WO2011125500A1 - Procédé pour produire des granules de particules fines contenant un médicament faiblement hydrosoluble - Google Patents

Procédé pour produire des granules de particules fines contenant un médicament faiblement hydrosoluble Download PDF

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Publication number
WO2011125500A1
WO2011125500A1 PCT/JP2011/057022 JP2011057022W WO2011125500A1 WO 2011125500 A1 WO2011125500 A1 WO 2011125500A1 JP 2011057022 W JP2011057022 W JP 2011057022W WO 2011125500 A1 WO2011125500 A1 WO 2011125500A1
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Prior art keywords
water
soluble drug
soluble
weight
average particle
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PCT/JP2011/057022
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English (en)
Japanese (ja)
Inventor
信男 宮台
顕二郎 東
久仁一 森部
保夫 池田
升成 伏見
恵司 山本
Original Assignee
エスエス製薬株式会社
国立大学法人千葉大学
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Application filed by エスエス製薬株式会社, 国立大学法人千葉大学 filed Critical エスエス製薬株式会社
Priority to JP2012509421A priority Critical patent/JP5825686B2/ja
Publication of WO2011125500A1 publication Critical patent/WO2011125500A1/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
    • A61K9/14—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
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to a process for producing a slightly water-soluble drug-containing fine particle granule having excellent dissolution properties.
  • Patent Document 1 a solid dispersion using a hydrophilic polymer and a solubility improver
  • Patent Document 2 a technique of coating by spraying a water-soluble polymer solution
  • Patent Document 3 Technology that uses a water-soluble polymer and a nonionic surfactant in combination
  • Patent Document 4 Technology that granulates a mixture of a poorly water-soluble drug and a fluidizing agent using a water-soluble polymer solution
  • the particle diameter of the poorly water-soluble drug-containing composition obtained by these conventional means is several hundred ⁇ m to several mm due to the large amount of components used for granulation, resulting in drug elution. Sex was not enough. Therefore, the object of the present invention is to reduce the additive components other than the poorly water-soluble drug which is an active ingredient as much as possible and to improve the dissolution property, and to mask the bitter taste of many of the poorly water-soluble drugs. Another object of the present invention is to provide a method for producing a poorly water-soluble drug-containing particle.
  • the present inventor has set the particle diameter of the raw material poorly water-soluble drug, the fluidizing agent, the water-soluble polymer and the coating speed within a specific range. As a result, fine particles having an average particle diameter of 5 times or less of the raw material poorly water-soluble drug can be obtained, and the obtained fine particles not only have excellent solubility of the poorly water-soluble drug, but also can mask bitterness and the like. As a result, the present invention has been completed.
  • the present invention provides a fluidized bed granulator having a water solubility of 1 to 10% by weight in a mixture containing 100 parts by weight of a poorly water soluble drug having an average particle size of 100 ⁇ m or less and 1 to 5 parts by weight of a fluidizing agent.
  • An aqueous solution or hydrous alcohol solution containing a polymer is sprayed at a spray air velocity of 300 to 900 m / sec, and 0.1 to 20 of the solid content weight in the water-soluble polymer solution or hydrous alcohol solution is applied to the mixture.
  • An object of the present invention is to provide a method for producing a granulated fine particle having an average particle diameter of 0.2 to 5 times that of a raw material poorly water-soluble drug, characterized by coating parts by weight.
  • the present invention also provides a slightly water-soluble drug-containing fine particle granulated product obtained by the above-mentioned production method.
  • Granules can be obtained stably. If the fine particle granule obtained by the method of the present invention is used, a pharmaceutical preparation excellent in dissolution property of poorly water-soluble drug and improved in bitterness can be produced.
  • Example 1 The SEM observation image of the microparticles
  • LASA indicates light anhydrous silicic acid
  • the poorly water-soluble drug used in the present invention is not particularly limited as long as it is a drug that is hardly soluble in water.
  • the poorly water-soluble drug those having a solubility in water of 1 g / 100 mL or less at 36 ° C. are preferable from the viewpoint of expression of the solubility improvement effect.
