WO2011108644A1 - Composition pharmaceutique solide et préparation pharmaceutique - Google Patents

Composition pharmaceutique solide et préparation pharmaceutique Download PDF

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Publication number
WO2011108644A1
WO2011108644A1 PCT/JP2011/054917 JP2011054917W WO2011108644A1 WO 2011108644 A1 WO2011108644 A1 WO 2011108644A1 JP 2011054917 W JP2011054917 W JP 2011054917W WO 2011108644 A1 WO2011108644 A1 WO 2011108644A1
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Prior art keywords
component
pharmaceutical composition
solid pharmaceutical
acid
mass
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PCT/JP2011/054917
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English (en)
Japanese (ja)
Inventor
武利 伊藤
千晶 高橋
里依 奥井
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ライオン株式会社
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Priority to JP2012503246A priority Critical patent/JP5817715B2/ja
Publication of WO2011108644A1 publication Critical patent/WO2011108644A1/fr

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    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a solid pharmaceutical composition containing non-steroidal anti-inflammatory of propionic acid or acetic acid type, and a pharmaceutical preparation comprising the same.
  • Propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drugs are often poorly soluble drugs with low solubility in water.
  • a technique for improving the dissolution property of a poorly soluble drug and increasing the dissolution rate a technique for preparing a composition containing a poorly soluble drug and a polymer compound is known (Patent Document 1: JP-A-3-83922, Patent Document 2: Japanese Patent Application Laid-Open No. 8-291063).
  • Japanese Patent Application Laid-Open No. 8-291063 proposes an easily absorbable preparation containing a poorly soluble drug containing a carboxyl group, a specific amino group-containing polymer compound, and an excipient.
  • the easily absorbable preparation has a problem that the composition is very easy to be cured and agglomerated and solidified immediately after production, and the dissolution property is low.
  • the present invention contains propionic acid or acetic acid-based non-steroidal anti-inflammatory, with good manufacturability, improved elution of propionic acid or acetic acid-based non-steroidal anti-inflammatory drugs, and suppressed aggregation and solidification
  • the object is to provide a solid pharmaceutical composition and a pharmaceutical preparation comprising the same.
  • the present inventors have used (A) a propionic acid or acetic acid-based non-steroidal anti-inflammatory drug in combination with a solid pharmaceutical composition containing (B) aminoalkyl methacrylate copolymer E, thereby
  • the problem that coagulation solidification occurs while improving the elution property of the component) includes (C) silicon dioxide, the content ratio of the component (B) to the component (A), and the component (A) to the component (A)
  • the present invention provides the following solid pharmaceutical composition and pharmaceutical preparation.
  • a propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug (B) an aminoalkyl methacrylate copolymer E, and (C) silicon dioxide, and represented by (B) / (A)
  • the mass ratio of the component (B) to the component (A) is 0.5 to 2
  • the mass ratio of the component (C) to the component (A) represented by (C) / (A) is 0.
  • a solid pharmaceutical composition that is 5-2. [2].
  • A The solid pharmaceutical composition according to [1], wherein the component is ibuprofen. [3].
  • a pharmaceutical preparation comprising the solid pharmaceutical composition according to any one of [6] and being a tablet, granule, fine granule or capsule.
  • the non-steroidal anti-inflammatory of propionic acid or acetic acid which has good manufacturability, improves the elution of propionic acid or acetic acid-based non-steroidal anti-inflammatory drugs, and suppresses aggregation and solidification, is achieved. It is possible to provide a solid pharmaceutical composition to be contained and a pharmaceutical preparation comprising the same.
  • the solid pharmaceutical composition of the present invention contains (A) a propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug, (B) an aminoalkyl methacrylate copolymer E, and (C) silicon dioxide. ) / (A), the content ratio of the component (B) to the component (A) is 0.5 to 2, and the component (A) represented by (C) / (A) ( The component mass ratio of component C) is 0.5-2.
  • Solid pharmaceutical composition (A) Propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug
  • Propionic acid-based and acetic acid-based compounds are those having a propionic acid group and an acetic acid group, respectively. Two or more kinds can be used in appropriate combination.
  • Non-steroidal anti-inflammatory drugs include known ones.
