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WO2019131891A1 - Particules contenant un médicament à amertume masquée et formulation contenant lesdites particules - Google Patents

Particules contenant un médicament à amertume masquée et formulation contenant lesdites particules Download PDF

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Publication number
WO2019131891A1
WO2019131891A1 PCT/JP2018/048185 JP2018048185W WO2019131891A1 WO 2019131891 A1 WO2019131891 A1 WO 2019131891A1 JP 2018048185 W JP2018048185 W JP 2018048185W WO 2019131891 A1 WO2019131891 A1 WO 2019131891A1
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Prior art keywords
drug
polymer
particle
agent
containing particles
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Ceased
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PCT/JP2018/048185
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English (en)
Japanese (ja)
Inventor
吉田　勝
光昭 木挽
拓海 淺田
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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Publication of WO2019131891A1 publication Critical patent/WO2019131891A1/fr
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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives

Definitions

  • the present invention relates to drug-containing particles for use in formulations. Specifically, the present invention relates to a drug-containing particle that suppresses unpleasant taste, and a preparation that uses the drug-containing particle to suppress unpleasant taste and achieve bioabsorbability.
  • An orally disintegrating tablet is a tablet that can be taken without water while leaving the tablet easy to handle.
  • OD tablets are rapidly disintegrated by saliva and a small amount of water, so they are easy to use even in children, elderly people, and patients with reduced swallowing ability (food and medicine swallowing ability).
  • the importance of society is increasing as the society progresses.
  • the drug dissolves in the oral cavity, and a living organ called a taste chamber present in the tongue reacts to the dissolved drug, and the taste of the drug is felt.
  • the drug has an unpleasant taste such as bitter taste or astringent taste, there is a problem in drug treatment that the user can not tolerate the bitter taste and vomits or compliance is lowered.
  • a physical masking method that uses a sweetening component or physical masking that reduces the dissolution rate of the drug in the oral cavity by coating and reduces the amount dissolved in the oral cavity
  • Bitter masking techniques such as methods are required.
  • the drug does not dissolve in the oral cavity while it is not dissolved or absorbed in the digestive tract such as the stomach or intestine, and a therapeutic effect is obtained. The problem of not being often arises. If the degree of coating is reduced again and the dissolution rate is improved to obtain a therapeutic effect, the drug dissolves in the oral cavity to give a bitter taste.
  • a bitter taste masking technology that achieves both suppression of unpleasant taste and bioabsorbability is very difficult.
  • Patent Document 1 describes a particle coated with a lubricant and a drug by spraying a core particle with a coating solution prepared by dissolving a drug having strong cohesiveness, a lubricant and a polymer in granules.
  • Patent Document 1 discloses that a lubricant is used to enhance dispersibility, and it is not disclosed that bitterness can be masked by the lubricant.
  • Patent Document 2 describes particles coated with drug-containing granules by spraying a liquid containing a polymer, a disintegrant and a lubricant.
  • the lubricant is merely used as a dispersing agent for improving the manufacturability, and it is not disclosed that the bitter taste can be masked by the lubricant.
  • bitter taste masking bitter taste mask
  • a lubricant in the coating film of the drug-containing particles, and tablets using the particles exhibit an unpleasant taste. It was not known that the bitter taste of drugs could be masked.
  • the present inventors have been able to mask the bitter taste of the drug of the present invention exhibiting extremely strong unpleasant taste by using sodium stearyl fumarate as a coating agent, which is usually used as a lubricant. I found it. Furthermore, it has been found that tablets using the present drug-containing particles using sodium stearyl fumarate surprisingly show dissolution and drug absorption comparable to tablets without coating. The present inventors have found an OD tablet subjected to bitter taste masking while maintaining drug absorbability, and have completed the present invention.
  • [Item 1] A composition for masking the bitter taste of a component having bitterness, which comprises sodium stearyl fumarate as a coating.
  • the component is (S) -4-amino-5-chloro-N-[ ⁇ 4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl ⁇ methyl] -2-methoxy
  • the composition according to Item 1 which is benzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • the composition according to item 1 or 2 wherein the component is contained in drug-containing particles.
  • the drug according to item 8 wherein the polymer is one or more selected from the group consisting of a water-insoluble polymer, an enteric polymer, a gastric polymer and a biodegradable polymer. Containing particles.
  • the water-insoluble polymer according to Item 9 selected from the group consisting of ethyl cellulose, cellulose acetate, ammonio alkyl methacrylate copolymer RS, vinyl acetate resin, and a mixture of one or more thereof. Composition.
  • the enteric polymer is selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, and a mixture of one or more thereof Item 11.
  • the drug-containing particle according to item 9 or 10 selected from the group consisting of [Item 12] The composition according to any one of Items 3 to 6, wherein the drug-containing particles further contain an additive for drug-containing particles.
  • the drug-containing particle additive is an excipient, a binder, a sweetening agent, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent, a disintegrant, a lubricant, and a plastic Item 13.
  • the additive for drug-containing particles is selected from the group consisting of an excipient, a binder, a sweetening agent, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent and a coating agent.
  • Item 13 The composition according to item 13.
  • the sweetening agent and the flavoring agent are at least one selected from the group consisting of aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, and acesulfame K, respectively.
  • the excipient is lactose, sucrose, sucrose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, reduced lactose, erythritol, sorbitol, maltitol, mannitol, xylitol, kaolin
  • [Item 17] The composition according to any one of Items 3 or 6 to 16, wherein the content of the sodium stearyl fumarate is 1 to 70% by weight per 100% by weight of the drug-containing particles.
  • [Item 18] The composition according to any one of Items 17, wherein the content of the sodium stearyl fumarate is 10 to 50% by weight per 100% by weight of the drug-containing particles.
  • [Item 19] The composition according to any one of items 18, wherein the content of the sodium stearyl fumarate is 20 to 40 wt% per 100 wt% of the drug-containing particles.
  • [Item 20] The composition according to any one of items 3 or 6 to 19, wherein the content of the drug is 0.1 to 96% by weight per 100% by weight of the drug-containing particles.
  • [Item 21] The composition according to item 20, wherein the content of the drug is 5 to 50% by weight per 100% by weight of the drug-containing particles.
  • [Item 22] The composition according to item 21, wherein the content of the drug is 15 to 30% by weight per 100% by weight of the drug-containing particles.
  • [Item 23] The composition according to items 8 to 22, wherein the content of the polymer is 1 to 70% by weight per 100% by weight of the drug-containing particles.
  • [Item 24] The composition according to item 23, wherein the content of the polymer is 10 to 30% by weight per 100% by weight of the drug-containing particles.
  • [Item 25] The composition according to any one of Items 3 to 6, wherein the drug-containing particles are particles consisting of a shell and a hollow portion.
  • [Item 26] The composition according to item 25, wherein the shell comprises the drug and the polymer.
  • [Item 27] The composition according to item 26, wherein the shell further comprises the drug-containing particle additive.
  • [Item 28] The composition according to any one of Items 25 to 27, wherein the hollow volume ratio to the whole particle is 1% to 50%.
  • [Item 29] The composition according to item 28, wherein the hollow volume ratio to the whole particle is 5% to 30%.
  • [Item 30] The composition according to any one of items 25 to 29, wherein the thickness of the shell is 15 ⁇ m or more.
  • [Item 31] The composition according to items 8 to 30, wherein the average particle size of the polymer used as a raw material is five or more times the average particle size of the drug used as a raw material.
  • [Item 32] The composition according to item 31, wherein the average particle size of the polymer used as a raw material is at least 10 times the average particle size of the drug used as a raw material.
  • [Item 33] The composition according to item 32, wherein the average particle size of the polymer used as a raw material is at least 15 times the average particle size of the drug used as a raw material.
  • the average particle size of the polymer used as a raw material is at least 5 times the average particle size of the mixed powder of the drug and the additive for drug-containing particles used as a raw material.
  • Composition as described.
  • [Item 35] The composition according to any one of Items 25 to 34, wherein the diameter of the hollow portion is 10 ⁇ m or more.
  • [Item 36] The composition according to any one of items 3 or 6 to 35, wherein the aspect ratio of the drug-containing particle is 1.0 to 1.5.
  • [Item 37] The composition according to any one of Items 3 to 6, wherein the particle shell strength of the drug-containing particles is 2.0 MP or more.
  • [Item 38] The composition according to any one of items 3 or 6 to 37, wherein the particle size distribution width (D90 / D10) of the drug-containing particles is 6 or less.
  • the average particle size of the drug-containing particles is 50 to 1000 ⁇ m.
  • [Item 40] The composition according to any one of items 3 or 6 to 39, wherein the composition comprises the drug-containing particles.
  • Drug-containing particles comprising: methyl] -2-methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • the drug-containing particle according to Item 41 further comprising a polymer.
  • the polymer is one or more selected from the group consisting of water insoluble polymers, enteric polymers, gastric polymers and biodegradable polymers. Containing particles.
  • the enteric polymer comprises hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, and mixtures of one or more thereof
  • the drug-containing particle according to item 43 or 44 selected from the group consisting of [Item 46]
  • the drug-containing particle additive is an excipient, a binder, a sweetening agent, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent, a disintegrant, a lubricant, and a plastic
  • the drug-containing particle according to item 46 selected from the group consisting of an agent, an anticoagulant agent and a coating agent.
  • the drug-containing particle additive is selected from the group consisting of an excipient, a binder, a sweetener, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent and a coating agent
  • the sweetening agent and the flavoring agent are at least one selected from the group consisting of aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, and acesulfame K, respectively.
  • Drug-containing particles as described in.
  • the excipient is lactose, sucrose, sucrose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, reduced lactose, erythritol, erythritol, sorbitol, maltitol, mannitol, xylitol, kaolin
  • the drug-containing particle according to any one of paragraphs 47 to 49 which is at least one selected from the group consisting of calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and crystalline cellulose.
  • [Item 54] The drug-containing particle according to any one of items 41 to 53, wherein the content of the drug is 0.1 to 96% by weight per 100% by weight of the drug-containing particle.
  • [Item 55] The drug-containing particle according to item 54, wherein the content of the drug is 5 to 50% by weight per 100% by weight of the drug-containing particle.
  • [Item 56] The drug-containing particle according to item 55, wherein the content of the drug is 15 to 30% by weight per 100% by weight of the drug-containing particle.
  • [Item 57] The drug-containing particles according to items 42 to 56, wherein the content of the polymer is 1 to 70% by weight per 100% by weight of the drug-containing particles.
