WO2019181876A1 - アルキル硫酸ナトリウムを含む医薬組成物 - Google Patents

アルキル硫酸ナトリウムを含む医薬組成物 Download PDF

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Publication number
WO2019181876A1
WO2019181876A1 PCT/JP2019/011251 JP2019011251W WO2019181876A1 WO 2019181876 A1 WO2019181876 A1 WO 2019181876A1 JP 2019011251 W JP2019011251 W JP 2019011251W WO 2019181876 A1 WO2019181876 A1 WO 2019181876A1
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Prior art keywords
compound
mass
lauryl sulfate
pharmaceutical composition
parts
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PCT/JP2019/011251
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English (en)
French (fr)
Japanese (ja)
Inventor
憲司 楠本
定弘 宮村
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Taiho Pharmaceutical Co Ltd
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Taiho Pharmaceutical Co Ltd
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Priority to RU2020133810A priority Critical patent/RU2759746C1/ru
Priority to KR1020207029418A priority patent/KR102473372B1/ko
Priority to EP19771998.2A priority patent/EP3769765B1/en
Priority to CN201980020022.5A priority patent/CN111867594A/zh
Priority to CA3094431A priority patent/CA3094431C/en
Priority to MYPI2020004844A priority patent/MY203305A/en
Priority to ES19771998T priority patent/ES2980333T3/es
Priority to AU2019239404A priority patent/AU2019239404B2/en
Priority to SG11202008435SA priority patent/SG11202008435SA/en
Priority to BR112020018697-0A priority patent/BR112020018697B1/pt
Priority to EP24207166.0A priority patent/EP4470621A3/en
Application filed by Taiho Pharmaceutical Co Ltd filed Critical Taiho Pharmaceutical Co Ltd
Priority to MX2020009762A priority patent/MX2020009762A/es
Priority to EP24160537.7A priority patent/EP4353222A1/en
Priority to FIEP19771998.2T priority patent/FI3769765T3/fi
Priority to JP2020507802A priority patent/JP6918204B2/ja
Priority to PL19771998.2T priority patent/PL3769765T3/pl
Priority to US16/982,377 priority patent/US11833151B2/en
Priority to DK19771998.2T priority patent/DK3769765T3/da
Publication of WO2019181876A1 publication Critical patent/WO2019181876A1/ja
Priority to PH12020551412A priority patent/PH12020551412A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • 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
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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    • 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
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    • 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
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    • 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
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    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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    • A61K9/2022—Organic macromolecular compounds
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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Definitions

  • the present invention relates to (S) -1- (3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl-1-
  • the present invention relates to a pharmaceutical composition containing pyrrolidinyl) -2-propen-1-one or a pharmaceutically acceptable salt thereof and sodium alkyl sulfate, and particularly to a pharmaceutical composition for oral administration.
  • Bioavailability is an index indicating how much the administered drug reaches and acts in the systemic circulation, and is a clinically important parameter closely related to drug efficacy and toxicity.
  • drugs with low bioavailability do not have the expected medicinal effects, or increase in intra-individual or inter-individual variation, making it difficult to predict and control the efficacy and toxicity. Therefore, it is important to obtain appropriate bioavailability in drug development.
  • Orally administered drugs are affected by absorption efficiency from the gastrointestinal tract and metabolism in the liver and gastrointestinal tract, but especially in the case of poorly soluble drugs, in order to obtain appropriate bioavailability, It is important to improve the dissolution property and solubility of the drug in water.
  • solubilizers such as surfactants
  • the surfactants that can be suitably used vary depending on the structure and properties of the active ingredient and the type of preparation, and therefore it is not easy to find an optimal preparation formulation for a poorly soluble drug.
  • Sodium lauryl sulfate a kind of anionic surfactant, is a stabilizer, surfactant, lubricant, solubilizer, base, binder, brightener, excipient, disintegrant, emulsifier It is known that it can be added to a preparation as a foaming agent, a dispersing agent or the like.
  • Patent Document 1 An example of preparing a preparation by adding sodium lauryl sulfate as a solubilizer to granules containing a specific compound has been reported (Patent Document 1).
  • (S) -1- (3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3] is a compound having an excellent FGFR inhibitory action and showing antitumor activity.
  • 3,4-d] pyrimidin-1-yl-1-pyrrolidinyl) -2-propen-1-one (hereinafter also referred to as “compound A”) has been reported (Patent Documents 2 to 6) .
  • Compound A has not been reported for use in combination with sodium alkyl sulfate for improving dissolution or for other purposes.
  • JP 2016-104762 A International Publication WO2013 / 108809 Pamphlet International Publication WO2015 / 008844 Pamphlet International Publication WO2015 / 008839 Pamphlet International Publication WO2016 / 159327 Pamphlet International Publication WO2017 / 150725 Pamphlet
  • Compound A has excellent FGFR inhibitory activity and antitumor activity, but there is room for improvement in securing appropriate bioavailability when formulated. For example, improvement in elution and neutral absorbency in a neutral pH region has been demanded. Accordingly, one of the objects of the present invention is to provide a pharmaceutical composition of Compound A or a pharmaceutically acceptable salt thereof that has superior dissolution properties, stability, and absorbability, and is easy to produce. It is in.
  • the present inventors have added various compounds to the composition containing Compound A or a pharmaceutically acceptable salt thereof, and variously examined whether or not compound A has an effect of improving the dissolution property, stability, and absorbability. Went.
  • Compound A or a pharmaceutically acceptable salt thereof by adding sodium alkyl sulfate, a pharmaceutical composition having excellent dissolution properties, stability, and absorbability, and excellent manufacturing suitability is obtained. It was found that it can be obtained.
  • the present inventors have further studied the more effective additive in the pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof and sodium alkyl sulfate, and completed the present invention.
  • (S) -1- (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidine-1- having the following structure
  • a pharmaceutical composition comprising yl-1-pyrrolidinyl) -2-propen-1-one or a pharmaceutically acceptable salt thereof and sodium lauryl sulfate.
  • composition according to any one of the above [1] to [7], which is in the form of a syrup, powder, granule, tablet or capsule.
  • (S) -1- (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl-1-pyrrolidinyl )
  • a method for improving the production suitability of a pharmaceutical which comprises adding sodium lauryl sulfate to a pharmaceutical composition containing 2-propen-1-one or a pharmaceutically acceptable salt thereof.
  • Compound A or a pharmaceutically acceptable salt thereof and sodium alkyl sulfate having excellent dissolution properties, stability, and absorbability, and excellent manufacturing suitability such as lubricity and fluidity are obtained.
  • Pharmaceutical compositions can be provided.