  • propionic acid non-steroidal anti-inflammatory drugs include ibuprofen, ketoprofen, naproxen, flurbiprofen, loxoprofen sodium and the like.
  • Examples of acetic acid non-steroidal anti-inflammatory drugs include diclofenac, diclofenac sodium, indomethacin, felbinac and the like. Of these, ibuprofen is preferred.
  • an antipyretic analgesic effect can be obtained.
  • the content of the component (A) is not particularly limited as long as it is within the permissible range of blending into an internal drug (drug approval standard amount).
  • the daily dose of ibuprofen is preferably 200 to 600 mg, more preferably 390 to 450 mg. Further, it is preferably 1 to 50% by mass in the solid pharmaceutical composition, more preferably 5 to 50% by mass, and even more preferably 10 to 50% by mass.
  • the aminoalkyl methacrylate copolymer E is a chemical name: methyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate copolymer, and is a component described in a pharmaceutical additive standard or a Japanese Pharmacopoeia pharmaceutical ingredient standard. .
  • component (B) commercially available products can be used.
  • Eudragit E100, Eudragit EPO (monomer molar ratio; methyl methacrylate 1: butyl methacrylate 1: dimethylaminoethyl methacrylate 2) of Evonik Product name) etc. can be used singly or in appropriate combination of two or more.
  • Component (A) is a poorly water-soluble drug, and improvement in dissolution is a problem, but by mixing (A) component and (B) component together, the dissolution property of (A) component is improved. .
  • the mechanism is unknown, but (A) a propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug has a carboxy group and (B) component (dimethylaminoethyl methacrylate) amino group ( It is expected that the component (A) and the component (B) are combined. Complexation can be confirmed by the component (A) becoming amorphous (non-crystallized). Amorphization of the component (A) can be confirmed by, for example, the peak of the component (A) in DSC or XRD.
  • the content of the component (B) is not particularly limited as long as it is within the range acceptable for internal use (unprecedented amount of pharmaceutical use), but the daily dose is preferably 60 to 1800 mg, more preferably 100 to 1200 mg. Further, the mass ratio of the component (B) to the component (A) represented by (B) / (A) is 0.5 to 2. When (B) / (A) is less than 0.5, the elution improvement of the component (A) is insufficient, and when it exceeds 2, the elution improvement of the component (A) and the coagulation solidification suppressing effect are obtained. Insufficient and adheres to manufacturing equipment such as a blender or a tableting machine.
  • the upper limit is preferably 1.5 or less, and more preferably 1 or less.
  • the effect of the present invention is greatly influenced by the content ratio of the component (B) to the component (A), and the content of the component (B) is not particularly limited, but is 0.1 to 50 in the solid pharmaceutical composition. % By weight is preferred, 1 to 50% by weight is more preferred, and 1 to 30% by weight is even more preferred.
  • (C) Silicon dioxide By mix
  • (D) Silicon dioxide has general names such as light anhydrous silicic acid, hydrous silicon dioxide, silica, white carbon and the like. Moreover, a commercial item can also be used, "Silicia” of Fuji Silysia Chemical Ltd., "Syrossphere” (all are brand names), etc. are mentioned, It can use individually by 1 type or in combination of 2 or more types. .
  • the content of the component (C) is not particularly limited as long as it is within a range acceptable as an internal medicine, but when it is used as an OTC pharmaceutical, it is preferably 1 to 3000 mg as a daily dose of silicon dioxide.
  • the content ratio of the component (C) to the component (A) represented by (C) / (A) is 0.5 to 2. If the above (C) / (A) is less than 0.5, the effect of improving the elution of the component (A) and the effect of suppressing aggregation and solidification are insufficient, and if it is too large, granulation may be difficult.
  • the upper limit is preferably 1 or less from the viewpoint of ease of production and administration.
  • the effect of the present invention is greatly influenced by the content ratio of the component (C) to the component (A), and the content of the component (C) is not particularly limited, but is 50% by mass or less in the solid pharmaceutical composition.
  • the content of the component (C) is not particularly limited, but is 50% by mass or less in the solid pharmaceutical composition.
  • a solid pharmaceutical composition having no powderiness and excellent feeling of administration can be obtained, and 5 to 30% by mass is more preferable.
  • Silicon dioxide is one of the excipients used as a lubricant, but usually a blending amount of about several mass% of the whole preparation is sufficient when a lubricant effect is expected.