  • [Item 63] The drug-containing particle according to Item 62, wherein the hollow volume ratio to the whole particle is 5% to 30%.
  • [Item 64] The drug-containing particle according to any one of Items 59 to 63, wherein the thickness of the shell is 15 ⁇ m or more.
  • [Item 65] The drug-containing particles according to items 42 to 64, wherein the average particle size of the polymer used as a raw material is five or more times the average particle size of the drug used as a raw material.
  • [Item 66] The drug-containing particles according to Item 65, wherein the average particle size of the polymer used as a raw material is at least 10 times the average particle size of the drug used as a raw material.
  • [Item 70] The drug-containing particle according to any one of items 41 to 69, wherein the aspect ratio of the drug-containing particle is 1.0 to 1.5.
  • [Item 71] The drug-containing particle according to any one of Items 41 to 70, wherein the particle shell strength of the drug-containing particle is 2.0 MPa or more.
  • [Item 72] The drug-containing particle according to any one of Items 41 to 71, wherein the particle size distribution width (D90 / D10) is 6 or less.
  • [Item 73] The drug-containing particle according to any one of Items 41 to 72, wherein the average particle size is 50 to 1000 ⁇ m.
  • a pharmaceutical composition comprising the drug-containing particle according to any one of items 41 to 73.
  • the formulation additive is an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent, a disintegrant, a lubricant, a plasticizer 79.
  • the formulation additive is selected from the group consisting of an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent and a coating agent 80.
  • the item 79 is at least one selected from the group consisting of high-intensity sweeteners such as aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, and acesulfame K, etc. [Item 81] Or the pharmaceutical composition according to 80.
  • high-intensity sweeteners such as aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, and acesulfame K, etc.
  • the excipient is lactose, sucrose, fructose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, powdered sugar, saccharides such as reduced lactose, erythritol, sorbitol, maltitol, mannitol,
  • the pharmaceutical composition according to item 79 or 80 which is at least one selected from the group consisting of sugar alcohols such as xylitol, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and crystalline cellulose.
  • IBS constipation-type irritable bowel syndrome
  • a therapeutic agent and / or a preventive agent for digestive system diseases or digestive system conditions comprising the drug-containing particle according to any one of items 41 to 73.
  • [Item 90] Use of the drug-containing particle according to any one of Items 41 to 73 for producing a therapeutic agent and / or a preventive agent for digestive system disease or digestive system condition.
  • the drug-containing particle according to item 92, wherein the digestive system disease is constipation-type irritable bowel syndrome (IBS), or chronic constipation.
  • FIG. 1 is a view showing the results of dissolution tests of Example 1-2 and Comparative Example 1-2.
  • FIG. 2 is a diagram showing the results of sensory evaluation tests of Example 1-2 and Comparative Example 1-2.
  • FIG. 3 is a view showing the results of the dissolution tests of Comparative Example 1-2 and Comparative Examples 1-9 to 1-14.
  • FIG. 4 is a view showing the results of sensory evaluation tests of Comparative Example 1-2 and Comparative Examples 1-9 to 1-14.
  • the "average particle size” means the 50% cumulative particle size D50 in the volume-based measurement of powder particles.
  • the average particle size is measured on a volume basis with a laser diffraction type particle size distribution measuring apparatus (for example, Particle Viewer manufactured by Powrex Corp. or SALD-3000 J manufactured by Shimadzu Corp. or HELOS & RODOS manufactured by Sympatec).
  • a laser diffraction type particle size distribution measuring apparatus for example, Particle Viewer manufactured by Powrex Corp. or SALD-3000 J manufactured by Shimadzu Corp. or HELOS & RODOS manufactured by Sympatec.
  • Drug-containing particles comprise (i) a drug and (ii) a sodium stearyl fumarate coating, optionally for (iii) a polymer, and / or (iv) for drug-containing particles It may contain an additive.
  • Preferred examples of the drug-containing particles of the present invention include (v) drug-containing hollow particles described later.
  • the particles mean both a single particle and an assembly of a plurality of particles.
  • drug-containing particles mean particles coated with sodium stearyl fumarate.
  • the "per 100% by weight of the drug-containing particles” means a weight percentage when the "weight of the drug-containing particles” is 100%.
  • the weight of the drug-containing particles means the weight of the entire drug-containing particles to which the amount of sodium stearyl fumarate is added.
  • the “drug” means (S) -4-amino-5-chloro-N-[ ⁇ 4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl ⁇ methyl ] 2-methoxybenzamide (the present compound) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • the drug may be present in the form of a hydrate or a solvate.
  • the salt, or a hydrate or solvate thereof is a serotonin 4 receptor agonist and is a therapeutic agent and / or prevention of digestive system diseases, digestive system conditions, neuropsychiatric diseases, or urological diseases It is effective as an agent.
  • the pharmaceutically acceptable salt is preferably a hydrochloride or bromate, and more preferably a bromate.
  • the content of the drug of the present invention is usually 0.1 to 96% by weight, preferably 1 to 70% by weight, more preferably 5 to 50% by weight, based on 100% by weight of the drug-containing particles. More preferably, it is 10 to 40% by weight, and most preferably 15 to 30% by weight.
  • the average particle size of the drug is usually 20 ⁇ m or less, preferably 15 ⁇ m or less, more preferably 10 ⁇ m or less.
  • the average particle size of the drug is usually 0.1 ⁇ m or more.
  • the average particle size of the drug may be within the above range as the raw material, and may be changed in the production process of the drug-containing particles and the like.
  • Sodium Stearyl Fumarate Sodium stearyl fumarate (PRUV) is generally used as a lubricant for pharmaceutical tablets, but has a feature of being used as a coating for particles in the present invention.
  • the content of sodium stearyl fumarate is usually 1 to 70% by weight, preferably 5 to 60% by weight, and more preferably 10 to 50% by weight, based on 100% by weight of the drug-containing particles. Preferably, it is 15 to 45% by weight, most preferably 20 to 40% by weight.
  • the average particle size of sodium stearyl fumarate is usually 30 ⁇ m or less, preferably 20 ⁇ m or less, more preferably 15 ⁇ m or less.
  • the average particle size of sodium stearyl fumarate is usually 0.1 ⁇ m or more.
  • the average particle diameter of sodium stearyl fumarate may be within the above range as a raw material, and may be changed in the production process of the drug-containing particles.
  • Polymer refers to a molecule having a large relative molecular mass and having a structure formed by many repetitions of a molecule having a small relative molecular mass, and particularly refers to a functional polymer.
  • the above-mentioned "molecule having a large relative molecular mass” usually refers to one having an average molecular weight (weight average molecular weight) of 1,000 or more, preferably 5,000 or more, and more preferably 10,000 or more.
  • the upper limit of the molecular weight is not particularly limited, but preferably 10,000,000 or less, more preferably 5000000 or less, more preferably 2000000 or less, and most preferably 1000000 or less.
  • the polymers may be used alone or in combination of two or more.
  • the polymer examples include water-soluble polymers, water-insoluble polymers, enteric polymers, gastric polymers, or biodegradable polymers.
  • the polymer is preferably a water-insoluble polymer, an enteric polymer, a gastric polymer, or a biodegradable polymer.
  • the polymer is more preferably a water-insoluble polymer, an enteric polymer, or a gastric polymer.
  • a water-insoluble polymer or an enteric polymer is mentioned.
  • the polymer is most preferably a water-insoluble polymer.
  • methylcellulose eg, trade name: SM-4, SM-15, SM-25, SM-100, SM-400, SM-1500, SM-4000, 60SH-50, 60SH- 4000, 60SH-10000, 65SH-50, 65SH-400, 65SH-4000, 90SH-100SR, 90SH-4000SR, 90SH-15000SR, 90SH-100000SR
  • hydroxypropyl cellulose eg, trade names: HPC-SSL, HPC- SL, HPC-L, HPC-M, HPC-H
  • hydroxypropyl methylcellulose eg, trade name: TC5-E, TC5-M, TC5-R, TC5-S, SB-4
  • hydroxyethylcellulose eg, Product Name: SP200, SP400, SP500, SP Cellulose derivatives such as 00, SP 850, SP 900, EP 850, SE 850, SE 400, SE 500, SE 600, SE 600, SE 850,
  • water-soluble polymer examples include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol and pregelatinized starch. More preferably, hydroxypropyl cellulose is mentioned as a water-soluble polymer.
  • water-insoluble polymer examples include water-insoluble cellulose ethers such as ethyl cellulose (eg, trade name: ETCELL (ETCEL 10P)), cellulose acetate, etc.
  • Ammonio alkyl methacrylate copolymer RS eg, trade name: Eudragit RL100, Eudragit RLPO, Water-insoluble acrylic acid copolymers such as Eudragit RL 30 D, Eudragit RS 100, Eudragit RSPO, Eudragit RS 30 D), ethyl acrylate / methyl methacrylate copolymer dispersion (eg, trade name: Eudragit NE 30 D), or vinyl acetate resin
  • One or two or more may be mixed and used.
  • a water-insoluble polymer as the polymer, it is possible to impart the function of a bitter taste mask of a drug having sustained release or bitter taste.
  • Preferred examples of the water-insoluble polymer include ethyl cellulose, cellulose acetate, ammonio alkyl methacrylate copolymer RS, vinyl acetate resin, and a mixture of one or more of them. More preferable examples of the water-insoluble polymer include ethyl cellulose, ammonio alkyl methacrylate copolymer RS, vinyl acetate resin, and a mixture of one or more thereof.
  • water-insoluble polymer examples include ethyl cellulose, ammonio alkyl methacrylate copolymer RS, and a mixture of one or more thereof.
  • the water insoluble polymer is most preferably an ammonio alkyl methacrylate copolymer RS.
  • enteric polymers examples include hydroxypropyl methylcellulose acetate succinate (eg, trade names: AQOAT LF, AQOAT MF, AQOAT HF, AQOAT LG, AQOAT MG, AQOAT HG), hydroxypropyl methylcellulose phthalate (eg, trade name: HPMCP50, HPMCP55, HPMCP55S), methacrylic acid copolymer L (eg, trade name: Eudragit L100), methacrylic acid copolymer LD (eg, trade name: Eudragit L30D-55), dry methacrylic acid copolymer LD (eg, trade name: Eudragit L100) -55), methacrylic acid copolymer S (eg, trade name: Eudragit S 100), or methacrylic acid copolymer such as methacrylic acid-n-butyl acrylate copolymer, etc.