  • the pharmaceutical composition of the present invention contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, but may contain other active ingredients as long as the effects of the present invention are exhibited.
  • Compound A ((S) -1- (3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl-1-pyrrolidinyl) ) -2-propen-1-one) is shown below.
  • Compound A or a pharmaceutically acceptable salt thereof may be a solvate (for example, hydrate etc.) or a non-solvate.
  • the pharmaceutically acceptable salt of Compound A is not particularly limited.
  • addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid, citric acid, tartaric acid and maleic acid, potassium, Examples thereof include salts with alkali metals such as sodium, salts with alkaline earth metals such as calcium and magnesium, salts with organic bases such as ammonium salts, ethylamine salts and arginine salts.
  • Compound A or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in Patent Document 2 or 5.
  • the description of “Compound A” may include a pharmaceutically acceptable “salt” of Compound A and the above “solvate”.
  • Compound A or a pharmaceutically acceptable salt thereof used in the present invention is preferably 1 to 50% by mass of the whole pharmaceutical composition from the viewpoints of elution, stability, absorbability and manufacturability. More preferably, it is 2 to 30% by mass, and further preferably 3 to 18% by mass.
  • a solubilizer may be used in a pharmaceutical composition having a sparingly soluble active ingredient.
  • the solubilizer include a surfactant, a polyether compound, and a poloxamer.
  • the surfactant include alkyl sulfate, sucrose fatty acid ester (DK ester, etc.), polysorbate (Tween 20, Tween 60, Tween 80, etc.), polyoxyethylene castor oil (Cremophor, Cremophor EL, etc.).
  • the polyether compound include polyethylene glycol (PEG400, PEG4000, PEG6000, macrogol, etc.) and the like.
  • the poloxamer include lutolol (such as Lutrol F68).
  • sodium alkyl sulfate examples include sodium sulfate having an alkyl group having 10 to 18 carbon atoms, specifically sodium decyl sulfate, sodium lauryl sulfate (also referred to as SLS or sodium dodecyl sulfate (SLS)), tetradecyl sulfate.
  • Examples thereof include sodium, sodium cetyl sulfate (sodium hexadecyl sulfate), and sodium stearyl sulfate (sodium octadecyl sulfate).
  • the sodium alkyl sulfate used in the present invention is preferably sodium lauryl sulfate from the viewpoint of elution, stability, absorbability, and production suitability.
  • Sodium lauryl sulfate can be suitably used by obtaining one having a name such as NIKKOL SLS (manufactured by Nikko Chemicals Co., Ltd.), Emar OS (Kao Corporation), Kolliphor SLS (BASF Corporation), or the like.
  • sodium alkyl sulfate in the range of 0.01 to 25 parts by mass with respect to 1 part by mass of Compound A can be used, and 0.05 to 15 parts by mass of sodium alkyl sulfate is preferable.
  • 0.1 to 10 parts by weight of sodium alkyl sulfate is preferred, 0.2 to 5 parts by weight of sodium alkyl sulfate is more preferred, 0.25 to 3 parts by weight is further preferred, and 0.75 to 1.5 parts by weight is further preferred.
  • 1 part by mass is particularly preferable.
  • the sodium alkyl sulfate is preferably 1 to 50% by mass of the total pharmaceutical composition, more preferably 2 to 30% by mass, more preferably 3 to 18% by mass, more preferably 4 to It is 12% by mass, particularly preferably 4 to 5% by mass, 6 to 7% by mass, or 9 to 10% by mass.
  • “elution” means the elution of Compound A from a composition (formulation) containing Compound A.
  • the dissolution property can be confirmed by the dissolution test method (paddle method) of the 16th revision Japanese Pharmacopoeia.
  • the improvement in dissolution can be judged by shortening the disintegration time or the dissolution rate when equilibrium is reached.
  • “Stability” in the present specification includes both the stability as a preparation containing a pharmaceutical composition and the chemical stability of Compound A.
  • the improvement in stability can be determined by comparing the state of the preparation before and after storage under the same conditions, and comparing the chemical purity of Compound A by high performance liquid chromatography or the like. Improving stability is always a very important issue for pharmaceutical compositions, considering the storage and distribution of pharmaceuticals.
  • absorbability means the absorbability of Compound A into the body of a subject to which Compound A has been administered. Absorbability can be confirmed by, for example, the area under the blood concentration-time curve (AUC) and the maximum blood concentration (Cmax) after the compound A eluted as described above is absorbed into the body of the subject. The improvement in absorbability can be determined by increasing the values of AUC and Cmax. Further, the absorption rate of Compound A after administration of the preparation can be evaluated by the maximum blood concentration arrival time (Tmax). The improvement in absorbency assessed by these parameters can better lead to the intended effect of Compound A and optimization of the dosing schedule.
  • AUC blood concentration-time curve
  • Cmax maximum blood concentration
  • “manufacturability” refers to a property capable of easily producing a pharmaceutical composition containing an active ingredient and sodium alkyl sulfate, and includes those excellent in lubricity and fluidity of the pharmaceutical composition.
  • the above-mentioned sodium alkyl sulfate satisfies all of the dissolution property, absorbability, and production suitability.
  • Lubricity in the present specification means the property that powders such as granulated products and granules used for tablet production do not adhere to a tableting machine or the like. Lubricity can be confirmed by the absence of sticking where the preparation adheres to the punch of the tableting machine, or the absence of binding where the preparation adheres to the die. Lubricity can also be confirmed by the fact that the extraction pressure, which is the pressure at the time of taking out the tablet, does not increase. By improving the lubricity at the time of producing the preparation, it is possible to produce tablets without damaging the produced tablets and production machines such as tableting machines.
  • the “fluidity” in the present specification refers to the ease of flow of the pharmaceutical composition before granulation, and can be evaluated by the angle of repose or the degree of compression.
  • a powder having extremely low fluidity becomes difficult to fluidize and cannot be granulated.
  • the granulation of the powder can be advanced, and a homogeneous granulated product can be obtained.
  • the additive in the pharmaceutical composition of the present invention is not particularly limited as long as it is generally used in pharmaceutical preparations.
  • fluidizing agents, excipients, binders, lubricants are not limited.
  • Swelling agents, coloring agents, disintegrating agents and the like can be used.
  • Examples of the fluidizing agent include silicon dioxide, sodium silicate, talc, magnesium stearate and the like.
  • examples of the excipient include lactose (including lactose hydrate), corn starch (corn starch), crystalline cellulose, D-mannitol and the like.
  • binder examples include hydroxypropyl cellulose, hypromellose and polyvinyl alcohol.
  • lubricants include hydrogenated oil, sucrose fatty acid ester, sodium lauryl sulfate, magnesium stearate and stearic acid.