  • the content of the component (D) is not particularly limited as long as it is within the range acceptable as an internal medicine, but when used as a wet granulation binder, the amount of hydroxypropyl cellulose relative to 100% by mass of the granulated product is particularly limited. However, it is preferably 0.1 to 20% by mass, more preferably 1 to 10% by mass.
  • the hydroxypropyl cellulose a commercially available product can be used, and for example, HPC-SSL, HPC-SL, HPC-L, HPC-M, HPC-H, etc. of Nippon Soda Co., Ltd. can be suitably used.
  • the total content of the components (A), (B) and (C) in the solid pharmaceutical composition of the present invention is preferably 50% by mass or more, more preferably 50 to 100% by mass.
  • other components can be blended in an appropriate amount within a range not impairing the effects of the present invention. In that case, the components (A), (B) and (C)
  • the total content of can be 95% by mass.
  • the total content of (A), (B), (C) component (D) as necessary in the solid pharmaceutical composition of the present invention is preferably 60 to 100% by mass, more preferably 80 to 100% by mass. 90 to 100% by mass is more preferable.
  • other components can be blended in appropriate amounts within a range that does not impair the effects of the present invention.
  • (E) aluminum hydroxide (such as dry aluminum hydroxide), magnesium aluminate metasilicate, and (F) acetaminophen are preferable.
  • Aluminum hydroxide or magnesium aluminate metasilicate can be used individually by 1 type or in combination of 2 or more types. Aluminum hydroxide and magnesium aluminate metasilicate are antacids, but by blending these components, the amorphous component (A) is prevented from recrystallizing during low-temperature storage and is eluted. The property is maintained even after low temperature storage. As a result, the crystallinity, dissolution property, and suppression of aggregation and solidification with time after low-temperature storage are improved.
  • the content of the component (E) is not particularly limited as long as it is within the range acceptable for internal use, but the daily dose is preferably 200 to 1500 mg, more preferably 200 to 1300 mg.
  • the mass ratio of the component (E) to the component (A) represented by (E) / (A) is preferably 0.3 to 5, more preferably 0.3 to 4, and 0.3 to 3 Is more preferable. If the above (E) / (A) is less than 0.3, the effect of suppressing recrystallization may be insufficient. If it exceeds 5, the composition blending amount increases, resulting in problems such as reduced dosing properties and uneconomical properties.
  • the effect of the present invention is greatly influenced by the content ratio of the component (E) to the component (A), and the content of the component (E) is not particularly limited, but is 1 to 50% by mass in the solid pharmaceutical composition. It is preferably 10 to 30% by mass, more preferably 15 to 20% by mass.
  • Acetaminophen is an antipyretic analgesic or an analgesic auxiliary agent.
  • (F) component is blended with the composition containing (A) component and (B) component. By doing so, aggregation and solidification over time (during high-temperature storage) is further suppressed.
  • the content of the component (F) is not particularly limited as long as it is within the range acceptable for internal use, but the daily dose of acetaminophen is preferably 60 to 1800 mg, more preferably 100 to 1200 mg.
  • the content ratio of the component (F) to the component (A) represented by (F) / (A) is preferably 0.3 to 3.
  • the ratio is 0.3 or more, the effect of the present invention is improved, that is, the dissolution property of the component (A) is improved and the aggregation and solidification is suppressed over time. May adhere to the manufacturing equipment, resulting in manufacturing problems such as difficulty in uniform mixing and tableting.
  • the lower limit is more preferably 0.4 or more, and further preferably 0.5 or more from the viewpoint of elution.
  • the upper limit is more preferably 2.5 or less, and even more preferably 2 or less.
  • the effect of the present invention is greatly influenced by the content ratio of the component (F) to the component (A), and the content of the component (F) is not particularly limited, but is 1 to 70% by mass in the solid pharmaceutical composition. It is preferably 5 to 60% by mass, more preferably 5 to 50% by mass.
  • ingredients include physiologically active ingredients such as active ingredients of pharmaceuticals other than the above ingredients and functional ingredients of functional foods, excipients such as binders and disintegrants, lubricants, fragrances, flavoring agents (sweetness) And sour agents), surfactants and the like.
  • excipients such as binders and disintegrants, lubricants, fragrances, flavoring agents (sweetness) And sour agents), surfactants and the like.