  • hydroxypropyl methylcellulose acetate succinate eg
  • enteric polymers include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, or a mixture of one or more thereof. More preferably, the enteric polymer is hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, or a mixture of one or more thereof.
  • the enteric polymer is further preferably a methacrylic acid copolymer L, a dry methacrylic acid copolymer LD, a methacrylic acid copolymer S, or a mixture of one or more thereof.
  • the enteric polymer is most preferably a dry methacrylic acid copolymer LD.
  • gastric soluble polymer examples include gastric soluble polyvinyl derivatives such as polyvinyl acetal diethylamino acetate, and gastric soluble acrylic acid copolymers such as aminoalkyl methacrylate copolymer E (eg, trade name: Eudragit E 100, Eudragit EPO). And one or more kinds may be mixed and used.
  • gastric soluble polymer examples include aminoalkyl methacrylate copolymer E.
  • a biodegradable polymer is a polymer that can be degraded in vivo.
  • polylactic acid, polyglycolic acid, polycaprolactone and copolymers thereof, collagen, chitin, or chitosan (eg, trade name: Flonac C-100M), etc. may be mentioned, and one or more of them may be mixed You may use.
  • Preferred biodegradable polymers include gelatin and chitosan.
  • the polymer can be selected according to the purpose. For example, in order to achieve rapid elution of drug from drug-containing particles in the digestive tract, it is preferable to use a water-soluble polymer as the polymer, and to achieve sustained release of the drug, as the polymer. It is preferable to use a water-insoluble polymer, and in order to achieve a bitter taste mask, it is preferable to use a water-insoluble polymer, an enteric polymer, a stomach-soluble polymer, etc. It is preferable to use an enteric polymer to accelerate elution in the small intestine, and it is preferable to use chitosan or the like to achieve colonic targeting. Moreover, you may mix and use 2 or more types of polymers which have a different function like a water-soluble polymer, a water-insoluble polymer etc. according to the objective.
  • a polymer in a powder state, and one having an appropriate average particle size and particle size distribution can be selected according to the average particle size and particle size distribution of the desired drug-containing particles.
  • those in the state of dispersion are also included, but they can be used in the present invention, for example, by using them as powder after being powdered by spray drying or the like.
  • a polymer powder with a narrow particle size distribution it is preferable to use a polymer powder with a narrow particle size distribution.
  • a polymer powder having a large average particle size in order to obtain drug-containing particles having a large average particle size, it is preferable to use a polymer powder having a large average particle size, and in order to obtain drug-containing particles having a small average particle size, a polymer having a small average particle size It is preferred to use a powder. This means that by adjusting the size and particle size distribution of the polymer powder, drug-containing particles having a particle size distribution according to the purpose can be produced.
  • the content of the polymer varies depending on the amount of drug, additive for drug-containing particles, particle diameter, strength of bonding force of polymer, etc., but usually 1 to 70% by weight per 100% by weight of drug-containing particles It is preferably 1 to 60% by weight, more preferably 1 to 40% by weight, still more preferably 10 to 40% by weight, and most preferably 10 to 30% by weight.
  • Another preferable embodiment of the content of the polymer is 5 to 50% by weight, more preferably 5 to 40% by weight, still more preferably 5 to 30% by weight, and most preferably 5 to 25% by weight. % Is listed.
  • the drug-containing particles of the present invention preferably include those containing 1 to 70% by weight of the drug and 1 to 30% by weight of the polymer per 100% by weight of the drug-containing particle. More preferably, the drug-containing particles contain 5 to 50% by weight of the drug and 1 to 40% by weight of the polymer per 100% by weight of the drug-containing particle. More preferably, the drug-containing particles contain 10 to 40% by weight of the drug and 10 to 40% by weight of the polymer per 100% by weight of the drug-containing particle.
  • the drug-containing particles are most preferably those containing 115 to 30% by weight of the drug and 10 to 30% by weight of the polymer per 100% by weight of the drug-containing particle.
  • the preferable average particle diameter of the polymer used as the raw material in the present invention is 0.5 ⁇ m or more, preferably 5 ⁇ m or more, and as a preferable embodiment, 20 ⁇ m or more, 25 ⁇ m or more, 40 ⁇ m or more, 50 ⁇ m or more 5 times or more, preferably 10 times or more, more preferably 15 times or more, more preferably 20 times or more, particularly preferably 25 times the average particle diameter of the drug and / or the additive for drug-containing particles described below The above are preferred.
  • the average particle size of the polymer used as the raw material is with respect to the average particle size of the drug used as the raw material and / or the drug-containing particle additive described below It is indicated by the particle size distribution ratio (D50 / D50) of the average particle size of the polymer used as the raw material, the drug used as the raw material and / or the additive for drug-containing particles described below.
  • D50 / D50 particle size distribution ratio
  • the D50 of the polymer (ammonio alkyl methacrylate copolymer RS (100-200 mesh)) used as the raw material is 107.78
  • the D50 of the drug used as the raw material (the present compound) is 4.66.
  • a particle size fraction can be selectively used by sieving.
  • a sieve having a sieve number described in USP US Pharmacopoeia
  • EP European Pharmacopoeia
  • JP Japanese Pharmacopoeia
  • the average particle size of the polymer may be within the above range as a raw material, and may be changed in the production process of the drug-containing particles.
  • the polymer is not used as a solution or suspension in the form of a granulation liquid, but is mixed with the drug in the form of a powder and then granulated while adding a solvent, eg, spraying It is preferable to do.
  • a solvent eg, spraying It is preferable to do.
  • a part of the polymer or the drug may be dissolved or suspended in a solvent and used.
  • the additive for drug-containing particles is not particularly limited as long as it is a commonly used additive, for example, an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a flavor, a fluidizing agent, Antistatic agents, coloring agents, disintegrants, lubricants, plasticizers, anticoagulants, coating agents and the like can be mentioned.
  • the additive for drug-containing particles preferably includes an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent, a disintegrant, or a coating agent.
  • the additive for drug-containing particles includes an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a fragrance, a fluidizing agent, an antistatic agent, a coloring agent and a coating agent. Further preferably, the additive for drug-containing particles includes an excipient, a binder, a sweetener, a flavoring agent, a fluidizer, an antistatic agent, a colorant and a coating agent. Most preferably, the additive for drug-containing particles includes an excipient, a binder, and a sweetener.
  • excipient for example, saccharides, sugar alcohols, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, or crystalline cellulose can be mentioned.
  • excipient used for drug-containing particles lactose, sucrose, sucrose, fructose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, reduced lactose, erythritol, sorbitol, maltitol, mannitol are preferably used.
  • the excipient used for the drug-containing particles includes lactose, sucrose, mannitol, xylitol, erythritol, calcium hydrogen phosphate, calcium carbonate and crystalline cellulose. More preferably, excipients used for drug-containing particles include lactose, mannitol, erythritol, and crystalline cellulose. Most preferably, the excipient used for the drug-containing particles includes mannitol.
  • sugars examples include lactose, sucrose, sucrose, fructose, fructooligosaccharides, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, or reduced lactose.
  • Sugar alcohols include, for example, erythritol, sorbitol, maltitol, xylitol, or mannitol.
  • the sugar alcohols used for the drug-containing particles include mannitol.
  • cellulose derivatives such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose and salts thereof, polyvinyl pyrrolidone, polyvinyl alcohol, copolyvidone, vinyl acetate / vinyl pyrrolidone copolymer, polyvinyl Water-soluble vinyl derivatives such as alcohol, polyethylene glycol and graft copolymer, pregelatinized starch, dextrin, dextran, pullulan, alginic acid, gelatin, pectin, ethyl cellulose, water-insoluble cellulose ether such as cellulose, acetate Ammonio alkyl methacrylate copolymer RS, acrylic acid Water, such as ethyl methyl methacrylate copolymer dispersion Soluble acrylic copolymer, vinyl acetate resin, hydroxypropyl methylcellulose a binder, for example, cellulose
  • hydroxypropyl cellulose, ethyl cellulose, ammonio alkyl methacrylate copolymer RS, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer E, chitosan And may be used alone or in combination of two or more.
  • hydroxypropyl cellulose, ammonio alkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer E may be mentioned, and one or more kinds may be mixed and used.
  • sweetening agent for example, saccharides, sugar alcohols, licorice extract which is a natural sweetener, stevia extract, lacanca extract, thaumatin, or a synthetic sweetener, aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, Sucralose or acesulfame K is mentioned.
  • sweetening agent used for drug-containing particles preferably erythritol, sorbitol, maltitol, mannitol, xylitol, aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia extract, thaumatin, sucralose, or acesulfame K. More preferably, as a sweetener used for the drug-containing particles, aspartame, thaumatin, sucralose, lactose, stevia extract, thaumatin, acesulfame K can be mentioned. More preferably, as a sweetening agent used for drug-containing particles, aspartame, thaumatin and sucralose can be mentioned. Most preferably, the sweetening agent used for the drug-containing particles includes aspartame.
  • Flavoring agents and flavoring agents include sweetening components such as sucrose, saccharin and various fruit syrups, organic acids such as fumaric acid, citric acid and tartaric acid, and fruit essences.
  • Examples of the flavor include croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, crospovidone, corn starch, or low-substituted hydroxypropyl cellulose.
  • grains corn starch and low substituted hydroxypropyl cellulose are mentioned preferably. More preferably, corn starch is mentioned as a fragrance used for drug-containing particles.
  • talc light anhydrous silicic acid, magnesium aluminometasilicate, hydrous silicic acid silicic acid
  • the fluidizing agent used for the drug-containing particles includes talc.
  • antistatic agent examples include magnesium aluminometasilicate.
  • colorants include tar dyes, lake dyes, yellow ferric oxide, ferric oxide, and titanium oxide.
  • the coloring agent used for drug-containing particles includes yellow ferric oxide.
  • croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, crospovidone, corn starch, low-substituted hydroxypropyl cellulose and carboxymethyl starch sodium can be mentioned, and one or more of them can be mixed You may use it.
  • stearic acid for example, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, carnauba wax or sucrose fatty acid ester may be mentioned, and one or more kinds may be mixed and used.
  • plasticizer for example, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin, glycerin fatty acid ester can be mentioned.
  • anticoagulant for example, silicon dioxide, light anhydrous silicic acid, talc, magnesium stearate, sodium stearyl fumarate may be mentioned.
  • the coating agent for example, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, carnauba wax or sucrose fatty acid ester may be mentioned, and one or more kinds may be mixed and used.
