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WO2025164725A1 - Composition pharmaceutique contenant un dérivé de dihydropyridone - Google Patents

Composition pharmaceutique contenant un dérivé de dihydropyridone

Info

Publication number
WO2025164725A1
WO2025164725A1 PCT/JP2025/003013 JP2025003013W WO2025164725A1 WO 2025164725 A1 WO2025164725 A1 WO 2025164725A1 JP 2025003013 W JP2025003013 W JP 2025003013W WO 2025164725 A1 WO2025164725 A1 WO 2025164725A1
Authority
WO
WIPO (PCT)
Prior art keywords
cellulose
pharmaceutical composition
polymer
formula
compound represented
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/JP2025/003013
Other languages
English (en)
Japanese (ja)
Inventor
正二朗 下川
真人 五味
健佑 堀内
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shionogi and Co Ltd
Original Assignee
Shionogi and Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi and Co Ltd filed Critical Shionogi and Co Ltd
Publication of WO2025164725A1 publication Critical patent/WO2025164725A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • 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.
  • Patent Documents 1 and 2 describe that the compounds represented by formula (I) and the like have an inhibitory effect on monoacylglycerol acyltransferase 2 (hereinafter also referred to as MGAT2) and are useful for treating diseases and disorders such as obesity.
  • MGAT2 monoacylglycerol acyltransferase 2
  • MGAT3 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.
  • Non-Patent Document 1 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 2 Fluthermore, in MGAT2 knockout mice, suppression of high-fat diet loading-induced weight gain, suppression of insulin resistance, suppression of blood cholesterol elevation, suppression of fatty liver formation, and enhancement of energy consumption has been confirmed (Non-Patent Document 2).
  • Patent Document 3 describes crystals of the compound represented by formula (I).
  • Patent Document 4 discloses a preparation containing hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, D-mannitol, and magnesium stearate as additives, and containing cefcapene pivoxil hydrochloride as an active ingredient.
  • none of the cited documents discloses the formulation of the present invention.
  • the object of the present invention is to provide a pharmaceutical composition containing a compound represented by formula (I), etc.
  • the present inventors have found that the use of a polymer in producing a pharmaceutical composition containing a compound represented by formula (I), etc. makes it possible to produce a pharmaceutical composition having an excellent dissolution concentration of the compound represented by formula (I), etc., and have completed the pharmaceutical composition of the present invention containing a compound represented by formula (I), etc., and a polymer. Furthermore, the present inventors have found that the compound represented by formula (I) is unstable under acidic, neutral and weakly alkaline conditions, and have completed a capsule preparation containing the compound represented by formula (I).
  • the present inventors have discovered a pharmaceutical composition containing the compound represented by formula (I) and a polymer, as shown below.
  • the present inventors have also discovered a capsule preparation containing a compound represented by formula (I) or the like and a polymer.
  • the polymer is a cellulose-based polymer
  • the cellulose-based 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.
  • 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.
  • the flat tablet is a tablet consisting of 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.
  • 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 formulation as a pharmaceutical composition with excellent dissolution properties and high stability.
  • 1 is a chromatogram obtained by measuring the compound represented by formula (I) by liquid chromatography. 1 shows the results of the dissolution test of the capsules of Example 11 and Reference Example 4. The vertical axis represents the dissolution rate (unit: %), and the horizontal axis represents time (unit: minutes).
  • the present invention relates to a pharmaceutical composition containing a compound represented by formula (I) and the like.
  • 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 aspect of the present invention is the pharmaceutical composition described above, which contains 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 are water-soluble cellulose-based polymers and water-soluble vinyl-based polymers.
  • 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.
  • hypromellose 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 methylacrylate-methacrylic acid copolymer, dry methacrylic acid copolymer, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, and aminoalkyl acrylate copolymer E.
  • Water-soluble acrylic acid-based polymers are preferred, and methacrylic acid copolymer, 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, and aminoalkyl acrylate copolymer E are preferred. Aminoalkyl methacrylate copolymer is particularly preferred.
  • polyether polymer polyethylene glycol and propylene oxide-ethylene oxide block copolymer are preferred. Water-soluble polyether polymers are preferred, and polyethylene glycol and propylene oxide-ethylene oxide block copolymer 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.
  • 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.
  • it is 0.5 to 30% by weight.
  • it is 0.5 to 10% by weight.
  • it is 0.5 to 5% by weight.
  • Another embodiment of the present invention is a pharmaceutical composition containing a compound represented by formula (I) or the like and a polymer such that when 1 ⁇ L of water is dropped onto a flat tablet made of the polymer, the contact angle is 85° or less.