  • anti-inflammatory agents other than the component (A) such as aspirin, acetaminophen, etodolac, mefenamic, meclofenamic, piroxicam, isopropylantipyrine, tranexamic acid; nitrazepam, triazolam, phenobarbital , Hypnotics and sedatives such as amibarbital, allylisopropylacetylurea, bromvalenylurea; antiepileptics such as phenytoin, metalbital, primidone, clonazepam, carbamazepine, valproic acid; antidepressants such as meclizine hydrochloride, dimenhydrinate Antidepressants such as imiplanin, noxiptylline, phenelzine; psychopsychiatric agents such as haloperidol, meprobamate, chlordiazepoxide,
  • binder for example, starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like can be used. .
  • excipients include disintegrants such as carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone; lactose, corn starch, talc, crystalline cellulose, Powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, L-cysteine and the like can be used.
  • disintegrants such as carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone
  • lactose corn starch, talc, crystalline cellulose
  • Powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, L-cysteine and the like can be used.
  • lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, sucrose fatty acid ester and the like can be used.
  • fragrances include menthol, limonene, plant essential oils (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) and the like.
  • sweetener examples include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose, fructose and the like.
  • acidulant examples include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.
  • surfactant examples include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants.
  • the solid pharmaceutical composition of the present invention can be produced, for example, by the following methods (1) to (4), among which the method (2) is preferable.
  • (1). Components (A), (B) and (C), and if necessary, (E), (F) and other optional components are mixed in a Bole type mixer, V type mixer, etc. Aged at night.
  • (2). (A), (B) and (C) components, (E), (F) and other optional components as required, wet granulation using fluidized bed granulation, stirring granulation, extrusion granulation, etc. To do.
  • the binder is preferably added with the component (D) liquid as a binder liquid.
  • Components (A), (B) and (C), and optionally (E), (F) and other optional components can be dry granulated with a roller compactor or the like. Depending on the granulation conditions, aging overnight may be necessary near room temperature. (4). Components (A), (B) and (C), and if necessary, (E), (F) and other optional components are mixed and pulverized by a pin mill, a ball mill or the like. In this case, aging is unnecessary. Furthermore, it can be pulverized, pulverized, and sized by a vibration sieve, a comb mill, a flash mill, a power mill or the like. The mixing of the component (A) and the component (B) is not particularly limited as long as it is at room temperature (20 ° C.) or more, and the component (A) becomes amorphous by the component (B).
  • the heated mixture refers to a mixture obtained by heating and mixing the component (A) and the component (B) and then cooling to a solid.
  • the heating and mixing temperature is preferably 40 ° C. or higher, more preferably 50 ° C. or higher, and further preferably 70 ° C. or higher.
  • the upper limit is preferably 100 ° C. or less from the viewpoint of stability such as discoloration.
  • the cooling temperature is preferably 35 ° C. or lower, more preferably 30 ° C.
  • the component (C) since the component (C) is used, there is little influence by the production method. However, by using a heated mixture, the component (A) made amorphous by the component (B) is prevented from recrystallizing during low-temperature storage. In addition, elution properties after low-temperature storage are easily maintained.
  • the method using the heated mixture includes a step of heating and mixing the component (A) and the component (B) in the range of the heating and mixing temperature, and examples thereof include the following methods. (5). A method in which the components (A), (B) and (C), and optional components as necessary, are heated and mixed within the range of the heating and mixing temperature. (6). The components (A) and (B) are heated and mixed within the range of the above heating and mixing temperature, and the resulting heated mixture, the component (C), and optional components as necessary are fluidized bed granulated, stirred granulated, Wet granulation using extrusion granulation or the like. The binder is preferably added with the component (D) liquid as a binder liquid. (7).
  • the components (A) and (B) are heated and mixed within the range of the above heating and mixing temperature, and the obtained heated mixture, the component (C), and optional components as needed are dry granulated with a roller compactor or the like. You can also (8).
  • the components (A) and (B) are heated and mixed within the range of the heating and mixing temperature, and the resulting heated mixture, the component (C), and optional components are mixed as necessary. Further, after heating, it may include a step of cooling to an environmental temperature, for example, room temperature (20 ° C.), and a step of pulverizing, crushing, and sizing with a vibration sieve, a com mill, a flash mill, a power mill, or the like.