  • Preferred examples of the coating agent used for the drug-containing particles include sodium stearyl fumarate, talc, and magnesium stearate, and one or more kinds of them may be mixed and used. More preferably, the coating agent used for the drug-containing particles includes sodium stearyl fumarate and talc. More preferably, sodium stearyl fumarate is mentioned as a coating agent used for drug-containing particles.
  • the content of the additive for drug-containing particles can be optionally set, but generally 95.9 wt% or less, preferably 90 wt% or less, more preferably 80 wt% or less, per 100 wt% of drug-containing particles, more preferably Is 70 wt% or less, most preferably 60 wt% or less. Specifically, 0.1 to 95.9% by weight, preferably 1 to 90% by weight, more preferably 5 to 80% by weight, still more preferably 10 to 70% by weight, per 100% by weight of the drug-containing particles, most preferably Is 20 to 60% by weight.
  • the drug-containing particle additive is preferably a powder.
  • the average particle size of the additive of the powder used as the raw material is 20 ⁇ m or less, preferably 15 ⁇ m or less, more preferably 10 ⁇ m or less, and may be similar to the average particle size of the drug powder used as the raw material Less than that is preferable.
  • the average particle size of the other additives is usually 0.005 ⁇ m or more.
  • the average particle diameter of the drug-containing particle additive may be within the above range as a raw material, and may be changed in the production process of the drug-containing particles.
  • Drug-containing hollow particles are "particles comprising a shell (or a wall) and a hollow portion and containing a drug and a polymer in the shell" or “containing a drug and a polymer” It means “particles having a structure in which a hollow portion is surrounded by a wall made of a composition.
  • the feature of the drug-containing hollow particle is that the inside of the particle has a hollow structure. This "hollow” is surrounded by the wall (shell (shell)) of the drug-containing composition and completely independent, unlike the state in which there are a large number of voids whose positions do not exist as in the case of ordinary tablets.
  • the hollow volume ratio to the total volume of the drug-containing hollow particles is preferably 1% to 50%, more preferably 1% to 30%, still more preferably 1.5% to 30%, most preferably 2% to There is about 30%.
  • Another preferred embodiment of the hollow volume ratio is about 4% to 50%, more preferably 4% to 40%, still more preferably 10% to 40%, and most preferably about 10 to 30%.
  • the hollow volume ratio is determined by dividing the hollow volume by the volume of the particles. Since the particles of the present invention generally have high sphericity, the volume is determined assuming that both hollow and particles are spherical.
  • the hollow and particle volumes are determined by X-ray CT (computed tomography apparatus) to determine the major and minor diameters of the hollow and particles at the center of the particle, assuming that the average is the hollow diameter and particle diameter, respectively.
  • X-ray CT computed tomography apparatus
  • Hollow volume ratio [%] (4/3 ⁇ ⁇ ⁇ (diameter of hollow portion / 2) 3 ) / (4/3 ⁇ ⁇ ⁇ (particle diameter of drug-containing particles / 2) 3 ) ⁇ 100
  • the particle diameter of the drug-containing particles and the diameter of the hollow portion are nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.
  • the drug-containing hollow particles have a wall (shell) outside the hollow.
  • the shell thickness can be set arbitrarily, but if the shell thickness is small, the strength of the particles is weakened.
  • the shell thickness of the present invention is preferably 10 ⁇ m or more, more preferably 15 ⁇ m or more, still more preferably 20 ⁇ m or more, and most preferably 30 ⁇ m or more.
  • the shell thickness can be measured, for example, by X-ray CT (computed tomography apparatus).
  • the shell thickness ratio of the present invention is arbitrary, and can be obtained by the following equation.
  • the shell thickness ratio is preferably 20 to 80%, more preferably 30 to 70%.
  • Shell thickness ratio [%] (shell thickness / (particle diameter of drug-containing particles / 2)) ⁇ 100
  • the characteristics of the drug-containing hollow particles are that the size of the particles can be freely adjusted. Therefore, the average particle diameter is about 1 to about 7000 ⁇ m, preferably about 5 to about 1000 ⁇ m, more preferably about 10 to about 500 ⁇ m, still more preferably about 10 to about 400 ⁇ m, still more preferably about 20 to about 300 ⁇ m, and most preferably about 50 to about 300 ⁇ m
  • the particles of the can be adjusted. From the viewpoint of the strength of the particles, the size of the particles is preferably about 50 to about 7000 ⁇ m, more preferably about 50 to about 1000 ⁇ m, and still more preferably about 50 to about 500 ⁇ m.
  • the particle size is preferably about 70 to about 7000 ⁇ m, more preferably about 70 to about 1000 ⁇ m, still more preferably about 70 to about 500 ⁇ m, particularly preferably about 70 to about 300 ⁇ m, and most preferably about 100 to about 300 ⁇ m Can be adjusted.
  • the size of the drug-containing particles can be adjusted by adjusting the average particle size of the polymer.
  • the diameter of the hollow portion is usually 10 ⁇ m or more.
  • the diameter of the hollow portion can be freely adjusted, and usually adjusted to about 10 to 5000 ⁇ m, preferably about 20 to 700 ⁇ m, more preferably about 30 to 300 ⁇ m, and still more preferably about 50 to 200 ⁇ m. it can. It is possible to freely change the proportion of hollow in combination with the size of the particles described above.
  • the drug-containing particles of the present invention also have an aspect that the "surface is smooth" as one aspect.
  • the surface being smooth means that there are no corners and the surface is not uneven. Since the flowability of the particles to be filled is required at the time of tablet-containing, drug-containing particle filling at the time of capsule preparation, etc., it is preferable that the drug-containing particles have a smooth surface. It is preferable that the drug-containing particles have a smooth surface, because the efficiency is improved also in coating for further imparting functionality to the drug-containing particles. Such surface smoothness can be observed visually, for example. When observing visually, you may expand and observe with a microscope etc.
  • the drug-containing particles of the present invention may be “not smooth” but are preferably “very smooth”, “smooth” or “smoothly”, more preferably “very smooth” or “smooth”, “Very smooth” is more preferred. Also, it can be measured using a shape measuring laser microscope VK-X200 (KEYENCE). Specifically, “surface is smooth” means that the surface roughness (Ra value) measured by the above-mentioned instrument is 3.5 or less, preferably 2.5 or less, more preferably 1.5 or less. means. The smoothness of the surface is influenced by the ratio of the average particle size of the polymer to the drug and / or other additives.
  • the drug-containing particles of the present invention have a spherical shape as one aspect.
  • “spherical” means that the aspect ratio is 1.0 to 1.5. Preferably, it is 1.0 to 1.4, more preferably 1.0 to 1.3.
  • the flowability at the time of tablet-containing, drug-containing particle filling at the time of capsule preparation, etc. is good at the time of tableting, and also the efficiency improves when processing such as coating.
  • the drug-containing particles of the present invention preferably contain 1 to 70% by weight of the drug, 1 to 30% by weight of the polymer, and 1 to 90% by weight of the additive for the drug-containing particle per 100% by weight of the drug-containing particle.
  • the drug-containing particles of the present invention contain 5 to 50% by weight of the drug, 1 to 40% by weight of the polymer, and 5 to 80% by weight of the additive for the drug-containing particle per 100% by weight of the drug-containing particle.
  • the drug-containing particles of the present invention contain 10 to 40% by weight of the drug, 10 to 40% by weight of the polymer, and 10 to 70% by weight of the additive for the drug-containing particle per 100% by weight of the drug-containing particle.
  • the drug-containing particles of the present invention most preferably contain 15 to 30% by weight of drug, 10 to 30% by weight of polymer, and 20 to 60% by weight of additive for drug-containing particle per 100% by weight of drug-containing particle The thing to do is mentioned.
  • the average particle size of the polymer used as the raw material is usually 5 times or more, preferably 10 times or more, more preferably 15 times the average particle size of the drug and / or the drug-containing particle additive used as the raw material Or more, more preferably 20 times or more, and most preferably 25 times or more. Also, those having a magnification of 1,000 times or less, preferably 500 times or less, more preferably 100 times or less can be mentioned. Furthermore, it is preferable that the particle size distribution of the polymer used as the raw material and the particle size distribution of the drug and / or the additive for drug-containing particles used as the raw material do not overlap.
  • the cumulative 10% particle diameter D10 in the volume-based measurement of the polymer is larger than the cumulative 90% particle diameter D90 of the drug and / or the additive for drug-containing particles.
  • the 10% particle diameter D10 of the polymer is preferably one or more times larger than the 90% particle diameter D90 of the drug and / or the drug-containing particle additive, and more preferably twice or more.
  • it is more preferably 4 times or more.
  • it is usually 5,000,000 times or less.
  • the drug-containing particles of the present invention preferably contain 1 to 70% by weight of the drug and 1 to 30% by weight of the polymer per 100% by weight of the drug-containing particle (more preferably 5 to 50% by weight of the drug) 1 to 40% by weight of a polymer; more preferably 10 to 40% by weight of a drug and 10 to 40% by weight of a polymer: most preferably 15 to 30% by weight of a drug
  • the polymer preferably contains 10 to 30% by weight) and the “preferred average particle size of the polymer used as the raw material” is usually 10 or more times the average particle size of the drug used as the raw material (preferably Those having 15 times or more, more preferably 25 times or more) can be mentioned.
  • the drug-containing particles of the present invention contain 1 to 70% by weight of the drug, 1 to 30% by weight of the polymer, and 1 to 90% by weight of the additive for the drug-containing particle per 100% by weight of the drug-containing particle (More preferably, 5 to 50% by weight of the drug, 1 to 40% by weight of the polymer, 5 to 80% by weight of the additive for drug-containing particles; further preferably, 10 to 40% by weight of the drug 10 to 40% by weight of a polymer and 10 to 70% by weight of an additive for drug-containing particles; most preferably, 15 to 30% by weight of a drug, 10 to 30% by weight of a polymer
  • the additive for particles is contained at 20 to 60% by weight), and the preferable average particle size of the polymer used as the raw material is 10 with respect to the average particle size of the mixed powder of the drug and other additives used as the raw material Times or more (preferably 15 times or more, Ri preferably include those that are more than 25 times).
  • the preparation of the present invention contains the drug-containing particles of (1), and may optionally contain (vi) a formulation additive.
  • a formulation additive examples include granules, tablets, capsules, suspensions (aqueous suspensions, oily suspensions), and emulsions.
  • Preferred examples of the dosage form include granules, tablets, or capsules. More preferably, a tablet is mentioned as a dosage form.