  • the compound represented by formula (I) or the like used in the flat tablet can be a hydrate of the compound represented by formula (I).
  • the contact angle can be measured according to the method described in the wettability evaluation in Test Example 2. Therefore, a person skilled in the art can select a polymer to be used in the pharmaceutical composition of the present invention.
  • a person skilled in the art can select a polymer that will produce a contact angle of 85 degrees or less when 1 ⁇ L of water is dropped onto a flat tablet consisting of a compound represented by formula (I) or the like and a polymer.
  • polymers include water-soluble cellulose-based polymers and water-soluble vinyl-based polymers.
  • the contact angle is 77 to 82 degrees
  • the contact angle is 80 to 85 degrees
  • the contact angle is 77 to 82 degrees.
  • a flat tablet comprising the compound represented by formula (I) or the like and a polymer
  • a flat tablet comprising 50 mg of the compound represented by formula (I) or the like and 10 mg of the 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 is a tablet with flat top and bottom surfaces.
  • the contact angle is 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 comes into contact with the solid wall, and is listed in a chemical dictionary.
  • the pharmaceutical composition of the present invention may further contain an excipient, a disintegrant and a lubricant.
  • excipients examples include mannitol, microcrystalline cellulose, crystalline cellulose, lactose, corn starch, and bailecho starch.
  • mannitol e.g., D-mannitol
  • crystalline cellulose e.g., crystalline cellulose
  • microcrystalline cellulose e.g., microcrystalline cellulose
  • microcrystalline cellulose e.g., and microcrystalline cellulose are preferred. D-mannitol is even more preferred.
  • disintegrants examples 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, polyvinyl alcohol, etc.
  • Preferred are low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone, and more preferred is low-substituted hydroxypropyl cellulose.
  • 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 ester, hydrogenated oil, white beeswax, hydrogenated soybean oil, beeswax, cetanol, sodium laurate, sucrose fatty acid ester, polyethylene glycol (macrogol), etc.
  • magnesium stearate sodium stearyl fumarate, and sucrose fatty acid ester, and even more preferred is magnesium stearate.
  • the pharmaceutical composition of the present invention contains an excipient, a disintegrant, and a lubricant, the amounts of these can be appropriately selected according to the knowledge and experience of a person skilled in the art.
  • the pharmaceutical composition of the present invention may contain additives used in the pharmaceutical field other than excipients, disintegrants, and lubricants, such as binders, fluidizing agents, flavoring agents, and the like.
  • binders that can be used include polyvinylpyrrolidone, crystalline cellulose, hydroxypropyl cellulose, hypromellose, and low-substituted hydroxypropyl cellulose. Hydroxypropyl cellulose is particularly preferred.
  • the fluidizing agent that can be used include light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, and talc. Light anhydrous silicic acid is particularly preferred.
  • Specific preferred flavorings 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 preferred flavoring agents are aspartame, sucralose, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and its salts, and anhydrous citric acid.
  • Pharmaceutically acceptable salts of the compound of formula (I) include, but are not limited to, hydrochlorides, sulfates, nitrates, fumarates and the like.
  • Solvates of the compound of formula (I) or a pharmaceutically acceptable salt thereof include hydrates, ethanolates, dioxaneates, etc. Hydrates are preferred, and 0.25 hydrates are more preferred.
  • a method for producing hydrates is described in Patent Document 3.
  • a hydrate of the compound represented by formula (I) is preferred, and a 0.25 hydrate of the compound represented by formula (I) is 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.
  • 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.
  • the size of the capsule is preferably 000 to 5 capsules, more preferably 2 to 4 capsules, and particularly preferably 2 or 4 capsules.
  • Another embodiment of the present invention is a capsule containing a compound represented by formula (I), etc.
  • capsules include those in which the compound represented by formula (II) is not detected when a dissolution test is carried out in 0.1 N aqueous hydrochloric acid solution (for example, 50 mL of 0.1 N aqueous hydrochloric acid solution) at 37°C with a paddle at 50 rpm for 5 minutes.
  • the capsules include those in which the compound represented by formula (II) is not detected when a 10-minute dissolution test is carried out, and more preferably, those in which the compound represented by formula (II) is not detected when a 15-minute dissolution test is carried out.
  • the measurement of formula (II) can be carried out according to the method described in Test Example 3.
  • capsule bases used for capsules include hypromellose, gelatin, pullulan, carboxymethylethyl cellulose, etc. Preferred are hypromellose and gelatin, and particularly preferred is hypromellose.
  • capsule bases other than enteric bases can be used for capsules. Examples include hypromellose, gelatin, pullulan, etc. Preferred are hypromellose and gelatin, and particularly preferred is hypromellose.
  • the total weight of the pharmaceutical composition of the present invention is not particularly limited, but is preferably 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 not particularly limited, but is preferably 40 to 250 mg, more preferably 88 to 210 mg, and particularly preferably 88 mg or 210 mg.