  • colorant examples include edible yellow No. 5 dye, edible blue No. 2 dye, edible lake dye, iron sesquioxide, yellow sesquioxide, and titanium oxide.
  • the coating agent examples include hydroxypropylmethylcellulose (hypromellose, TC-5, METOLOSE, etc.) and polyethylene glycol (PEG400, PEG1500, PEG4000, PEG6000, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, etc.). Can do.
  • disintegrant examples include low-substituted hydroxypropylcellulose, corn starch (corn starch), partially pregelatinized starch, crystalline cellulose, carmellose sodium, carmellose calcium, D-mannitol, crospovidone, preferably crystalline cellulose, D-mannitol or crospovidone.
  • the pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof and sodium alkyl sulfate can further contain a disintegrant.
  • Crospovidone (cross-linked PVP) as a disintegrant is a commercially available pharmaceutical additive. In the present invention, it is 1 to 20% by mass, and preferably 2 to 15% by mass of the whole pharmaceutical composition.
  • crospovidone is 0.1 to 20 parts by weight, preferably 0.2 to 5 parts by weight, more preferably 0.2 to 3 parts by weight, based on 1 part by weight of Compound A, and 0.9 to 1.1 parts by weight, 1.4 to 1.6 parts by weight, or 1.9 to 2.1 parts by weight are particularly preferred.
  • Crospovidone is 0.1 to 20 parts by mass, more preferably 0.2 to 5 parts by mass, and more preferably 0.2 to 3 parts by mass with respect to 1 part by mass of sodium alkyl sulfate. Particularly preferred is 0.9 to 1.1 parts by weight, 1.4 to 1.6 parts by weight, or 1.9 to 2.1 parts by weight.
  • the pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof and sodium alkyl sulfate can further contain carmellose sodium as a disintegrant.
  • the carmellose sodium is an additive for pharmaceuticals, and in the present invention, it is 1 to 10% by mass of the whole pharmaceutical composition.
  • Carmellose sodium is 0.1 to 5 parts by mass, preferably 0.2 to 2 parts by mass, or 0.2 to 0.4 parts by mass, or 0.9 parts by mass with respect to 1 part by mass of Compound A. Particularly preferred is -1.2 parts by weight. Carmellose sodium is 0.1 to 5 parts by weight, more preferably 0.2 to 2 parts by weight, particularly preferably 0.2 to 0.4 parts by weight, based on 1 part by weight of sodium alkyl sulfate. Part, or 0.9 to 1.2 parts by mass.
  • the pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof and sodium alkyl sulfate can further contain carmellose calcium as a disintegrant. ⁇ 10% by mass.
  • Carmellose calcium is 0.1 to 5 parts by weight, preferably 0.2 to 2 parts by weight, or 0.2 to 0.4 parts by weight, or 0.9 parts by weight with respect to 1 part by weight of Compound A. Particularly preferred is -1.2 parts by weight. Carmellose calcium is 0.1 to 5 parts by mass of sodium alkyl sulfate, more preferably 0.2 to 2 parts by mass, particularly preferably 0.2 to 0.4 parts by mass, or 0.0. 9 to 1.2 parts by mass.
  • the pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof and sodium alkyl sulfate can further contain D-mannitol as a disintegrant.
  • D-mannitol as a disintegrant is known as a disintegrant in an intraoral quick disintegrant, and the amount that can be used in the present invention is 10 to 80% by mass of the whole pharmaceutical composition, and 15 to 70% by mass. 20 to 60% by mass is preferable.
  • the amount of D-mannitol that can be used in the present invention is 1 to 20 parts by weight, preferably 2 to 15 parts by weight, more preferably 2 to 12 parts by weight, based on 1 part by weight of Compound A. Particularly preferred is 2 to 4 parts by weight, 6 to 8 parts by weight, or 9 to 11 parts by weight.
  • the pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof and sodium alkyl sulfate can further contain lactose as an excipient.
  • the amount of lactose that can be used in the present invention is 1 to 80% by mass, preferably 2 to 70% by mass, more preferably 3 to 60% by mass, based on the entire pharmaceutical composition.
  • the amount of lactose that can be used in the present invention is 1 to 30 parts by weight, preferably 1 to 10 parts by weight, more preferably 1 to 5 parts by weight with respect to 1 part by weight of Compound A. Particularly preferred is 1 to 2 parts by mass, or 4 to 5 parts by mass.
  • Examples of the pharmaceutical composition of the present invention include a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof as an active ingredient and containing sodium alkyl sulfate, preferably Compound A or a pharmaceutically acceptable salt thereof. And a sodium lauryl sulfate-containing pharmaceutical composition.
  • the pharmaceutical composition of the present invention contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and contains 0.05 to 15 parts by mass of sodium lauryl sulfate relative to 1 part by mass of Compound A. It is a pharmaceutical composition. More preferably, it is a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient and containing 0.1 to 10 parts by mass of sodium lauryl sulfate with respect to 1 part by mass of Compound A.
  • it is a pharmaceutical composition
  • a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient and containing 0.2 to 5 parts by mass of sodium lauryl sulfate relative to 1 part by mass of Compound A. More preferably, it is a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient and containing 0.25 to 3 parts by mass of sodium lauryl sulfate relative to 1 part by mass of Compound A.
  • it is a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and containing 0.75 to 1.5 parts by mass of sodium lauryl sulfate relative to 1 part by mass of Compound A. . More preferably, it is a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient and containing 1 part by mass of sodium lauryl sulfate with respect to 1 part by mass of Compound A.
  • Compound A or a pharmaceutically acceptable salt thereof as an active ingredient contains 1 part by weight of sodium lauryl sulfate per 1 part by weight of Compound A, and further contains crospovidone, carmellose sodium, carmellose A pharmaceutical composition comprising one additive selected from the group consisting of calcium.
  • the pharmaceutical composition of the present invention preferably contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, contains sodium lauryl sulfate, crospovidone, carmellose sodium, carmellose calcium
  • composition More preferably, it contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, contains sodium lauryl sulfate, and further contains 0.2 to 5 parts by mass of crospovidone relative to 1 part by mass of Compound A. It is a pharmaceutical composition. More preferably, a pharmaceutical comprising compound A or a pharmaceutically acceptable salt thereof as an active ingredient, containing sodium lauryl sulfate, and containing 0.2 to 3 parts by mass of crospovidone relative to 1 part by mass of compound A It is a composition.
  • compound A or a pharmaceutically acceptable salt thereof as an active ingredient contains sodium lauryl sulfate, and is 0.9 to 1.1 parts by weight, 1.4 to A pharmaceutical composition containing 1.6 parts by mass or 1.9 to 2.1 parts by mass of crospovidone.