  • the tablet preferably includes an orally disintegrating tablet.
  • the "per 100% by weight of the preparation" means a weight percentage when the "weight of the whole preparation containing the drug-containing particles" is 100%.
  • Additives for formulation are not particularly limited as long as it is a commonly used additive, and examples of the additive are as described in the “drug-containing particle additive” in (iv) above.
  • Preferred additives used for formulation include excipients, binders, sweeteners, flavoring agents, flavoring agents, flavoring agents, fluidizers, antistatic agents, coloring agents, disintegrants and lubricants. .
  • the additive used in the formulation includes an excipient, a binder, a sweetening agent, a flavoring agent, a flavoring agent, a flavor, a fluidizing agent, a disintegrant and a lubricant.
  • an excipient, a disintegrant, and a lubricant are mentioned more preferably.
  • Excipients binders, sweeteners, flavoring agents, flavoring agents, flavors, fluidizers, antistatic agents, coloring agents, disintegrants, lubricants, plasticizers, anticoagulants, coatings used in formulation Examples of the agent are as described in the “drug-containing particle additive” of (iv) above.
  • Excipients used for formulation include, for example, saccharides, sugar alcohols, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, or crystalline cellulose.
  • lactose, sucrose, sucrose, fructose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, reduced lactose, erythritol, sorbitol, maltitol, mannitol are preferably used.
  • the excipient used for formulation includes lactose, sucrose, erythritol, mannitol, calcium carbonate, or crystalline cellulose. More preferably, the excipient used for formulation includes lactose, mannitol, calcium carbonate, or crystalline cellulose. Most preferably, the excipient used for formulation includes mannitol or crystalline cellulose.
  • lactose sucrose, sucrose, fructose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered sugar, or reduced lactose is preferably mentioned.
  • Preferred sugar alcohols used for formulation include erythritol, sorbitol, maltitol, xylitol or mannitol. More preferably, the sugar alcohols used for formulation include mannitol.
  • Preferred binders used for formulation are cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose and salts thereof, polyvinyl pyrrolidone, polyvinyl alcohol, copolyvidone, vinyl acetate / vinyl acetate Water-soluble vinyl derivatives such as pyrrolidone copolymers, polyvinyl alcohol / polyethylene glycol graft copolymers, etc., pregelatinized starch, dextrin, dextran, pullulan, alginic acid, gelatin, pectin, ethyl cellulose, water insoluble cellulose ethers such as cellulose acetate, ammonio alkyl Methacrylate copolymer RS, ethyl acrylate, methyl methacrylate Water-insoluble acrylic acid-based copolymers such as Rimmer dispersion, vinyl acetate resin, hydroxypropyl methylcellulose
  • Stomach-soluble acrylic acid-based copolymer polylactic acid, polyglycolic acid, polycaprolactone and their copolymers, collagen, chitin, or chitosan (eg, trade name: Flonac C-100M), and one or two kinds thereof. You may mix and use the above.
  • sweetening agent used for formulation preferably erythritol, sorbitol, maltitol, mannitol, xylitol, aspartame, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia extract, thaumatin, sucralose or acesulfame K can be mentioned. More preferably, as a sweetening agent used for formulation, aspartame, mannitol, thaumatin, sucralose, or acesulfame K can be mentioned. More preferably, as a sweetening agent used for formulation, aspartame, mannitol, thaumatin can be mentioned. Most preferably, the sweetening agent used for formulation includes aspartame.
  • flavoring agents and flavoring agents used for formulation include sucrose, saccharin, sweetening ingredients such as various fruit syrups, organic acids such as fumaric acid, citric acid and tartaric acid, and fruit essences. More preferably, fumaric acid, citric acid and fruit essence are used as flavoring agents and flavoring agents used for formulation. As the flavoring agent and flavoring agent used for formulation, fumaric acid and fruit essence are more preferable. Most preferably, as a flavoring agent and a flavoring agent used for formulation, a fruit essence is mentioned.
  • croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, crospovidone, corn starch, low substituted hydroxypropyl cellulose are mentioned. More preferably, as a fragrance used for formulation, corn starch and low substituted hydroxypropyl cellulose are mentioned. More preferably, corn starch is mentioned as a fragrance used for formulation.
  • talc light anhydrous silicic acid, magnesium aluminometasilicate, hydrous silicic acid silicic acid
  • talc light anhydrous silicic acid and magnesium aluminometasilicate are mentioned as a fluidizing agent used for formulation.
  • magnesium aluminometasilicate is mentioned.
  • a coloring agent used for formulation a tar pigment, lake pigment, yellow ferric oxide, ferric oxide, titanium oxide are preferably mentioned. More preferably, the coloring agent used for formulation includes lake pigment and yellow ferric oxide. More preferably, yellow ferric oxide is mentioned as a coloring agent used for formulation.
  • disintegrants used for formulation preferably, croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, crospovidone, corn starch, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch are mentioned.
  • Plasticizers used for formulation include, for example, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin, glycerin fatty acid ester.
  • anticoagulant used for formulation for example, silicon dioxide, light anhydrous silicic acid, talc, magnesium stearate, sodium stearyl fumarate may be mentioned.
  • a coating agent used for formulation preferably hypromellose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, ammonio alkyl methacrylate copolymer RS, ethyl acrylate ⁇ ethyl acrylate ⁇
  • a base such as methyl methacrylate copolymer
  • a plasticizer such as polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin, glycerin fatty acid ester and the like can be mentioned.
  • additives such as titanium oxide, talc and coloring agents can also be added.
  • carnauba wax, talc and the like can be added as a brightening agent.
  • the apparatus classified into a coating pan is mentioned, for example.
  • an apparatus classified as a vented coating system can be mentioned.
  • the content of additives used for formulation can be optionally set, but generally 95.9 wt% or less, preferably 90 wt% or less, more preferably 80 wt% or less, per 100 wt% of the formulation, more preferably Is 70 wt% or less, most preferably 60 wt% or less. Specifically, 0.1 to 95.9 wt%, preferably 1 to 90 wt%, more preferably 5 to 80 wt%, further preferably 10 to 70 wt%, most preferably 20 to 100 wt% of the preparation. Up to 60% by weight can be mentioned.
  • the drug-containing hollow particles (the above (v)) of the present invention are a drug (the above (i)) and a polymer (the above It can be manufactured by adding a solvent capable of dissolving the polymer to a powdered mixture containing (iii)) and other additives (the above (iv)), for example, granulating while spraying. . Thereafter, sodium stearyl fumarate ((ii) above) is added to and mixed with the drug-containing hollow particles, and then a solvent capable of dissolving the polymer is added, for example, mixed while spraying, and dried.
  • Drug-containing hollow particles coated with an outer layer with sodium stearyl fumarate can be produced.
  • the granulation method can be appropriately selected as long as it has a function of rolling core particles into a coating.
  • it can be manufactured using a stirring granulation method, a mixing stirring granulation method, a high speed stirring granulation method, a high speed mixing stirring granulation method, a rolling stirring fluidized bed granulation method, a rolling granulation method.
  • a granulator used for stirring granulation, mixing stirring granulation, etc. for example, intensive mixer (manufactured by Nippon Eirich), universal mixer (manufactured by Shinagawa Kogyosho), super mixer (manufactured by Kawata Co., Ltd.), FM mixer (manufactured by Japan) Coke Industry Co., Ltd.
  • intensive mixer manufactured by Nippon Eirich
  • universal mixer manufactured by Shinagawa Kogyosho
  • super mixer manufactured by Kawata Co., Ltd.
  • FM mixer manufactured by Japan
  • drying method a method known per se can be appropriately selected. For example, drying by a tray dryer or a fluidized bed may, for example, be mentioned. From the viewpoint of manufacturability, drying by a fluidized bed is preferable.
  • a mixing method any one having a mixing function can be appropriately selected. For example, a convective mixer such as a tumble mixer, a V-type mixer, a diffusion mixer such as a W-type mixer, a ribbon mixer, a Nauta mixer, or a planetary mixer can be used.
  • Production method 2 Method for producing orally disintegrating tablet using drug-containing hollow particles
  • the orally disintegrating tablet using the drug-containing hollow particles of the present invention is formulated as drug-containing hollow particles (above (v)) and (vi)
  • the additives can be mixed and manufactured into tablets.
  • a mixing method any one having a mixing function can be appropriately selected.
  • a convective mixer such as a tumble mixer, a V-type mixer, a diffusion mixer such as a W-type mixer, a ribbon mixer, a Nauta mixer, or a planetary mixer can be used.
  • a tableting method can be appropriately selected as long as it has a function of compression molding a powder.
  • a tableting device classified as a tablet press can be mentioned.
  • a lubricant can also be added to the tablet of the present invention by an external lubricant method.
  • solvent in the present invention means all solvents acceptable in the fields of pharmaceuticals, quasi-drugs, cosmetics, food and the like, and any solvent can be used as long as it can dissolve the polymer used. From the viewpoint of using the drug-containing particles of the present invention as a medicament, pharmaceutically acceptable solvents are preferred. Such a solvent is appropriately selected according to the type of drug, polymer, additive and the like, and several solvents may be mixed and used.
  • solvent for example, water, alcohol solvents (eg, methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, etc. may be substituted)
  • the lower alkanol), ketone solvents (for example, lower alkyl ketones such as acetone and methyl ethyl ketone), ester solvents (for example, lower alkyl esters of acetic acid such as ethyl acetate and the like), and mixed solvents thereof can be mentioned.
  • a solvent capable of dissolving the polymer for example, water, a water-containing alcohol solvent, etc.
  • Water or hydrous ethanol can be used particularly preferably.
  • a solvent capable of dissolving the polymer for example, an alcohol-based solvent, a ketone-based solvent, an ester-based solvent, etc.
  • polymers such as polymers, enteric polymers, and chitosan can all be used as solvents which can dissolve the polymers (for example, alcohol solvents, more specifically, ethanol).
  • the amount of solvent used in the present invention varies depending on the type and amount of drug, polymer, etc., but usually 5 to 60% by weight, preferably 10 to 53% by weight, per 100% by weight of the total amount of each component constituting particles. More preferably, it is 10 to 40% by weight, still more preferably 15 to 40% by weight.
  • the addition to the powdered mixture containing drug and polymer is preferably carried out by spraying.
  • Spraying of the solvent in the present invention may be carried out using a spray gun usually used in granulation.
  • a needle spray gun manufactured by Tomita Engineering Co., Ltd.