  • the pharmaceutical composition of the present invention is a capsule, it can be produced as follows, although there are no particular limitations on the method: Specifically, the compound represented by formula (I) and additives such as a polymer, an excipient, a disintegrant, and a lubricant are mixed to produce a mixed powder, and the mixed powder is filled into capsules to produce the capsule.
  • the pharmaceutical composition of the present invention is in the form of granules, it can be produced as follows, although there are no particular limitations. Specifically, a mixed powder is produced as described above, and the mixed powder is granulated.
  • the granulation step can be preferably carried out using 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 which does not use water.
  • a pharmaceutical composition of the present invention is a tablet, it is not particularly limited, but for example, tablets can be produced by producing granules as described above and compressing the granules using a tablet press. Alternatively, tablets can be produced by producing a mixed powder as described above and compressing the mixed powder using a tablet press.
  • tablets can be produced by mixing a compound represented by formula (I) or the like with additives such as a polymer to produce a mixed powder, granulating the mixed powder, mixing a disintegrant, a lubricant, etc., and compressing the mixture using a tablet press.
  • additives such as a polymer to produce a mixed powder, granulating the mixed powder, mixing a disintegrant, a lubricant, etc., and compressing the mixture using a tablet press.
  • the pharmaceutical composition of the present invention is in the form of powder, pills, etc., it can be prepared according to the knowledge and experience commonly possessed by those skilled in the art.
  • the granules or tablets may be coated with a coating layer.
  • a fluidized bed granulation coating machine a fluidized bed tumbling coating machine, or the like can be used.
  • a pan coating machine a ventilated coating machine, or the like can 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.
  • D50 and D90 refer to the particle diameters at the 50% and 90% points of a cumulative curve when the total volume of the powder mass is taken as 100%, and can be measured using either the dry or wet method.
  • the pharmaceutical composition of the present invention can be administered orally.
  • the compound represented by formula (I) can be administered at a dose of 3 to 30 mg/day. Doses of 3, 10, or 30 mg/day are particularly preferred.
  • 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 promote or treat energy consumption.
  • the pharmaceutical composition of the present invention can improve obesity and other conditions.
  • Measurement method 1 Detector: ultraviolet absorption photometer (measurement wavelength 267 nm)
  • 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 ⁇ m filter, and the concentration of the compound of formula (I) in the filtrate was measured using a liquid chromatography method shown in Measurement Method 2, with an injection volume of 10 ⁇ L. In Reference Example 1, a similar test was carried out using only 30 mg of the compound of formula (I) without adding any polymer.
  • Measurement method 2 Detector: ultraviolet absorption photometer (measurement wavelength 267 nm)
  • Test Example 2 Evaluation of Wettability 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 under conditions of a diameter of 7.5 mm and a tableting pressure of 5 kN to obtain flat tablets. A 1 ⁇ L droplet of water was dropped on 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.
  • the polymers used were hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd.), and polyvinylpyrrolidone (manufactured by BASF).
  • 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 ⁇ m 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 ⁇ L under the conditions of Measurement Method 1, and the amount of the compound of formula (II) was measured.
  • Capsules containing the compound of formula (I) were produced. Table 6 shows the formulation per capsule.
  • the compound of formula (I), D-mannitol (Roquette), low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.), hydroxypropyl cellulose (Nippon Soda Co., Ltd.), and magnesium stearate (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.
  • 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 ⁇ m 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.
  • Example 11 The results of the above test for Example 11 and Reference Example 4 are shown in Figure 2.
  • the capsules of Example 11 exhibited rapid dissolution behavior.
  • Examples 10 and 12 also exhibited rapid dissolution behavior similar to Example 11.
  • the pharmaceutical composition containing the dihydropyridinone derivative of the present invention has an excellent soluble concentration and exhibits excellent dissolution properties and stability, making it useful for treating diseases and disorders such as obesity.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant un composé représenté par la formule (I), un sel pharmaceutiquement acceptable de celui-ci, ou un solvate de ceux-ci.　L'invention concerne en outre une composition pharmaceutique contenant le composé représenté par la formule (I) ou similaire et ayant une excellente concentration de dissolution de composé du fait qu'elle contient un polymère. L'utilisation d'une formulation encapsulée contenant un composé représenté par la formule (I) ou similaire, permet de fournir une formulation encapsulée qui est stable dans des conditions acides.
PCT/JP2025/003013 2024-01-31 2025-01-30 Composition pharmaceutique contenant un dérivé de dihydropyridone Pending WO2025164725A1 (fr)

