I) without adding any polymer. Hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd.), polyvinyl alcohol (manufactured by Merck), and polyvinylpyrrolidone (manufactured by BASF) were used as polymers.

[0032] Measurement method: 2 Detector: ultraviolet absorption photometer (measurement wavelength 267 nm) Column: YMC-Triart C18 ExRS, 3.0 × 100 mm, 1.9 μm Column temperature: constant temperature around 60°C Mobile phase A: diluted formic acid (1 → 1000), mobile phase B: acetonitrile Mobile phase delivery: concentration gradient was controlled so that the mixing ratio of mobile phase A and mobile phase B was 3:2.

[0033] (Results) The results of the test on the dissolved concentration of the compound represented by formula (I) are shown in the table below. As a result, the dissolved concentration of the compound represented by formula (I) was significantly improved by adding a polymer.

[0034] (Test Example 2) Wettability Evaluation 50 mg of the compound represented by formula (I) and 10 mg of each of the water-soluble polymers shown in Examples 5 to 7 were mixed, and then compressed using a static compressor at a diameter of 7.5 mm and a tableting pressure of 5 kN to obtain flat tablets. A 1 μL droplet of water was dropped onto the surface of each obtained flat tablet, and the contact angle at this time was measured using an automatic contact angle meter DMo-601 (Kyowa Interface Science Co., Ltd.). Repeated measurements were performed four or five times, and the average was calculated. In Reference Example 2, flat tablets were prepared using only 50 mg of the compound represented by formula (I) without adding any polymer, and a similar test was performed. Hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd.), and polyvinylpyrrolidone (manufactured by BASF) were used as polymers.

[0035] (Results) The following table shows the contact angles of flat tablets formed from the compound of formula (I) and the polymers shown in Examples 5 to 7, and the contact angle of the flat tablet of Reference Example 2. As a result, it was found that the contact angle of the compound of formula (I) was reduced by adding the polymer, and wettability was improved.

[0036] (Test Example 3) Test for Confirmation of Impurity Inhibitory Effect 30 mg of the compound of formula (I) was filled into hypromellose capsules or gelatin capsules to obtain capsules (Examples 8 and 9). This was added to 50 mL of 0.1 N HCl heated to 37°C, and a dissolution test was performed at 50 rpm. After 5, 10, 15, and 20 minutes, 3 mL of the solution was withdrawn, filtered through a 0.45 μm filter, and then diluted 2-fold with a carbonate buffer solution at pH 9.7 to prepare a test solution. A related substance test was performed using an injection volume of 10 μL under the conditions of Measurement Method 1, and the amount of the compound of formula (II) was measured. In Reference Examples 3, 4, 5, and 6, similar tests were performed using only 30 mg of the compound of formula (I) and test solutions with different pH values. The test solution extracted at each elapsed time was diluted 2-fold with an appropriate solution to a pH of approximately 6.5, and the amount of related substances was calculated as a percentage (N=1), with the total peak area of ​​the chromatogram on the HPLC chart taken as 100%.

[0037] (Results) The amount of the compound represented by formula (II) when the compound represented by formula (I) was filled into capsules and a dissolution test was conducted using 50 mL of 0.1 N HCl, and the results of Reference Examples 3 to 6 are shown in Table 5. As a result, when the dissolution test was conducted using only the compound represented by formula (I) (Reference Examples 3 to 6), the compound represented by formula (II) was detected, whereas when the compound represented by formula (I) was filled into hypromellose capsules (Example 8) and a similar dissolution test was conducted, the compound represented by formula (II) was not detected. Furthermore, when the compound represented by formula (I) was filled into gelatin capsules (Example 9) and a similar dissolution test was conducted, the compound represented by formula (II) was not detected up to 15 minutes after the start of the test.

[0038] (Method of manufacturing capsules) Capsules containing the compound represented by formula (I) were manufactured. Table 6 shows the formulation per capsule. The compound represented by formula (I), D-mannitol (manufactured by Roquette), low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), and magnesium stearate (manufactured by SpecGx LLC) were mixed, sieved through a 30-mesh sieve, and remixed to obtain a mixed powder. The obtained mixed powder was filled into capsules of the size shown in Table 6 to produce capsules.