  • the solid pharmaceutical composition of the present invention is a compound in which the component (A) is non-crystallized and the component (A) and the component (B) are combined.
  • the structure of the solid pharmaceutical composition of the present invention is such that, for example, a composite composed of (A) component and (B) component in which (A) component is amorphized and co-melted is between the particles of (C) component. Predicted to be held.
  • the average particle size of the solid pharmaceutical composition is preferably 20 to 1000 ⁇ m, more preferably 50 to 850 ⁇ m, and even more preferably 80 to 600 ⁇ m.
  • the average particle size is a median diameter by a laser diffraction scattering particle size distribution measuring instrument (dry) (D 50).
  • the solid pharmaceutical composition can be taken internally, in this case (in this case, the solid pharmaceutical composition and the pharmaceutical preparation are the same composition) or mixed with other optional ingredients to form a pharmaceutical preparation be able to.
  • it can be used as a granule (granule, fine granule, powder) or tableted as necessary to obtain a solid pharmaceutical preparation for internal use such as a tablet or capsule.
  • the content of the solid pharmaceutical composition is preferably 30 to 100% by mass, more preferably 50 to 100% by mass in the pharmaceutical preparation.
  • an appropriate amount of optional ingredients other than the solid pharmaceutical composition can be blended in the pharmaceutical preparation.
  • blended with a tablet, a granule, and a capsule can be mix
  • These components can be used individually by 1 type or in combination of 2 or more types, The appropriate quantity can be mix
  • said pharmaceutical (C) can be mix
  • the content of the component (C) in the pharmaceutical preparation is not particularly limited as long as it is an amount acceptable as an OTC pharmaceutical, but it is usually preferably 10 to 60% by mass.
  • anti-inflammatory agents other than the component (A) such as aspirin, acetaminophen, etodolac, mefenamic, meclofenamic, piroxicam, isopropylantipyrine, tranexamic acid; nitrazepam, triazolam, phenobarbital , Hypnotics and sedatives such as amibarbital, allylisopropylacetylurea, bromvalenylurea; antiepileptics such as phenytoin, metalbital, primidone, clonazepam, carbamazepine, valproic acid; antidepressants such as meclizine hydrochloride, dimenhydrinate Antidepressants such as imiplanin, noxiptylline, phenelzine; psychopsychiatric agents such as haloperidol, meprobamate, chlordiazepoxide,
  • binder examples include starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like. Can be used.
  • excipients include disintegrants such as carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone; lactose, corn starch, talc, crystalline cellulose, Powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, L-cysteine and the like can be used.
  • disintegrants such as carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone
  • lactose corn starch, talc, crystalline cellulose
  • Powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, L-cysteine and the like can be used.
  • lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, sucrose fatty acid ester and the like can be used.
  • fragrances include menthol, limonene, plant essential oils (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) and the like.
  • sweetener examples include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose, fructose and the like.
  • acidulant examples include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.
  • surfactant examples include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants.
  • Examples 1 to 16 Comparative Examples 1 to 10
  • Each component in Tables 1 to 4 was wet granulated according to a conventional method using an LFS-GS-2J high speed mixer (wet agitation granulator) manufactured by Fukae Pautech Co., Ltd.
  • As the binder liquid an 8% by mass aqueous solution of hydroxypropylcellulose (Nippon Soda Co., Ltd. HPC-SSL) was used, and the amount of the aqueous solution that was 5% by mass of the total amount of (A) to (C) was dropped. did.
  • the obtained granule (solid pharmaceutical composition) was dried at 50 ° C. for 18 hours, and the following evaluation was performed.
  • the composition did not adhere to the production apparatus, and the manufacturability was also good.
  • the average particle diameter (median diameter (D 50 ) by laser diffraction scattering type particle size distribution analyzer (dry type)) in the examples was in the range of 80 to 600 ⁇ m.
  • Example 17 The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
  • Composition g Example 1 Granules (solid pharmaceutical composition) 390 g Acetaminophen 130g Bromhexine hydrochloride 4g Cremastine fumarate 0.45g Anhydrous caffeine 25g Ascorbic acid 100g Dextromethorphan hydrobromide hydrate 16g dl-Methylephedrine hydrochloride 20g Silicon dioxide (Silicia 740) 10g 150 g of crystalline cellulose (Theolas KG801) Lactose 150g Low substituted hydroxypropylcellulose 30g Croscarmellose sodium 20g Magnesium stearate 3g
  • Example 18 The following composition was mixed to obtain a fine granule.