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JP2024-013082 2024-01-31
JP2024013082 2024-01-31
JP2024084738A JP2024100975A (ja) 2024-01-31 2024-05-24 ジヒドロピリジノン誘導体を含有する医薬組成物
JP2024-084738 2024-05-24

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WO2025164725A1 true WO2025164725A1 (fr) 2025-08-07

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JP (1) JP2024100975A (fr)
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014030204A1 (fr) * 2012-08-20 2014-02-27 大日本住友製薬株式会社 Particule creuse contenant un médicament
WO2019013311A1 (fr) * 2017-07-14 2019-01-17 塩野義製薬株式会社 Dérivé à cycle condensé ayant une activité inhibitrice de ｍｇａｔ２
WO2023038039A1 (fr) * 2021-09-08 2023-03-16 塩野義製薬株式会社 Médicament destiné à la prévention et au traitement de maladies liées à l'activité anti-obésité
WO2023243616A1 (fr) * 2022-06-13 2023-12-21 塩野義製薬株式会社 Cristal d'un dérivé de dihydropyridinone ou d'un solvate de celui-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014030204A1 (fr) * 2012-08-20 2014-02-27 大日本住友製薬株式会社 Particule creuse contenant un médicament
WO2019013311A1 (fr) * 2017-07-14 2019-01-17 塩野義製薬株式会社 Dérivé à cycle condensé ayant une activité inhibitrice de ｍｇａｔ２
WO2023038039A1 (fr) * 2021-09-08 2023-03-16 塩野義製薬株式会社 Médicament destiné à la prévention et au traitement de maladies liées à l'activité anti-obésité
WO2023243616A1 (fr) * 2022-06-13 2023-12-21 塩野義製薬株式会社 Cristal d'un dérivé de dihydropyridinone ou d'un solvate de celui-ci

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
?? ??, ??? ???????????, ????????????, ?????????, ?? ??, non-official translation (TAKAHASHI, Yoshiteru, chapter 7, Improved Drug Solubility and Absorption, Design and Evaluation of Oral Dosage Forms, KABUSHIKI KAISHA YAKUGYO JIHOSHA, TAKEDA, Shozo) pages 172-192 *
??????????, ????????????, first edition, 28 February 2007, 700-710, 825-893, (Japan Pharmaceutical Excipients Council, Handbook of Pharmaceutical Excipients) in particular, all additives, "7. Application to Pharmaceutical Formulations" *
SHIMOKAWA SHOJIRO, GOMI MASATO, NAKAGAWA YUTA, INOUE ATSUSHI, FUNAKI TAKESHI: "Simultaneous Overcoming Approach for Poor Wettability and Low Stability in Stomach by Simple Methods; Formulation Design and Development of Monoacylglycerol Acyltransferase 2 Inhibitor, S-309309", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 72, no. 10, 18 October 2024 (2024-10-18), JP , pages 894 - 898, XP093342133, ISSN: 0009-2363, DOI: 10.1248/cpb.c24-00405 *

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