[0039] (Test Example 4) Dissolution Test A dissolution test was conducted on the capsules of Examples 10-12 and Reference Example 4. Using 900 mL of pH 6.8 phosphate buffer as the test solution, the test was conducted using the paddle method at 50 revolutions per minute. A sinker was used for the test. One capsule was taken and the test was initiated. 5 mL of the dissolution solution was accurately taken at 5, 10, 15, 20, 30, 45, and 60 minutes, and filtered through a 0.45 μm membrane filter. The first 3 mL of filtrate was discarded, and the next filtrate was used as the test solution. Separately, 11.1 mg of the compound represented by formula (I) was precisely weighed and dissolved in acetonitrile to make exactly 10 mL. 1 mL of this solution was accurately weighed, and pH 6.8 phosphate buffer was added to make 100 mL to prepare the standard solution. 5 μL of each of the test solution and standard solution was accurately taken and tested by liquid chromatography under the following conditions. The peak areas of each compound represented by formula (I) were measured. Test conditions Detector: ultraviolet absorption photometer (measurement wavelength: 267 mm) Column: YMC-Triart C18 ExRS, 3.0 × 100 mm, 1.9 μm Column temperature: constant temperature around 60°C Mobile phase A: diluted formic acid (1 → 1000), mobile phase B: acetonitrile Mobile phase delivery: concentration gradient was controlled so that the mixing ratio of mobile phase A and mobile phase B was 3:2.

[0040] The results of the above test are shown in Figure 2 for Example 11 and Reference Example 4. The capsules of Example 11 showed a rapid dissolution behavior. In addition, Examples 10 and 12 also showed a rapid dissolution behavior similar to Example 11.

[0041] The pharmaceutical composition containing the dihydropyridinone derivative of the present invention has an excellent soluble concentration and exhibits excellent dissolution properties and stability, and is therefore useful for treating diseases and disorders such as obesity.

Claims

1. Formula (I): A pharmaceutical composition comprising a compound represented by the formula:

2. The pharmaceutical composition according to claim 1, wherein the polymer is one or more selected from the group consisting of cellulose-based polymers, vinyl-based polymers, acrylic acid-based polymers and polyether-based polymers.

3. The pharmaceutical composition according to claim 2, wherein the polymer is a cellulose-based polymer or a vinyl-based polymer.

4. The pharmaceutical composition according to claim 3, wherein the polymer is a cellulosic polymer and the cellulosic polymer is one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, carboxymethylethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxyethyl methylcellulose, hydroxyethyl cellulose, carmellose sodium, carmellose calcium, cellulose acetate phthalate, methylhydroxyethyl cellulose, ethyl cellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose-carmellose sodium, carmellose, powdered cellulose, low-substituted hydroxypropyl cellulose, and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose.

5. The pharmaceutical composition of claim 4, wherein the cellulosic polymer is hydroxypropyl cellulose or hydroxypropyl methylcellulose.

6. The pharmaceutical composition according to claim 3, wherein the polymer is a vinyl polymer, and the vinyl polymer is one or more selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpolypyrrolidone, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl acetal diethylaminoacetate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, crospovidone, carboxyvinyl polymer, and polyvinyl alcohol copolymer.

7. The pharmaceutical composition according to claim 6, wherein the vinyl polymer is polyvinylpyrrolidone.

8. The pharmaceutical composition according to claim 1, wherein the polymer is a polymer that, when 1 μL of water is dropped onto a flat tablet comprising the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and the polymer, the contact angle is 85 degrees or less.

9. The pharmaceutical composition according to claim 8, wherein the flat tablet comprises 50 mg of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and 10 mg of the polymer, and has a diameter of 7.5 mm.

10. The pharmaceutical composition according to any one of claims 1 to 9, further comprising an excipient, a disintegrant and a lubricant.

11. The pharmaceutical composition of claim 10, comprising D-mannitol, low-substituted hydroxypropyl cellulose and magnesium stearate.

12. A pharmaceutical composition according to any one of claims 1 to 11, comprising a hydrate of the compound of formula (I).

13. The pharmaceutical composition according to any one of claims 1 to 12, which is in the form of a capsule.

14. Formula (I): A capsule containing a compound represented by the formula (I): or a pharmaceutically acceptable salt thereof or a solvate thereof.

15. When a dissolution test was carried out in a 0.1N hydrochloric acid aqueous solution at 37°C with a paddle at 50 rpm for 5 minutes, the compound represented by formula (II): The capsule according to claim 14, wherein the compound represented by the formula:

16. The capsule according to claim 14 or 15, wherein the capsule base is a capsule base other than an enteric base.

17. A capsule according to any one of claims 14 to 16, wherein the capsule base is hydroxypropylmethylcellulose.

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