  • Composition g 399 g of the granule of Example 4 solid pharmaceutical composition
  • Anhydrous caffeine 25g Bromhexine hydrochloride 4g Cremastine fumarate 0.45g Ascorbic acid 100g Dihydrocodeine phosphate 8g dl-Methylephedrine hydrochloride 20g 30 g of silicon dioxide (Silicia 740) D-mannitol 150g Fragrance 0.5g
  • Example 19 The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
  • Composition g Granules of Example 5 solid pharmaceutical composition
  • Anhydrous caffeine 25g 150 g of crystalline cellulose (Theolas PH302)
  • Low substituted hydroxypropylcellulose 30g
  • Crospovidone (XL-10) 20g
  • Example 20 The following composition was mixed to obtain a fine granule.
  • Composition g 630 g of the granule of Example 6 solid pharmaceutical composition
  • Example 21 The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
  • Composition g 315 g of the granule of Example 5 solid pharmaceutical composition
  • Acetaminophen 100g
  • Anhydrous caffeine 25g
  • Ambroxol hydrochloride 15g
  • Cremastine fumarate 0.45g
  • Ascorbic acid 100g
  • Dextromethorphan hydrobromide hydrate 16g dl-Methylephedrine hydrochloride
  • Example 22 The following composition was mixed to obtain a fine granule.
  • Example 23 The following composition was mixed and filled into gelatin capsules to form capsules.
  • the elution properties of the component (A) in Examples 17 to 23 were as high as those in Examples 1 to 16, and there was no aggregation and solidification.
  • Examples 24 to 28 Each component in Table 5 was wet granulated in accordance with a conventional method using an LFS-GS-2J high speed mixer (wet stirring granulator) manufactured by Fukae Pautech Co., Ltd. Water was used as the binder liquid, and an amount of the aqueous solution that was 5% by mass of the total amount of (A) to (C) was added dropwise. The obtained granule (solid pharmaceutical composition) was dried at 50 ° C. for 18 hours. In the examples, the composition did not adhere to the production apparatus, and the manufacturability was also good. About the obtained granule (solid pharmaceutical composition), the elution test of ibuprofen and the aggregation solidification suppression evaluation after drying were performed similarly to the said Example.
  • Examples 29 to 38 Each component in Tables 6 and 7 was wet granulated according to a conventional method using an LFS-GS-2J high speed mixer (wet stirring granulator) manufactured by Fukae Pautech Co., Ltd. Water was used as the binder liquid, and the hydroxypropylcellulose aqueous solution was added dropwise so that the solid content was 5% by mass of the total amount of (A) to (C). The granules were dried at 50 ° C. for 18 hours. The obtained granule (solid pharmaceutical composition) was stored at 50 ° C.
  • LFS-GS-2J high speed mixer wet stirring granulator
  • Example 39 The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
  • Example 40 The following composition was mixed to obtain a fine granule.
  • Composition g 415 g of granulated particles of Example 26 Bromhexine hydrochloride 4g Cremastine fumarate 0.45g Ascorbic acid 100g Dihydrocodeine phosphate 8g dl-Methylephedrine hydrochloride 20g 30 g of silicon dioxide (Silicia 740) D-mannitol 150g Fragrance 0.5g
  • Example 41 The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
  • Composition g 460 g of granulated particles of Example 27 Anhydrous caffeine 25g 150 g of crystalline cellulose (Theolas PH302) D-mannitol 150g Low substituted hydroxypropylcellulose 30g Crospovidone (XL-10) 20g Magnesium stearate 3g Sucralose 1.5g Fragrance 0.5g
  • Example 42 The following composition was mixed to obtain a fine granule.