  • the spray on the portion other than the powder in the granulation container, that is, the inner wall of the granulation container is as small as possible, and the solvent is sprayed over the widest possible range of the powder in the granulation container. It is preferable to do.
  • the average particle size of the mixed powder of the drug used as a raw material and the drug-containing particle additive is important in producing the drug-containing particles.
  • the average particle size of the polymer used as the raw material is 5 times or more, preferably 10 times or more, more preferably 15 times the average particle size of the mixed powder of the drug used as the raw material and the additive for drug-containing particles.
  • the above, particularly preferably 25 times or more is preferable. Also, it is usually 1000 times or less, preferably 500 times or less, more preferably 100 times or less.
  • the particle size distribution of the polymer used as the raw material and the particle size distribution of the mixed powder of the drug used as the raw material and the additive for the drug-containing particles do not overlap.
  • the cumulative 10% particle diameter D10 of the polymer used as the raw material is preferably 1 or more times the 90% particle diameter D90 of the mixed powder of the drug used as the raw material and the additive for drug-containing particles It is more preferably twice or more, and more preferably 4 times or more. Also, it is usually 500 times or less, preferably 250 times or less, more preferably 50 times or less.
  • the “aspect ratio” in the present invention is the ratio of the minor axis to the major axis of the particle, and serves as a standard indicating the sphericity.
  • the aspect ratio can be calculated, for example, by the following equation.
  • Aspect ratio long diameter of particle / short diameter of particle
  • the long diameter and short diameter of the particle are nondestructively measured by a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used. Moreover, it can measure using Millitrack JPA (Nikkiso Co., Ltd.).
  • the “particle size distribution width” in the present invention is determined by the ratio (D90 / D10) of the 90% cumulative particle diameter D90 to the cumulative 10% particle diameter D10 in the volume-based measurement of powder particles.
  • the particle size distribution can be simply adjusted by adjusting the particle size of the polymer, and, for example, particles having a narrow particle size distribution width can be produced.
  • the particle size distribution width is measured on a volume basis with a laser diffraction type particle size distribution measuring apparatus (Powrex Inc., Particle Viewer).
  • the particle size distribution width is narrow means that the specific particle size distribution width (D90 / D10) is 6.0 or less, preferably 5.0 or less, more preferably 4.0 or less, still more preferably 3. It means that it is 0 or less.
  • the strength of hollow particles can be evaluated by the particle shell strength.
  • the breaking test force of the particles and the diameter of the drug-containing particles are measured by Shimadzu micro compression tester MCT-W500 (manufactured by Shimadzu Corporation).
  • the “hollow portion diameter” in the present invention can be calculated by the following equation.
  • Hollow part diameter [ ⁇ m] (long diameter of hollow part + short diameter of hollow part) / 2
  • the major axis and minor axis of the hollow portion of such particles are nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.
  • the drug-containing particles are coated with a functional polymer or the like using a fluid bed granulator or various fine particle coating devices that require mechanical strength of the particles to impart additional functions. It is desirable to have sufficient particle strength such that it can be coated efficiently without cracking and cracking and can remain hollow without tableting.
  • the drug-containing hollow particles of the present invention have sufficient particle strength. Since the drug-containing hollow particle has a hollow portion, the hollow shell can not be correctly evaluated by calculating the hollow portion as a solid by the ordinary method of measuring the particle strength, and therefore the particle shell strength excluding the hollow portion can be measured. It is.
  • “sufficient particle strength” in the present invention means that the particle shell strength of the drug-containing particles is 2.0 MPa or more, preferably 3.0 MPa or more, more preferably 4.0 MPa or more, and still more preferably 5. It means that it is 0 MPa or more.
  • the “particle diameter of drug-containing particles” in the present invention can be calculated by the following equation.
  • Particle diameter of drug-containing particles [ ⁇ m] (long diameter of particles + short diameter of particles) / 2
  • the major axis and minor axis of the particles are nondestructively measured by a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.
  • Shell thickness [ ⁇ m] (particle diameter of drug-containing particle-diameter of hollow portion) / 2
  • the particle diameter of the drug-containing particles and the diameter of the hollow portion are nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.
  • the “shell thickness ratio” in the present invention is calculated by the following equation.
  • Shell thickness ratio [%] (shell thickness / (particle diameter of drug-containing particles / 2)) ⁇ 100
  • the particle diameter of the drug-containing particles is nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.
  • the “hollow volume ratio” in the present invention is calculated by the following equation.
  • Hollow volume ratio [%] (4/3 ⁇ ⁇ ⁇ (diameter of hollow portion / 2) 3 ) / (4/3 ⁇ ⁇ ⁇ (particle diameter of drug-containing particles / 2) 3 ) ⁇ 100
  • the particle diameter of the drug-containing particles and the diameter of the hollow portion are nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times is used.
  • the “particle size distribution ratio of polymer to drug (D50 / D50)” in the present invention can be calculated by the following equation.
  • Particle size distribution ratio of polymer to drug (D50 / D50) polymer D50 / drug D50
  • the “particle size distribution ratio of the polymer, the mixture end of the drug and the other additive (D50 / D50)” in the present invention can be calculated by the following formula.
  • Particle size distribution ratio of polymer, mixed powder of drug and other additive polymeric D50 / mixed powder of drug and other additive D50
  • the particle size distribution of the mixed powder of such a polymer, drug, drug and other additives may be obtained by using a laser diffraction particle size distribution measuring apparatus (Powlec Co., Ltd., Particle Viewer) or a laser diffraction particle size distribution measuring apparatus (Shimadzu Corporation, SALD) -Measured on a volume basis with -3000 J, SYMPATEC HELOS & RODOS).
  • the “particle size distribution ratio of polymer to drug (D10 / D90)” in the present invention can be calculated by the following equation.
  • Particle size distribution ratio of polymer to drug (D10 / D90) polymer D10 / drug D90
  • the “particle size distribution ratio of the polymer, the mixture end of the drug and the other additive (D10 / D90)” in the present invention can be calculated by the following equation.
  • Particle size distribution ratio of polymer, mixed powder of drug and other additive polymer D10 / mixed powder of drug and other additive D90
  • the particle size distribution of the mixed powder of such a polymer, drug, drug and other additives may be obtained by using a laser diffraction particle size distribution measuring apparatus (Powlec Co., Ltd., Particle Viewer) or a laser diffraction particle size distribution measuring apparatus (Shimadzu Corporation, SALD) -Measured on a volume basis with -3000 J, SYMPATEC HELOS & RODOS).
  • the present invention also includes a step of granulation while spraying a solvent capable of dissolving a polymer into a powdery mixture containing a drug and a polymer, and a method for producing hollow particles, and the method It also relates to the hollow particles produced.
  • the solvent capable of dissolving the drug, the polymer and the polymer include the same as those described above for the method for producing the drug-containing particle of the present invention.
  • other additives may be contained as needed, and examples of the other additives are the same as those described above for the method of producing the drug-containing particle of the present invention.
  • the granulation method, the drying method, the spraying method of the solvent and the like those similar to those described above for the method for producing the drug-containing particle of the present invention are exemplified.
  • the present invention relates to a pharmaceutical composition, a therapeutic agent for treating and / or preventing digestive diseases or digestive conditions, which comprises drug-containing particles containing the drug of the present invention. And / or preventative agents.
  • said digestive system disorder is constipation type irritable bowel syndrome (IBS), or chronic constipation.
  • the drug-containing particles containing the drug of the present invention preferably include the drug-containing particles of the above (1), and more preferably include the above (v) drug-containing hollow particles.
  • the pharmaceutical composition, the therapeutic agent and / or the prophylactic agent preferably include a preparation containing the above (2) drug-containing particles.
  • prevention refers to the act of administering the drug of the present invention, which is an active ingredient, to healthy individuals who do not develop disease or have a poor health at the time of administration. It is intended to be administered to such healthy people, for example, for the purpose of preventing the onset of the disease, and in particular, the risk of suffering from a person who has had a symptom of the disease or suffering from the disease is increased. It is expected to be appropriate for those who are considered to be "Treatment” is the act of administering the drug of the present invention, which is the active ingredient, to a person (patient) who has been diagnosed as having a disease by a doctor, and the "therapeutic agent" is such a patient.
  • “digestive system diseases or digestive system conditions” specifically include the following diseases or conditions (i) to (iii): (I) For example, irritable bowel syndrome, flaccid constipation, chronic constipation, chronic constipation, drug-induced constipation with drugs such as morphine and antipsychotics, constipation with Parkinson's disease, constipation with multiple sclerosis, diabetes Gastrointestinal diseases such as constipation with constipation or constipation or dysphagia due to contrast media (as pretreatment at endoscopy or barium enteral x-ray examination); (Ii) functional dyspepsia, acute and chronic gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer, gastric neuropathy, postoperative paralytic ileus, senile ileus, non-diffuse gastroesophageal reflux disease, NSAID ulcer, diabetic Gastrointestinal diseases such as gastroparesis, post-gastrectomy syndrome, or pseudo intestinal obstruction; And
  • the administration mode of the drug of the present invention may be oral administration or parenteral administration.
  • the dose varies depending on the administration method, patient's condition, age, etc., it is usually 0.01-30 mg / kg / day, preferably 0.05-10 mg / kg / day, more preferably 0.1-3 mg / kg. / Day range.
  • it is usually 0.01 mg to 1000 mg / day, preferably 0.1 mg to 500 mg / day, more preferably 0.5 mg to 300 mg / day, still more preferably 1 mg to 200 mg / day, most preferably Is in the range of 5 mg to 100 mg / day.
  • the number of daily doses may be, for example, once, or several times a day, for example 1, 2 or 3 doses each time.
  • the preparation for oral administration for example, granules, tablets, capsules, suspensions (aqueous suspensions, oily suspensions), emulsions, etc. can be mentioned, and for parenteral administration
  • the preparation include injections, drips, suppositories (rectal administrations), nasals, sublinguals, transdermal absorbents [lotion, milky lotion, ointment, cream, jelly, gel] Patch (tape agent, transdermal patch preparation, poultice, etc.), external use powder, etc.] and the like.
  • the drug of the present invention is orally administered as a drug-containing particle or formulation of the present invention.
  • the dosage form of the preparation for oral administration includes a tablet as described in the above-mentioned (2) preparation containing drug-containing particles. Further, as tablets, preferred are orally disintegrating tablets.