  • the pharmaceutical composition of the present invention is preferably a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, containing sodium lauryl sulfate, and further containing crospovidone. is there.
  • compound A or a pharmaceutically acceptable salt thereof as an active ingredient contains 0.1 to 10 parts by weight of sodium lauryl sulfate with respect to 1 part by weight of compound A, and further 1 part by weight of compound A Is a pharmaceutical composition containing 0.1 to 20 parts by mass of crospovidone.
  • compound A or a pharmaceutically acceptable salt thereof as an active ingredient contains 0.25-3 parts by mass of sodium lauryl sulfate relative to 1 part by mass of compound A, and further 1 part by mass of compound A Is a pharmaceutical composition containing 0.2 to 5 parts by mass of crospovidone.
  • compound A or a pharmaceutically acceptable salt thereof as an active ingredient contains 0.75 to 1.5 parts by mass of sodium lauryl sulfate relative to 1 part by mass of compound A, and further contains compound A-1 A pharmaceutical composition containing 0.2 to 3 parts by mass of crospovidone relative to parts by mass.
  • composition containing 1.9 to 1.1 parts by weight, 1.4 to 1.6 parts by weight, or 1.9 to 2.1 parts by weight of crospovidone.
  • the pharmaceutical composition of the present invention preferably contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, contains sodium lauryl sulfate, crospovidone, carmellose sodium, carmellose calcium
  • a pharmaceutical composition further containing D-mannitol.
  • one or more additives selected from the group consisting of compound A or a pharmaceutically acceptable salt thereof as an active ingredient, containing sodium lauryl sulfate, and consisting of crospovidone, carmellose sodium, and carmellose calcium And further containing 2 to 4 parts by weight, 6 to 8 parts by weight, or 9 to 11 parts by weight of D-mannitol with respect to 1 part by weight of Compound A.
  • the pharmaceutical composition of the present invention preferably contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, contains sodium lauryl sulfate, crospovidone, carmellose sodium, carmellose calcium And a pharmaceutical composition containing one or more additives selected from the group consisting of D-mannitol and lactose.
  • one or more additives selected from the group consisting of compound A or a pharmaceutically acceptable salt thereof as an active ingredient, containing sodium lauryl sulfate, and consisting of crospovidone, carmellose sodium, carmellose calcium , D-mannitol, and further 1 to 30 parts by mass of lactose per 1 part by mass of Compound A.
  • one or more additives selected from the group consisting of compound A or a pharmaceutically acceptable salt thereof as an active ingredient, containing sodium lauryl sulfate, and consisting of crospovidone, carmellose sodium, and carmellose calcium , D-mannitol, and further 1 to 10 parts by mass of lactose per 1 part by mass of Compound A.
  • one or more additives selected from the group consisting of compound A or a pharmaceutically acceptable salt thereof as an active ingredient, containing sodium lauryl sulfate, and consisting of crospovidone, carmellose sodium, and carmellose calcium And 2 to 12 parts by mass of D-mannitol per 1 part by mass of Compound A and further 1 to 5 parts by mass of lactose per 1 part by mass of Compound A.
  • the pharmaceutical composition of the present invention preferably contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, contains sodium lauryl sulfate, and further contains D-mannitol. It is a thing.
  • a pharmaceutical comprising compound A or a pharmaceutically acceptable salt thereof as an active ingredient, containing sodium lauryl sulfate, and further containing 1 to 20 parts by mass of D-mannitol relative to 1 part by mass of compound A It is a composition. More preferably, it contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, contains sodium lauryl sulfate, and further contains 2 to 15 parts by mass of D-mannitol with respect to 1 part by mass of Compound A. It is a pharmaceutical composition.
  • Compound A or a pharmaceutically acceptable salt thereof as an active ingredient contains sodium lauryl sulfate, contains 2 to 12 parts by weight of D-mannitol per 1 part by weight of Compound A, and A pharmaceutical composition containing one or more additives selected from the group consisting of crospovidone, carmellose sodium, and carmellose calcium.
  • the pharmaceutical composition of the present invention is preferably a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, containing sodium lauryl sulfate, and further containing lactose. is there.
  • the pharmaceutical composition contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, contains sodium lauryl sulfate, and further contains 1-30 parts by weight of lactose relative to 1 part by weight of Compound A. It is. More preferably, the pharmaceutical composition contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, contains sodium lauryl sulfate, and further contains 1 to 10 parts by mass of lactose relative to 1 part by mass of Compound A. It is.
  • compound A or a pharmaceutically acceptable salt thereof as an active ingredient contains sodium lauryl sulfate, contains 1 to 5 parts by weight of lactose per 1 part by weight of compound A, and It is a pharmaceutical composition containing one or more additives selected from the group consisting of povidone, carmellose sodium, and carmellose calcium.
  • the pharmaceutical composition of the present invention is preferably a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and containing sodium lauryl sulfate, crospovidone, lactose, and D-mannitol. It is a composition.
  • compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and 0.01 to 25 parts by weight of sodium lauryl sulfate, 0.1 to 20 parts by weight of cloth per 1 part by weight of compound A
  • a pharmaceutical composition comprising povidone, 0.1 to 20 parts by mass of D-mannitol, and 0.1 to 30 parts by mass of lactose.
  • Compound A or a pharmaceutically acceptable salt thereof as an active ingredient 0.1 to 10 parts by weight of sodium lauryl sulfate, 0.1 to 20 parts by weight of cross to 1 part by weight of Compound A
  • a pharmaceutical composition comprising povidone, 0.1 to 20 parts by mass of D-mannitol, and 0.1 to 30 parts by mass of lactose.
  • it contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and 0.2 to 5 parts by mass of sodium lauryl sulfate, 0.1 to 20 parts by mass of cross with respect to 1 part by mass of Compound A
  • a pharmaceutical composition comprising povidone, 0.1 to 20 parts by mass of D-mannitol, and 0.1 to 30 parts by mass of lactose.
  • it contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and 0.25-3 parts by weight of sodium lauryl sulfate, 0.1-20 parts by weight of cloth per 1 part by weight of Compound A
  • a pharmaceutical composition comprising povidone, 0.1 to 20 parts by mass of D-mannitol, and 0.1 to 30 parts by mass of lactose.
  • it contains compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and 0.75 to 1.5 parts by mass of sodium lauryl sulfate, 0.1 to 20 parts by mass with respect to 1 part by mass of compound A Of crospovidone, 0.1 to 20 parts by mass of D-mannitol, and 0.1 to 30 parts by mass of lactose.