  • Composition g 460 g of granulated particles of Example 36 Anhydrous caffeine 25g 60 g of allyl isopropyl acetyl urea 150 g of crystalline cellulose (Theolas KG801) Lactose 150g
  • Example 43 The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
  • Composition g 575 g of granulated particles of Example 28 Ambroxol hydrochloride 15g Cremastine fumarate 0.45g Ascorbic acid 100g Dextromethorphan hydrobromide hydrate 16g dl-Methylephedrine hydrochloride 20g 70g of dry aluminum hydroxide gel 150 g of crystalline cellulose (Theolas KG801) Croscarmellose sodium 20g Magnesium stearate 3g Fragrance 0.5g
  • Example 44 The following composition was mixed to obtain a fine granule.
  • Example 45 The following composition was mixed and filled into gelatin capsules to obtain capsules.
  • the elution properties of the component (A) of Examples 40 to 45 were as high as those of Examples 25 to 38 even after storage at 50 ° C. for 1 month, and there was no aggregation and solidification.
  • Example 46 to 50 Each component of Table 8 was mixed at 80 ° C. for 10 minutes, and stored at 5 ° C. and 50 ° C. (encapsulated in an aluminum pouch). About the mixture after a preservation

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Abstract

La présente invention concerne une composition pharmaceutique solide qui contient (A) un anti-inflammatoire non stéroïdien à base d'acide propionique ou d'acide acétique, (B) un copolymère E de méthacrylate d'aminoalkyle, et (C) du dioxyde de silicium. Le rapport de masse du composant (B) sur le composant (A) exprimé comme (B)/(A) est de 0,5 à 2, et le rapport de masse du composant (C) sur le composant (A) exprimé comme (C)/(A) est de 0,5 à 2.
PCT/JP2011/054917 2010-03-03 2011-03-03 Composition pharmaceutique solide et préparation pharmaceutique WO2011108644A1 (fr)

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JPH05148139A (ja) * 1991-11-29 1993-06-15 Lion Corp イブプロフエン含有解熱鎮痛剤
JPH05246845A (ja) * 1992-03-03 1993-09-24 Lion Corp イブプロフェン含有解熱鎮痛剤
JPH08291063A (ja) * 1995-04-21 1996-11-05 Maruho Kk 易吸収性製剤及びその製造法
JP2000007557A (ja) * 1998-06-22 2000-01-11 Lion Corp 不快な味がマスキングされた造粒組成物及びその製造方法
JP2000239185A (ja) * 1999-02-16 2000-09-05 Taisho Pharmaceut Co Ltd 医薬組成物
JP2000273037A (ja) * 1999-03-19 2000-10-03 Kyoto Pharmaceutical Industries Ltd 解熱・鎮痛チュアブル錠およびその製造法
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JP2006182726A (ja) * 2004-12-28 2006-07-13 Lion Corp 粒状医薬組成物及びその製造方法
JP2009089982A (ja) * 2007-10-11 2009-04-30 Ohara Yakuhin Kogyo Kk 打錠用造粒物の造粒方法

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JP4575654B2 (ja) * 2003-09-05 2010-11-04 エスエス製薬株式会社 溶解性と流動性を改善した医薬組成物

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JPH05148139A (ja) * 1991-11-29 1993-06-15 Lion Corp イブプロフエン含有解熱鎮痛剤
JPH05246845A (ja) * 1992-03-03 1993-09-24 Lion Corp イブプロフェン含有解熱鎮痛剤
JPH08291063A (ja) * 1995-04-21 1996-11-05 Maruho Kk 易吸収性製剤及びその製造法
JP2000007557A (ja) * 1998-06-22 2000-01-11 Lion Corp 不快な味がマスキングされた造粒組成物及びその製造方法
JP2000239185A (ja) * 1999-02-16 2000-09-05 Taisho Pharmaceut Co Ltd 医薬組成物
JP2000273037A (ja) * 1999-03-19 2000-10-03 Kyoto Pharmaceutical Industries Ltd 解熱・鎮痛チュアブル錠およびその製造法
JP2006514660A (ja) * 2003-01-28 2006-05-11 レーム ゲゼルシャフト ミツト ベシュレンクテル ハフツング ウント コンパニー コマンディートゲゼルシャフト 直接崩壊し、かつ作用物質を放出する経口薬剤形を製造するための方法
JP2006182726A (ja) * 2004-12-28 2006-07-13 Lion Corp 粒状医薬組成物及びその製造方法
JP2009089982A (ja) * 2007-10-11 2009-04-30 Ohara Yakuhin Kogyo Kk 打錠用造粒物の造粒方法

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