  • salts such as magnesium sulfate, magnesium oxide, magnesium citrate and the like, for example, infiltrating agents such as dioctyl sodium, sulfosuccinate, casanthranol Laxatives, for example, swelling laxatives such as carmellose, for example, large intestine stimulating laxatives such as bisacodyl, picosulfa, senna, sennoside, for example, small intestine irritating laxatives such as castor oil, for example, intestinal detergents such as Be Functional dyspepsia, acute and chronic gastritis, reflux esophagitis, non-diffuse gastroesophageal reflux disease, diabetic gastroparesis, gastric ulcer, duodenal ulcer, NSAID ulcer, gastric neurosis, postoperative ileus, senile ileus
  • digestive system diseases such as post-gastrectomy syndrome or pseudo intestinal
  • the present invention is provided based on the finding that the bitter taste of a component having bitterness was significantly masked when sodium stearyl fumarate was used for coating. It provides a new application of masking the bitter taste of sodium stearyl fumarate.
  • the bitter taste of the pharmaceutically acceptable salt, or the hydrate or solvate thereof is masked by coating sodium stearyl fumarate. More preferably, sodium stearyl fumarate is included as a coating of drug-containing particles.
  • the invention also relates to sodium stearyl fumarate and (S) -4-amino-5-chloro-N-[ ⁇ 4-[(1-hydroxyacetyl-4-piperidinyl) methyl] -2-morpholinyl ⁇ methyl]-
  • the present invention relates to a composition for masking bitter taste, which comprises 2-methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • sodium stearyl fumarate is included as a coating.
  • the composition according to the invention comprises drug-containing particles, which are (S) -4-amino-5-chloro-N-[ ⁇ 4-[(1-hydroxyacetyl-4-piperidinyl) Methyl] -2-morpholinyl ⁇ methyl] -2-methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • drug-containing particles which are (S) -4-amino-5-chloro-N-[ ⁇ 4-[(1-hydroxyacetyl-4-piperidinyl) Methyl] -2-morpholinyl ⁇ methyl] -2-methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • the composition for masking bitter taste of the present invention is characterized in that the outer layer of the drug-containing particle of the present invention is coated with the above sodium stearyl fumarate.
  • bitter taste masking (bitter taste mask) of the drug of the present invention exhibiting extremely strong unpleasant taste can be performed. This effect was found to be extremely remarkable as compared with the case of simply containing sodium stearyl fumarate.
  • the drug-containing particles of the present invention preferably include the above (1) drug-containing particles, and more preferably include the above (v) drug-containing hollow particles.
  • any coating method known in the art can be mentioned, and one example is a drug (the above (i)) as a raw material and a polymer (the above)
  • a solvent capable of dissolving the polymer is added to a powdery mixture containing the above (iii) and the other additives (the above (iv)), for example, by granulating while spraying, (v) a drug
  • a solvent capable of dissolving the polymer is added, for example, mixed while spraying.
  • the degree of bitterness of the composition can be evaluated to confirm the bitterness masking effect.
  • any test method known in the art can be mentioned, and as an example, the following test methods can be mentioned.
  • Several subjects contain each sample in the oral cavity, hold it until it breaks down in the oral cavity, and then discharge it, and evaluate the bitter taste in the oral cavity, at the time of discharge (immediately after the collapse) and one minute after discharge.
  • Bitterness is acceptable, setting two criteria that it is not acceptable, "0" to “2" are evaluated in 5 steps of 0.5, and if the average score is 0.5 or less, there is a problem with taking about bitterness If the average score is 1.0 or more, it is judged that it is difficult to take because of bitter taste. It is recognized that the composition has a bitter taste masking effect if the bitter taste is not a problem for taking.
  • Aspartame (aspartame): Ajinomoto magnesium stearate (magnesium stearate): Taiping Chemical Industries, Ltd. magnesium aluminometasilicate (Neusilin UFL2): Fuji Chemical Co., Ltd. Company D-Mannitol 80% and corn starch 20% premixed product (PEARLITOL FLASH): Rocket Japan Fumaric acid Co., Ltd. Stearyl sodium (PRUV): JRS PHARMA Fragrance (Lemonmicron ZD-4061): Takasago Fragrance Industry Co., Ltd. Hardened oil (Labry wax-103): Freund Industrial Co., Ltd. Light anhydrous silica (Adsolider 101): Freund Industrial Co., Ltd.
  • Talc Japan Talc Sucrose fatty acid ester (DK ester): Daiichi Kogyo Seiyaku Co., Ltd. sodium lauryl sulfate (sodium lauryl sulfate): Merck anhydrous ethanol: Wako Pure Chemical Industries, Ltd. yellow ferric oxide: San-Ei Gen FFI
  • the test methods in the examples, test examples and comparative examples are as follows.
  • Particle size distribution The particle size distribution of the drug, polymer, other additives, mixed powder of drug and other additives, and the drug-containing particles obtained is obtained by using a laser diffraction type particle size distribution measuring device (Powlec, Particle Viewer) or a laser diffraction type. It was measured on a volume basis with a particle size distribution measuring apparatus (SALD-3000J, manufactured by Shimadzu Corporation).
  • SALD-3000J particle size distribution measuring apparatus
  • SALD-3000J particle size distribution measuring apparatus
  • S-3400N scanning electron microscope
  • Aspect ratio major axis of particle / minor axis of particle (measurement of particle strength of comparative example)
  • Particle strength [MPa] 2.8 P / ( ⁇ ⁇ d 2 ) ⁇ 1000
  • P Destructive test force of particles [mN]
  • d Diameter of drug-containing particles [ ⁇ m] (Measurement of particle shell strength)
  • Particle shell strength [MPa] 2.8 P / ( ⁇ ⁇ d 2 ⁇ ⁇ d ′ 2 ) ⁇ 1000
  • P Destructive test force of particle [mN]
  • d diameter of drug-containing particle [ ⁇ m]
  • d ' diameter of hollow portion [ ⁇ m]
  • the diameter of the hollow portion is a value calculated from the shell thickness ratio (measured and calculated using a desktop micro CT scanner described below). That is, it is calculated by the following equation.
  • Hollow diameter [ ⁇ m] diameter of drug-containing particle ⁇ (1 ⁇ shell thickness ratio / 100)
  • the breaking test force of the particles and the diameter of the drug-containing particles were measured by Shimadzu micro compression tester MCT-W500 (manufactured by Shimadzu Corporation).
  • Hollow part diameter [ ⁇ m] (long diameter of hollow part + short diameter of hollow part) / 2
  • the major axis and minor axis of the hollow portion of the particles were measured nondestructively with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times was used.
  • Shell thickness The shell thickness was calculated by the following equation.
  • Shell thickness [ ⁇ m] (particle diameter of drug-containing particle-diameter of hollow portion) / 2
  • the particle diameter of the drug-containing particles and the diameter of the hollow portion were nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times was used.
  • Shell thickness ratio (Shell thickness ratio) The “shell thickness ratio” in the present invention was calculated by the following equation.
  • Shell thickness ratio [%] (shell thickness / (particle diameter of drug-containing particles / 2)) ⁇ 100
  • the particle diameter of the drug-containing particles was nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times was used.
  • Hollow volume ratio The hollow volume ratio was calculated by the following equation.
  • Hollow volume ratio [%] (4/3 ⁇ ⁇ ⁇ (diameter of hollow portion / 2) 3 ) / (4/3 ⁇ ⁇ ⁇ (particle diameter of drug-containing particles / 2) 3 ) ⁇ 100
  • the particle diameter of the drug-containing particles and the diameter of the hollow portion were nondestructively measured with a desktop micro CT scanner (SKYSCAN 1172, manufactured by SKYSCAN), and an average value measured ten times was used.
  • Particle size distribution ratio of polymer to drug (D50 / D50); Particle size distribution ratio of polymer, drug and other additives (D50 / D50)
  • the particle size distribution ratio (D50 / D50) of the polymer and the drug was determined by the following equation.
  • the particle size distribution ratio (D50 / D50) of the mixture end of the polymer, the drug and the other additives was calculated by the following equation.
  • the particle size distribution of the mixed powder of such a polymer, drug, drug and other additives is determined by using a laser diffraction particle size distribution measuring apparatus (Powlec Co., Ltd., Particle Viewer) or a laser diffraction particle size distribution measuring apparatus (Shimadzu Corporation, SALD Measured by volume basis at -3000 J).
  • Particle size distribution ratio of polymer to drug (D10 / D90); Particle size distribution ratio of polymer, drug and other additives (D10 / D90))
  • the particle size distribution ratio of the polymer to the drug was determined by the following equation.
  • Particle size distribution ratio of polymer to drug (D10 / D90) polymer D10 / drug D90
  • the particle size distribution ratio (D10 / D90) of the mixture end of the polymer, the drug and the other additives was calculated by the following equation.
  • Particle size distribution ratio of polymer, mixed powder of drug and other additive polymer D10 / mixed powder of drug and other additive D90
  • the particle size distribution of the mixed powder of such a polymer, drug, drug and other additives is determined by using a laser diffraction particle size distribution measuring apparatus (Powlec Co., Ltd., Particle Viewer) or a laser diffraction particle size distribution measuring apparatus (Shimadzu Corporation, SALD Measured by volume basis at -3000 J). (Smoothness of surface) It observed visually. In the evaluation, “very smooth” is represented by (+++), “smooth” is represented by (++), “smoothly smooth” is represented by (+), and “not smooth” is represented by ( ⁇ ).
  • the dissolution rate of the drug-containing hollow particles and the tablet was measured by the following method. Japan Pharmacopoeia 18 stations Paddle method was followed. The paddle rotation speed was 50 rpm, and the dissolution test solution used was the second solution of the dissolution test solution of Japanese Pharmacopoeia. The sampling of the elution test solution was performed by selecting from elution times 1, 3, 5, 10, 15, 30, and 60 minutes. 5 mL was sampled with a 5 mL plastic syringe with a SUS cannula.
  • the eluate was filtered through a membrane filter (Millex-HV, ⁇ 13 mm) with a pore diameter of 0.45 ⁇ m, 2 mL of the first filtrate was removed, and the next filtrate was subjected to HPLC measurement as a sample solution.
  • the filter was replaced every sampling. The dissolution rate was calculated based on the following equation.
  • Comparative Example 1-1 ⁇ Drug-containing core particles>
  • the raw materials listed in Table 1 were charged into a stirring granulator (FM-VG-05, manufactured by Powrex Corp.) and pre-mixed for 2 minutes (stirring blade speed 400 min -1 , broken blade speed 3000 min -1 , all the same in mixing operation) Done under stirring conditions).