  • it contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and 0.75 to 1.5 parts by mass of sodium lauryl sulfate, 0.2 to 5 parts by mass with respect to 1 part by mass of Compound A Of crospovidone, 0.1 to 20 parts by mass of D-mannitol, and 0.1 to 30 parts by mass of lactose.
  • it contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and 0.75 to 1.5 parts by mass of sodium lauryl sulfate, 0.2 to 3 parts by mass with respect to 1 part by mass of Compound A Of crospovidone, 0.1 to 20 parts by mass of D-mannitol, and 0.1 to 30 parts by mass of lactose.
  • Compound A More preferably, it contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and 0.75 to 1.5 parts by mass of sodium lauryl sulfate, 0.2 to 3 parts by mass with respect to 1 part by mass of Compound A
  • a pharmaceutical composition comprising 2 to 15 parts by weight of D-mannitol and 1 to 10 parts by weight of lactose.
  • Compound A More preferably, it contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and 0.75 to 1.5 parts by mass of sodium lauryl sulfate, 0.2 to 3 parts by mass with respect to 1 part by mass of Compound A
  • a pharmaceutical composition comprising 2 to 12 parts by weight of D-mannitol and 1 to 5 parts by weight of lactose.
  • it contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, and 1 part by weight of sodium lauryl sulfate, 0.9 to 1.1 parts by weight, 1.4 parts per 1 part by weight of Compound A 1.6 parts by mass, or 1.9-2.1 parts by mass of crospovidone, 2-4 parts by mass, 6-8 parts by mass, or 9-11 parts by mass of D-mannitol, and 1-2 parts by mass Or a pharmaceutical composition containing 4 to 5 parts by mass of lactose.
  • the pharmaceutical composition of the present invention may employ a route normally used for oral administration, transdermal administration, intraperitoneal administration, intravenous administration, etc., and oral administration is preferred. Accordingly, in a preferred embodiment, the pharmaceutical composition of the present invention is a pharmaceutical composition for oral administration comprising Compound A and sodium alkyl sulfate.
  • Examples of the pharmaceutical composition for oral administration include, but are not limited to, syrups, powders, granules, tablets, capsules and the like.
  • the pharmaceutical composition of the present invention can be produced by a known preparation method. For example, as a granulation method, a fluidized bed granulation method, a stirring granulation method, a tumbling fluid granulation method, an extrusion granulation method, or the like.
  • the granulated product can be produced using a method, a spray granulation method, a crushing granulation method, or the like.
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is formulated as a tablet, a coating can be applied to the surface of the tablet to provide a stable and easy-to-use pharmaceutical composition for oral administration.
  • the coating includes film coating and sugar coating.
  • the coating base include hypromellose, ethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, sucrose and the like.
  • the pharmaceutical composition of the present invention can be used with various flavors such as orange and lemon as flavoring agents for easy oral administration, and l-menthol, camphor, mint and the like as flavoring agents. Can be used as
  • the pharmaceutical composition of the present invention is useful as an antitumor agent because Compound A has excellent FGFR inhibitory activity.
  • the target cancer is not particularly limited.
  • head and neck cancer gastrointestinal cancer [for example, esophageal cancer, stomach cancer, gastrointestinal stromal tumor, duodenal cancer, liver cancer, biliary tract cancer (for example, gallbladder / bile duct cancer, etc.) Pancreatic cancer, small intestine cancer, colon cancer (eg, colorectal cancer, colon cancer, rectal cancer, etc.), lung cancer, breast cancer, ovarian cancer, uterine cancer (eg, cervical cancer, endometrial cancer, etc.), renal cancer , Bladder cancer, prostate cancer, urothelial cancer, bone / soft tissue sarcoma, blood cancer (eg B cell lymphoma, chronic lymphocytic leukemia, peripheral T cell lymphoma, myelodysplastic syndrome, acute myeloid leukemia, acute lymph Leukemia), multiple mye
  • the present invention relates to head and neck cancer, gastrointestinal cancer [for example, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, duodenal cancer, liver cancer, biliary tract cancer (for example, gallbladder / bile duct cancer, etc.), pancreatic cancer, small intestine cancer.
  • gastrointestinal cancer for example, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, duodenal cancer, liver cancer, biliary tract cancer (for example, gallbladder / bile duct cancer, etc.), pancreatic cancer, small intestine cancer.
  • Colorectal cancer eg, colorectal cancer, colon cancer, rectal cancer, etc.
  • lung cancer breast cancer, ovarian cancer, uterine cancer (eg, cervical cancer, endometrial cancer, etc.), renal cancer, bladder cancer, prostate cancer , Urothelial cancer, bone / soft tissue sarcoma, blood cancer (eg B cell lymphoma, chronic lymphocytic leukemia, peripheral T cell lymphoma, myelodysplastic syndrome, acute myeloid leukemia, acute lymphocytic leukemia), frequent occurrence
  • a pharmaceutical composition for use for the treatment or prevention of a tumor selected from multiple myeloma, skin cancer, and mesothelioma is provided.
  • the present invention relates to elution of Compound A from a pharmaceutical composition, characterized in that sodium lauryl sulfate is added to the pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof.
  • a method for improving sex is provided.
  • the present invention provides a method for improving the absorbability of Compound A, which comprises adding sodium lauryl sulfate to a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof. To do.
  • the present invention provides a method for improving production suitability, wherein sodium lauryl sulfate is added to a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention also provides, in another aspect, the use of sodium lauryl sulfate for improving the dissolution property of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention also provides, in another aspect, the use of sodium lauryl sulfate for improving the absorbability of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of sodium lauryl sulfate for improving the production suitability of a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention also provides, in another aspect, the use of sodium lauryl sulfate for producing a pharmaceutical composition containing compound A or a pharmaceutically acceptable salt thereof.
  • a test solution was obtained by suspending 25 mg of Compound A in the second solution (50 mL) of the JP dissolution test at pH 6.8 and heating at 37 ° C. for 60 minutes.
  • PEG6000 Microgol 6000, manufactured by Nippon Oil & Fats Co., Ltd.
  • poloxamer Litrol F68, manufactured by BASF Corporation
  • ⁇ Comparative Example 9> 0.5 g of polyoxyethylene sorbitan monolaurate (Tween 20) is dissolved in the second solution (50 mL) of a JP 6.8 dissolution test at pH 6.8, and then 25 mg of compound A is suspended and heated at 37 ° C. for 60 minutes. To obtain a test solution.