  • poorly water-soluble drugs include gastrointestinal analgesics, antacids, analgesics, anti-inflammatory agents, anti-inflammatory / analgesic / antipyretic agents, anti-inflammatory agents, antibacterial agents, antifungal agents, antianginal agents, inorganic preparations Peptic ulcer, coronary vasodilator, peripheral and cerebral vasodilator, anti-infective, anxiolytic, neuroleptic, central nervous system stimulant, antidepressant, antihistamine, antidiarrheal, laxative, Nutritional supplements, cholesterol-lowering agents, antipruritics, anti-bitter remedies, cardiac rhythm movement drugs, arterial hypertension drugs, anti-migraine drugs, blood coagulation drugs, thyroid dysfunction drugs, diuretics, appetite suppressants Anti-asthma, expectorant, antitussive, antipruritic, mucus regulator, antiemetic, uric acid excretion, gout, arrhythmia, hyperlipidemia, bronchodilator
  • Particularly preferred poorly water-soluble drugs include ibuprofen, ketoprofen, spironolactone, furosemide, dipyridamole, mefenamic acid, piroxicam, trichlormethiazide, pindolol and the like. Of these, it is particularly preferable to use ibuprofen.
  • the average particle size of the poorly water-soluble drug used in the present invention is preferably 100 ⁇ m or less, preferably 1 to 100 ⁇ m from the viewpoint of increasing the dissolution property from the granulated product and the surface area.
  • a thickness of 100 ⁇ m is particularly preferable.
  • Examples of the fluidizing agent used in the present invention include light anhydrous silicic acid, hydrous silicic acid, talc, magnesium stearate, lactose and the like. These fluidizing agents may be commercially available.
  • light anhydrous silicic acid such as AdSolider 101 (manufactured by Freund Sangyo Co., Ltd.), Aerosil 200, Aerosil 300 (manufactured by Nippon Aerosil Co., Ltd.), AdSolider 102 (manufactured by Freund Sangyo Co., Ltd.), Carplex # 67, # And hydrous silicon dioxide such as 80, # 100, # 1120 (manufactured by Shionogi Pharmaceutical Co., Ltd.).
  • light anhydrous silicic acid and hydrous silicon dioxide are preferable, and light anhydrous silicic acid is particularly preferable.
  • the fluidizing agent may be used alone or in combination as necessary.
  • a mixture containing 100 parts by weight of the poorly water-soluble drug and 1 to 5 parts by weight of a fluidizing agent is added to a fluidized bed granulator.
  • a fluidizing agent is 1 to 4 parts by weight, more preferably 1 to 3 parts by weight with respect to 100 parts by weight of the poorly water-soluble drug.
  • a small amount of lubricant may be added to the mixture containing the poorly water-soluble drug and the fluidizing agent, but it is preferable not to add them.
  • an aqueous solution or water-containing alcohol solution containing 1 to 10% by weight of a water-soluble polymer is sprayed at a spraying air speed of 300 to 900 m / sec in a fluidized bed granulator for coating.
  • the water-soluble polymer used here include hydroxypropylmethylcellulose (hereinafter sometimes referred to as HPMC), hydroxypropylcellulose (hereinafter sometimes referred to as HPC), and polyvinylpyrrolidone (hereinafter referred to as PVP).
  • HPMC hydroxypropylmethylcellulose
  • HPC hydroxypropylcellulose
  • PVP polyvinylpyrrolidone
  • Macrogol methylcellulose
  • pullulan polyvinyl alcohol
  • sodium carboxymethylcellulose hydroxyethylcellulose
  • methylhydroxyethylcellulose methylhydroxyethylcellulose
  • Commercially available water-soluble polymers may be used.
  • hydroxypropyl methylcellulose such as trade names (hereinafter the same) TC-5E, TC-5M, TC-5R, TC-5S, Metroles 90SH, Metrows 65SH (manufactured by Shin-Etsu Chemical Co., Ltd.); HPC-L, HPC- Hydroxypropyl cellulose such as SL, HPC-SSL, HPC-M, HPC-H (manufactured by Nippon Soda Co., Ltd.); polyvinylpyrrolidone such as PVP-K30, PVP-K90 (manufactured by BASF Takeda Vitamin Co., Ltd.), etc. Can be mentioned.
  • water-soluble polymer hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone are preferable, and hydroxypropylmethylcellulose and hydroxypropylcellulose are particularly preferable.
  • the water-soluble polymer may be used alone or in combination as necessary.
  • the water-containing alcohol used here is preferably a water-containing alcohol containing 90% by weight or less of a lower alcohol such as ethanol or isopropanol, and particularly preferably water-containing ethanol.
  • concentration of the water-soluble polymer in this aqueous solution or aqueous alcohol solution is preferably 1 to 10% by weight, more preferably 2.5 to 10% by weight, and particularly preferably 2.5 to 5% by weight.
  • the amount of these aqueous solutions or water-containing alcohol solutions used is 0.9 to 2000 parts by weight, more preferably 2 to 1000 parts by weight, especially 2 to 500 parts by weight, based on 100 parts by weight of the poorly water-soluble drug. This is preferable.