  • Granulation was performed by mixing while spraying with absolute ethanol to obtain drug-containing core particles in a wet powder state.
  • the wet powder particles were charged into a fluid bed granulator (MP-01, manufactured by Powrex Corp.) and dried to obtain drug-containing core particles. Further, magnesium aluminometasilicate was added to the fluid bed granulator and mixed to obtain Comparative Example 1-1.
  • Example 1-1 After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half of the sodium stearyl fumarate was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, 1 ⁇ 4 volume of sodium stearyl fumarate was added, and coating was performed by spraying and mixing with absolute ethanol. Further, a mixture of 1 ⁇ 4 volume of sodium stearyl fumarate and yellow ferric oxide was added, and coating was carried out by mixing while spraying with absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed to obtain Example 1-1. The preparation amounts of the respective raw materials of Example 1-1 are as described in Table 2.
  • Example 1-2 comparative example 1-2
  • the ingredients were weighed according to Table 3 and mixed in a V-type mixer.
  • the mixed tableted powder was tableted with a rotary tableting machine ( ⁇ : 8 mm ⁇ , 12 R) to obtain Example 1-2 and Comparative Example 1-2.
  • Example 1 The dissolution test of Example 1-2 and Comparative Example 1-2 was performed (FIG. 1). The dissolution test was conducted according to the Japanese Pharmacopoeia 18 station paddle method. The paddle rotation speed was 50 rpm, and the dissolution test solution used was the second solution of the dissolution test solution of Japanese Pharmacopoeia. The sampling of the elution test solution was performed at elution times 1, 3, 5, 10, 15, 30, and 60 minutes. Elution Test The dissolution rate at 15 minutes was equal.
  • Test example 2 The sensory evaluation of Example 1-2 and Comparative Example 1-2 was performed (FIG. 2).
  • the subjects were 5 persons, and each sample was contained in the oral cavity and was discharged after being held until it collapsed in the oral cavity.
  • the bitter taste was acceptable, and two criteria were set: unacceptable.
  • Example 1-2 had an acceptable taste, but Comparative Example 1-2 had a strong bitter taste and an unacceptable taste.
  • Example 1-2 had the same dissolution property as Comparative Example 1-2, and an excellent bitterness masking effect was observed.
  • Example 1-2 was revealed to be a desirable preparation having the feature of "high bitter taste masking property" while securing the dissolution property.
  • Comparative Example 1-3 After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half of the magnesium stearate was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, half of the amount of magnesium stearate was added, and coating was carried out by mixing while spraying with absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-3. The preparation amounts of the respective raw materials of Comparative Example 1-3 are as described in Table 4.
  • Comparative Example 1-4 After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half of the hydrogenated oil (castor oil) was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, half of the hydrogenated oil (castor oil) was added, and coating was performed by spraying and mixing with absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-4. The preparation amounts of the respective raw materials of Comparative Example 1-4 are as described in Table 4.
  • Comparative Example 1-5 After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half of the light anhydrous silicic acid was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, half of light anhydrous silicic acid was added and coating was carried out by mixing while spraying absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-5. The preparation amounts of the respective raw materials of Comparative Example 1-5 are as described in Table 4.
  • Comparative Example 1-6 After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, a half amount of talc was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, the coating was carried out by adding a half amount of talc and mixing while spraying with absolute ethanol after drying mixing was performed again for 1 minute. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-6. The preparation amounts of the respective raw materials of Comparative Example 1-6 are as described in Table 5.
  • Comparative Example 1-7 After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half of the sucrose fatty acid ester was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, a half amount of sucrose fatty acid ester was added, and coating was performed by spraying and mixing with absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-7. The preparation amounts of the respective raw materials of Comparative Example 1-7 are as described in Table 5.
  • Comparative Example 1-8 After producing drug-containing core particles in a wet powder state as in Comparative Example 1-1, dry mixing was performed for 1 minute. Subsequently, half the amount of sodium lauryl sulfate was charged in a powdery state into a stirring granulator, mixed while spraying with absolute ethanol, and coated on drug-containing core particles. In the same manner as above, after 1 minute of dry mixing, coating was carried out by adding half of the amount of sodium lauryl sulfate and mixing while spraying with absolute ethanol. The coated granules were dried in a fluid bed dryer. Further, magnesium aluminometasilicate was added to the fluid bed dryer and mixed, to obtain Comparative Example 1-8. The preparation amounts of the respective raw materials of Comparative Example 1-8 are as described in Table 5.
  • Comparative Example 1-9 to Comparative Example 1-14 Each component was weighed according to Tables 6 and 7 and mixed in a V-type mixer. The mixed tableted powder was tableted using a rotary tableting machine ( ⁇ : 8 mm ⁇ , 12 R) to obtain Comparative Examples 1-9 to 1-14.
  • Test Example 3 The dissolution tests of Comparative Examples 1-9, 1-10, 1-11, 1-12, 1-13, and Comparative Example 1-14 were conducted (FIG. 3).
  • the dissolution test was conducted according to the Japanese Pharmacopoeia 18 station paddle method. The paddle rotation speed was 50 rpm, and the dissolution test solution used was the second solution of the dissolution test solution of Japanese Pharmacopoeia.
  • the sampling of the elution test solution was performed at elution times 5, 10, 15, 30, and 60 minutes. While the dissolution properties are worse in Comparative Examples 1-9, 1-12, 1-13, and 1-14 compared to Comparative Example 1-2, the dissolution properties in Comparative Examples 1-10, and 1-11 was maintained.
  • Test Example 4 The sensory evaluation of Comparative Examples 1-9, 1-10, 1-11, 1-12, 1-13, and Comparative Example 1-14 was performed in the same manner as in Test Example 2 (FIG. 4). The bitter taste was suppressed in Comparative Example 1-13, and the taste was acceptable. Comparative examples 1-9 and 1-12 have slightly suppressed bitter taste but are not acceptable taste, while comparative examples 1-10, 1-11 and 1-14 have strong bitter taste and unacceptable taste Met.
  • (S) -4-amino-5-chloro-N-[ ⁇ 4-[(1-hydroxyacetyl-4-piperidinyl) methyl] has a very high dissolution rate and a very strong unpleasant taste.
  • -2-morpholinyl ⁇ methyl] -2-methoxybenzamide or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof it is possible to provide a drug-containing particle in which bitter taste is masked.
  • the drug-containing particles it is possible to provide a preparation subjected to bitter taste masking while maintaining the absorbability of the drug. By using the preparation, it is possible to achieve both a good therapeutic effect and medication adherence.

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Abstract

L'invention concerne : des particules contenant un médicament à amertume masquée ; et une formulation à amertume masquée qui utilise lesdites particules contenant un médicament pour maintenir l'absorption du médicament. La présente invention concerne : des particules contenant un médicament dont la couche extérieure est revêtue de fumarate de stéaryle sodique, et contenant un (S)-4-amino-5-chloro-N-[{4-[(1-hydroxyacétyl-4-pipéridinyl))méthyl]-2-morpholinyl}méthyl]-2-méthoxybenzamide ou un sel pharmacologiquement acceptable de celui-ci, un hydrate de celui-ci ou un solvate de celui-ci ; et une formulation contenant lesdites particules contenant un médicament.
PCT/JP2018/048185 2017-12-28 2018-12-27 Particules contenant un médicament à amertume masquée et formulation contenant lesdites particules Ceased WO2019131891A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020080472A1 (fr) * 2018-10-18 2020-04-23 大日本住友製薬株式会社 Procédé de revêtement
US11696895B2 (en) 2017-12-28 2023-07-11 Sumitomo Pharma Co., Ltd. Fine particle coating (drug-containing hollow particle and method for manufacturing same)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007063263A (ja) * 2005-08-01 2007-03-15 Dainippon Sumitomo Pharma Co Ltd アムロジピン含有粒子およびそれからなる口腔内崩壊錠
WO2007083679A1 (fr) * 2006-01-20 2007-07-26 Dainippon Sumitomo Pharma Co., Ltd. Nouveau comprimé pelliculé
JP2008214334A (ja) * 2007-01-31 2008-09-18 Dainippon Sumitomo Pharma Co Ltd 被覆された薬物含有粒子および該粒子を含む固形製剤
WO2009104729A1 (fr) * 2008-02-21 2009-08-27 大日本住友製薬株式会社 Dérivé amide et composition pharmaceutique le contenant
JP2012036140A (ja) * 2010-08-10 2012-02-23 Kyoto Pharmaceutical Industries Ltd 苦味を抑制した速崩壊錠
JP2012526047A (ja) * 2009-05-01 2012-10-25 アプタリス ファーマテック インコーポレイテッド 非オピオイドおよびオピオイド鎮痛薬の組み合わせを含む口腔内崩壊錠組成物
WO2016129140A1 (fr) * 2015-02-10 2016-08-18 富士フイルム株式会社 Comprimé à désintégration intrabuccale rapide et son procédé de fabrication

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007063263A (ja) * 2005-08-01 2007-03-15 Dainippon Sumitomo Pharma Co Ltd アムロジピン含有粒子およびそれからなる口腔内崩壊錠
WO2007083679A1 (fr) * 2006-01-20 2007-07-26 Dainippon Sumitomo Pharma Co., Ltd. Nouveau comprimé pelliculé
JP2008214334A (ja) * 2007-01-31 2008-09-18 Dainippon Sumitomo Pharma Co Ltd 被覆された薬物含有粒子および該粒子を含む固形製剤
WO2009104729A1 (fr) * 2008-02-21 2009-08-27 大日本住友製薬株式会社 Dérivé amide et composition pharmaceutique le contenant
JP2012526047A (ja) * 2009-05-01 2012-10-25 アプタリス ファーマテック インコーポレイテッド 非オピオイドおよびオピオイド鎮痛薬の組み合わせを含む口腔内崩壊錠組成物
JP2012036140A (ja) * 2010-08-10 2012-02-23 Kyoto Pharmaceutical Industries Ltd 苦味を抑制した速崩壊錠
WO2016129140A1 (fr) * 2015-02-10 2016-08-18 富士フイルム株式会社 Comprimé à désintégration intrabuccale rapide et son procédé de fabrication

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11696895B2 (en) 2017-12-28 2023-07-11 Sumitomo Pharma Co., Ltd. Fine particle coating (drug-containing hollow particle and method for manufacturing same)
WO2020080472A1 (fr) * 2018-10-18 2020-04-23 大日本住友製薬株式会社 Procédé de revêtement

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