  • ⁇ Comparative example 14> 0.05 g of polyoxyethylene castor oil (Cremophor EL, manufactured by Sigma-Aldrich) was dissolved in the second solution (50 mL) of a JP 6.8 dissolution test at pH 6.8, and 25 mg of Compound A was suspended therein for 37 minutes for 60 minutes. A test solution was obtained by heating at 0 ° C.
  • Test Example 2 Absorbency Test Using the sodium lauryl sulfate and sucrose fatty acid monoester that gave a good solubility improvement effect to Compound A in Test Example 1, the absorbability test was performed as follows.
  • ⁇ Comparative Example 16> 0.8 g of Compound A was suspended in 0.5% hypromellose aqueous solution (40 mL), which is widely used in drug absorption tests, to obtain a suspension of Compound A.
  • Pretreatment Intramuscular administration of 10 ⁇ g / 0.1 mL / kg of atropine sulfate intravenous solution and 10 ⁇ g / 0.1 mL / kg of pentagastrin intramuscular solution 30 minutes before administration of the administration sample, and then pentagastrin muscle at intervals of 45 minutes
  • Injection solution 10 ⁇ g / 0.1 mL / kg was intramuscularly administered twice.
  • Blood samples were collected from each animal 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, and 8 hours after the oral administration of the formulation examples and comparative examples, and the blood concentration of Compound A was measured as (liquid AUC and Cmax values were calculated by measurement (by chromatography mass spectrometry). The results are shown in Table 3.
  • Comparative Example 17 containing Compound A together with sucrose fatty acid monoester showed the same level of absorbability as Comparative Example 16 which was a suspension of Compound A alone.
  • Formulation Example 3 containing sodium lauryl sulfate with Compound A showed significantly higher absorbability of Compound A than Comparative Example 17 containing the same amount of sucrose fatty acid monoester. It became clear that it is useful for improving the absorption of sucrose.
  • ⁇ Formulation example 4> Compound A 2 g, sodium lauryl sulfate 0.5 g, lactose 9.5 g, and corn starch 4 g were mixed in a glass bottle for 1 minute. The whole amount was passed through a sieve having an opening of 500 ⁇ m, and then mixed again in a glass bottle for 1 minute. While mixing using a pestle and mortar, add 3400 ⁇ L of 10% low-viscosity hydroxypropylcellulose (HPC-SL), sift through the whole volume with a sieve having an opening of 850 ⁇ m, and then use a moisture meter (AND, MX-50). And dried at 70 ° C. Further, the whole amount was sieved with a sieve having an opening of 1000 ⁇ m to obtain Compound A granules.
  • HPC-SL 10% low-viscosity hydroxypropylcellulose
  • HPC-SL 10% low-viscosity hydroxypropylcellulose
  • ⁇ Formulation example 6> Compound A (1.4 g), sodium lauryl sulfate (4.2 g), lactose (3.9 g), and corn starch (1.9 g) were mixed in a glass bottle for 1 minute. The whole amount was passed through a sieve having an opening of 500 ⁇ m, and then mixed again in a glass bottle for 1 minute. While mixing 6.4 g of the obtained mixed product using a pestle and mortar, 1030% low-viscosity hydroxypropylcellulose (HPC-SL) 1330 ⁇ L was added, and the whole amount was sieved with a sieve having an opening of 850 ⁇ m, and then moisture content was measured. And dried at 70 ° C. using a vessel (AND, MX-50). Further, the whole amount was sieved with a sieve having an opening of 1000 ⁇ m to obtain Compound A granules.
  • HPC-SL low-viscosity hydroxypropylcellulose
  • Pretreatment Intramuscular administration of 10 ⁇ g / 0.1 mL / kg of atropine sulfate intravenous solution and 10 ⁇ g / 0.1 mL / kg of pentagastrin intramuscular solution 30 minutes before administration of the administration sample, and then pentagastrin muscle at intervals of 45 minutes
  • Injection solution 10 ⁇ g / 0.1 mL / kg was intramuscularly administered twice.
  • blood was collected from each animal 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, and 8 hours after the oral administration of Formulation Examples and Comparative Examples. was measured (by liquid chromatography mass spectrometry) to calculate AUC and Cmax values. The results are shown in Table 4.
  • the disintegrant was screened by evaluating the tableting pressure at which the target hardness (65N) was obtained and the disintegration property of the tablets.
  • the disintegration property was evaluated by the disintegration test of the 16th revision Japanese Pharmacopoeia using water as a test solution.
  • ⁇ Formulation example 7> Compound A (120 g), sodium lauryl sulfate (120 g), lactose (516 g), and corn starch (276 g) were mixed in a plastic bag for 1 minute, passed through a sieve having a mesh size of 500 ⁇ m, and mixed again in a vinyl bag for 5 minutes. Of the obtained mixed powder, 340 g was put in a fluidized bed granulator (Freund Sangyo Co., Ltd.) and granulated while spraying 161 g of 7.5% low-viscosity hydroxypropylcellulose to obtain a granulated product.
  • a fluidized bed granulator Frund Sangyo Co., Ltd.
  • Crystalline cellulose, crospovidone and magnesium stearate were added to the resulting granulated product and mixed in a glass bottle. The whole amount was passed through a sieve having an opening of 850 ⁇ m, and then mixed again in a glass bottle to obtain a tableting powder.
  • a tablet of Compound A was produced using a universal tensile compression tester (Shimadzu Corporation) at a tableting pressure at which the target hardness (65N) was obtained.
  • a tablet of Compound A was produced using a universal tensile compression tester (Shimadzu Corporation) at a tableting pressure at which the target hardness (65N) was obtained.
  • ⁇ Formulation example 9 Crystalline cellulose, carmellose sodium and magnesium stearate were added to the granulated product obtained in the same manner as in Formulation Example 7 and mixed in a glass bottle. The whole amount was passed through a sieve having an opening of 850 ⁇ m, and then mixed again in a glass bottle to obtain a tableting powder.
  • a tablet of Compound A was produced using a universal tensile compression tester (Shimadzu Corporation) at a tableting pressure at which the target hardness (65N) was obtained.
  • ⁇ Formulation example 10 Crystalline cellulose, carmellose sodium and magnesium stearate were added to the granulated product obtained in the same manner as in Formulation Example 7 and mixed in a glass bottle. The whole amount was passed through a sieve having an opening of 850 ⁇ m, and then mixed again in a glass bottle to obtain a tableting powder.
  • a tablet of Compound A was produced using a universal tensile compression tester (Shimadzu Corporation) at a tableting pressure at which the target hardness (65N) was obtained.
  • ⁇ Formulation example 11 Crystalline cellulose, carmellose calcium and magnesium stearate were added to the granulated product obtained in the same manner as in Formulation Example 7 and mixed in a glass bottle. The whole amount was passed through a sieve having an opening of 850 ⁇ m, and then mixed again in a glass bottle to obtain a tableting powder.
  • a tablet of Compound A was produced using a universal tensile compression tester (Shimadzu Corporation) at a tableting pressure at which the target hardness (65N) was obtained.
  • ⁇ Formulation example 12 Crystalline cellulose, carmellose calcium and magnesium stearate were added to the granulated product obtained in the same manner as in Formulation Example 7 and mixed in a glass bottle. The whole amount was passed through a sieve having an opening of 850 ⁇ m, and then mixed again in a glass bottle to obtain a tableting powder.
  • a tablet of Compound A was produced using a universal tensile compression tester (Shimadzu Corporation) at a tableting pressure at which the target hardness (65N) was obtained.
  • ⁇ Formulation example 13 Crystalline cellulose, sodium carboxymethyl starch and magnesium stearate were added to the granulated product obtained in the same manner as in Formulation Example 7 and mixed in a glass bottle. The whole amount was passed through a sieve having an opening of 850 ⁇ m, and then mixed again in a glass bottle to obtain a tableting powder.
  • a tablet of Compound A was produced using a universal tensile compression tester (Shimadzu Corporation) at a tableting pressure at which the target hardness (65N) was obtained.
  • a tablet of Compound A was produced using a universal tensile compression tester (Shimadzu Corporation) at a tableting pressure at which the target hardness (65N) was obtained.
  • ⁇ Formulation example 15 Crystalline cellulose and magnesium stearate were added to the granulated product obtained in the same manner as in Formulation Example 7 and mixed in a glass bottle. The whole amount was passed through a sieve having an opening of 850 ⁇ m, and then mixed again in a glass bottle to obtain a tableting powder. A tablet of Compound A was produced using a universal tensile compression tester (Shimadzu Corporation) at a tableting pressure at which the target hardness (65N) was obtained. Table 5 shows the results of Formulation Examples 7 to 15 for the disintegration test.
  • the low-substituted hydroxypropylcellulose and sodium carboxymethyl starch did not show a shortening of the disintegration time and required a high tableting pressure, and the moldability tended to decrease. From these results, it was suggested that any disintegrant was acceptable as a tablet, but crospovidone, carmellose sodium, and carmellose calcium were particularly useful.
  • Test Example 5 Tablet Moldability and Disintegration Test
  • crospovidone and carmellose sodium which were found to have a high moldability and disintegration improving effect in a tablet containing Compound A and sodium lauryl sulfate
  • Ingredients other than these disintegrants were the same mass, and the tablets were prepared and compared as follows using a tableting pressure with which a target hardness (60 N) was obtained using a rotary tableting machine. The results are shown in Table 6.
  • ⁇ Formulation example 16> Compound A (200 g), sodium lauryl sulfate (NIKKOL SLS, manufactured by Nikko Chemicals) (200 g), lactose (860 g), and corn starch (460 g) were mixed in a plastic bag for 1 minute. And mixed for 1 minute. The obtained mixed powder was put into a fluidized bed granulator (Freund Sangyo Co., Ltd.) and granulated while spraying 800 g of 7.5% low-viscosity hydroxypropylcellulose to obtain a granulated product. The obtained granulated product was all sieved with a sieve having an opening of 850 ⁇ m.
  • NIKKOL SLS sodium lauryl sulfate
  • lactose 860 g
  • corn starch 460 g
  • ⁇ Formulation example 20> A film coating solution consisting of 6.8 g of coating agent and 81.2 g of purified water was sprayed onto 180 g of the tablet obtained in Formulation Example 19 with a coating machine (Freund Sangyo Co., Ltd.) to obtain a film-coated tablet of Formulation Example 20.
  • the coating agent used had a general composition consisting of low-viscosity hydroxypropylcellulose, polyethylene glycol, titanium oxide and a colorant.
  • ⁇ Formulation example 21> Compound A (12 g), sodium lauryl sulfate (NIKKOL SLS, manufactured by Nikko Chemicals Co., Ltd.) (12 g), lactose (354 g), and corn starch (138 g) were mixed in a plastic bag for 1 minute. And mixed for 1 minute. The obtained mixed powder was put into a fluidized bed granulator (Paurec Co., Ltd.) and granulated while spraying 239 g of 7.5% low-viscosity hydroxypropylcellulose to obtain a granulated product. The obtained granulated product was all sieved with a sieve having an opening of 850 ⁇ m.
  • the absorptivity test was implemented as follows. ⁇ Absorption experiment conditions> Animals used: Beagle dog (Kitayama Labes, 6 males) Meal conditions: 20 hours from the previous day Fasting dose: 20 mg / body Administration sample: Formulation Examples 20 and 21 Administration method: Oral administration with 50 mL of water
  • Pretreatment Intramuscular administration of 10 ⁇ g / 0.1 mL / kg of atropine sulfate intravenous solution and 10 ⁇ g / 0.1 mL / kg of pentagastrin intramuscular solution 30 minutes before administration of the administration sample, and then pentagastrin muscle at intervals of 45 minutes Injection solution 10 ⁇ g / 0.1 mL / kg was intramuscularly administered twice.
  • blood was collected from each animal 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, and 8 hours, and the blood concentration of Compound A was measured as (liquid AUC, Cmax and Tmax values were calculated by measurement (by chromatography mass spectrometry). The results are shown in Table 7.
  • ⁇ Formulation example 22> Compound A (60 g), sodium lauryl sulfate (NIKKOL SLS, manufactured by Nikko Chemicals) (60 g), lactose (258 g), and corn starch (138 g) were mixed in a plastic bag for 1 minute. And mixed for 1 minute. The obtained mixed powder was put into a fluidized bed granulator (Paurec Co., Ltd.) and granulated while spraying 241 g of 7.5% low-viscosity hydroxypropyl cellulose to obtain a granulated product. The obtained granulated product was all sieved with a sieve having an opening of 850 ⁇ m.
  • Lactose hydrate (Super Tab 11SD, DFE Pharma), crystalline cellulose (CEOLUS pH-102, Asahi Kasei Co., Ltd.), crospovidone (Kollidon CL, BASF Corporation) and magnesium stearate are added to the obtained granulated product, and the glass bottle is added.
  • a tableting powder A 500 mg tablet was produced using a universal tensile compression tester (Shimadzu Corporation).
  • ⁇ Formulation example 24 Crystalline cellulose (CEOLUS pH-102), crospovidone (Kollidon CL) and magnesium stearate were added to the granulated product obtained in the same manner as in Formulation Example 22, and mixed in a glass bottle to obtain a tableting powder.
  • a 300 mg tablet was produced using a universal tensile compression tester (Shimadzu Corporation).
  • a 500 mg tablet was produced using a universal tensile compression tester (Shimadzu Corporation).
  • ⁇ Formulation example 29> D-mannitol (Pearlitol 100SD), crystalline cellulose (CEOLUS KG-802), crospovidone (Kollidon CL-SF) and magnesium stearate are added to the granulated product obtained in the same manner as in Formulation Example 22, and mixed in a glass bottle. I got a tableting powder. 400 mg tablets were produced using a universal tensile compression tester (Shimadzu Corporation).
  • a 500 mg tablet was produced using a universal tensile compression tester (Shimadzu Corporation).
  • Test Example 8 The amount of the late additive was different, and the tablets of Formulation Examples 33 and 34 containing 20 mg of Compound A and Formulation Example 35 containing 4 mg of Compound A were prepared as follows, and in vivo absorbability was obtained in the same manner as in Test Example 2. evaluated. The results are shown in Table 9.
  • ⁇ Formulation example 33> Compound A (80 g), sodium lauryl sulfate (NIKKOL SLS, manufactured by Nikko Chemicals Co., Ltd.) (80 g), lactose (108 g), and corn starch (120 g) were mixed in a plastic bag for 1 minute, passed through a sieve with an opening of 500 ⁇ m, and then passed through a vinyl bag again. And mixed for 1 minute. The obtained mixed powder was put into a fluidized bed granulator (Paurec Co., Ltd.) and granulated while spraying 241 g of 7.5% low-viscosity hydroxypropyl cellulose to obtain a granulated product.
  • NIKKOL SLS sodium lauryl sulfate
  • lactose 108 g
  • corn starch 120 g
  • the obtained granulated product was all sieved with a sieve having an opening of 850 ⁇ m.
  • Tableting was performed with a tableting machine (Kikusui Seisakusho Co., Ltd.) to obtain tablets.
  • a film coating solution consisting of 7.7 g of coating agent and 92.3 g of purified water was sprayed on 180 g of the obtained tablets with a coating machine (Freund Sangyo Co., Ltd.) to obtain film-coated tablets of Formulation Example 33.
  • the coating agent used had a general composition consisting of low-viscosity hydroxypropylcellulose, polyethylene glycol, titanium oxide and a colorant.
  • ⁇ Formulation example 34 125 g of the granulated product obtained in the same manner as in Formulation Example 33, 72.5 g of D-mannitol (Pealitol 100SD), 25 g of crystalline cellulose (CEOLUS KG-802), 25 g of crospovidone (Kollidon CL), and magnesium stearate 2 0.5 g was added and mixed in a plastic bag, and then tableted with a tableting machine (Kikusui Seisakusho Co., Ltd.) to obtain a tablet.
  • a tableting machine Koreansui Seisakusho Co., Ltd.
  • a film coating solution consisting of 7.5 g of coating agent and 90.4 g of purified water was sprayed on 180 g of the obtained tablets with a coating machine (Freund Sangyo Co., Ltd.) to obtain a film-coated tablet of Formulation Example 35.
  • Pretreatment Intramuscular administration of 10 ⁇ g / 0.1 mL / kg of atropine sulfate intravenous solution and 10 ⁇ g / 0.1 mL / kg of pentagastrin intramuscular solution 30 minutes before administration of the administration sample, and then pentagastrin muscle at intervals of 45 minutes
  • Injection solution 10 ⁇ g / 0.1 mL / kg was intramuscularly administered twice. Blood was collected from each animal 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours after the oral administration of Formulation Examples 33, 34 and 35, and the compound A was collected in the blood. The concentration was measured (by liquid chromatography mass spectrometry) to calculate AUC, Cmax and Tmax values. The results are shown in Table 9.
  • ⁇ Formulation example 36 60 g of compound A screened with 1700 ⁇ m mesh sieve, 60 g of sodium lauryl sulfate, 81 g of lactose and 90 g of corn starch were placed in a fluidized bed granulator (Freund Sangyo Co., Ltd.) while spraying 180 g of 5% low-viscosity hydroxypropylcellulose. Granulated product was obtained.
  • ⁇ Comparative Example 18> Add 60g of Compound A, sieved with a 1700 ⁇ m screen, 141g of lactose, 90g of corn starch into a fluidized bed granulator (Freund Sangyo Co., Ltd.) and spray 5% low-viscosity hydroxypropylcellulose to carry out the granulation process. However, granulation was not possible because the powder did not flow.
  • Tablets were prepared as follows by granulating the granulated product not containing sodium alkyl sulfate, and the influence of sodium alkyl sulfate in the tablet production process was evaluated.
  • ⁇ Formulation example 37> The granulated product obtained in Formulation Example 36 was all sieved with a sieve having an opening of 600 ⁇ m. In a plastic bag, add 261.61 g of D-mannitol (Pearlitol 100SD), 48 g of crystalline cellulose (CEOLUS KG-802), 48 g of crospovidone (Kollidon CL) and 2.4 g of magnesium stearate to 120 g of the granulated product. After mixing, tableting was performed with a tableting machine (Kikusui Seisakusho Co., Ltd.) to obtain tablets.

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EP4470621A3 (en) 2025-05-07
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JPWO2019181876A1 (ja) 2020-10-08
PH12020551412A1 (en) 2021-09-01
MX2020009762A (es) 2021-01-08
BR112020018697A2 (pt) 2020-12-29
US11833151B2 (en) 2023-12-05
PL3769765T3 (pl) 2024-06-10
DK3769765T3 (da) 2024-05-13
FI3769765T3 (fi) 2024-05-15
KR102473372B1 (ko) 2022-12-05
JP2021167346A (ja) 2021-10-21
EP3769765B1 (en) 2024-04-17
EP4353222A1 (en) 2024-04-17
MA52093A (fr) 2021-01-27
PT3769765T (pt) 2024-05-13
TWI790364B (zh) 2023-01-21
EP3769765A1 (en) 2021-01-27
CN111867594A (zh) 2020-10-30
US20210030755A1 (en) 2021-02-04
SG11202008435SA (en) 2020-10-29
AU2019239404A1 (en) 2020-11-05
HUE067430T2 (hu) 2024-10-28
TW201938564A (zh) 2019-10-01
KR20200131873A (ko) 2020-11-24
EP3769765A4 (en) 2021-12-15
JP6918204B2 (ja) 2021-08-11
JP7322103B2 (ja) 2023-08-07
MY203305A (en) 2024-06-23
CA3094431A1 (en) 2019-09-26
AU2019239404B2 (en) 2021-12-23
RU2759746C1 (ru) 2021-11-17

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