  • the amount of water-soluble polymer used is 0.1 to 20 parts by weight, more preferably 0.1 to 15 parts by weight, particularly 0.5 to 11 parts by weight, based on 100 parts by weight of the poorly water-soluble drug. This is preferable.
  • the spray air velocity of the aqueous solution or hydrous alcohol solution for coating is 300 to 900 m / sec in order to uniformly coat a small amount of water-soluble polymer on the hardly water-soluble drug particles.
  • the speed is higher than 900 m / sec, the poorly water-soluble drug particles are broken, resulting in aggregation and the like, and a desired fine particle granule cannot be obtained.
  • the speed is lower than 300 m / sec, aggregation, adhesion, excessive granulation, and the like occur, and a desired fine particle granulated product cannot be obtained.
  • a more preferable spray air velocity is 300 to 750 m / sec, and further preferably 300 to 600 m / sec. At this time, it is preferable to use a nozzle that generates fine mist even at a weak spraying air speed and adjust the liquid speed to generate a mist smaller than the average particle diameter of the drug.
  • the atomizing air speed is initially 300 to 450 m / sec and then 450 to 600 m / sec.
  • the ratio of the time of the low speed spray to the high speed spray is preferably 1:20 to 5: 5, particularly 1:10 to 3: 7.
  • Such a fluidized bed granulation apparatus includes a processing container, a draft tube disposed inside the processing container, and a crushing mechanism that disperses the aggregation of the powder particles by a mechanical crushing force.
  • the fluidized gas introduced from the bottom of the processing vessel raises the space between the inner wall of the processing vessel and the draft tube to the powder particles in the processing vessel, and the inside of the draft tube Form a fluidized bed that circulates in the descending direction
  • the agglomeration of the powder particles descending along the inside of the draft tube is dispersed by the crushing mechanism (Japanese Patent Laid-Open No. 2004-148291), for example, a fine particle coating apparatus manufactured by POWREC (Super Fine Processor; hereinafter referred to as SFP).
  • a part can also be removed and used as needed. For example, when a low melting point drug such as ibuprofen is handled, the desired fine particles may be obtained by removing the screen and smoothing the flow.
  • a fine granulated product having an average particle size of 0.2 to 5 times that of the raw material poorly water-soluble drug can be obtained.
  • the resulting fine particle granule is uniformly coated with a small amount of water-soluble polymer on the poorly water-soluble drug particles, so that the dissolution property of the poorly water-soluble drug is good and the masking effect such as bitterness is also good.
  • a poorly water-soluble drug has a sublimation effect (for example, ibuprofen)
  • sublimation can be suppressed.
  • a more preferable average particle diameter is 0.2 to 5 times, more preferably 0.2 to 3 times that of the raw material poorly water-soluble drug.
  • the average particle size of the obtained fine particle granule may be 0.2 to 5 times the raw material poorly water-soluble drug as described above, but is 15 to 200 ⁇ m, more preferably 15 to 150 ⁇ m, particularly 15 to 100 ⁇ m. Is preferred.
  • the average particle diameter can be measured by a sieving method or a laser diffraction particle size distribution measuring apparatus.
  • the form of the fine particle granule obtained by the present invention is a form in which a water-soluble polymer is coated on a primary particle, that is, one poorly water-soluble drug particle from the viewpoint of increasing the dissolution property and surface area of the poorly water-soluble drug. Is preferred.
  • a drug other than the poorly water-soluble drug and components usually used in solid preparations are appropriately selected depending on the purpose. May be blended.
  • examples include excipients such as starch, calcium carbonate, calcium sulfate, crystalline cellulose, and plant powder, coloring agents, flavoring agents, flavoring agents, light blocking agents, flavoring agents, and sweetening agents.
  • the particulate granule produced in this way has good fluidity and improved dissolution, so that it can be used as a powder as it is, but it can be used as a granule, capsule, etc.
  • a fast-dissolving tablet-type pharmaceutical preparation can be easily produced.
  • solid pharmaceutical preparations obtained using the fine granulated product of the present invention include granules, powders, tablets, capsules and the like.
  • further components normally used in solid preparations for example, excipients such as starch, calcium carbonate, calcium sulfate, crystalline cellulose, plant powder, coloring agents, flavoring agents, flavoring agents. , A light blocking agent, a flavoring agent, a sweetening agent, and the like may be blended.
  • HPMC TC-5E manufactured by Shin-Etsu Chemical Co., Ltd.
  • Macrogol 6000 Nippon Yushi Co., Ltd. PEG # 6000
  • the spraying air speed at this time was 300 m / sec when the coating liquid amount was 0 to 280 g, 450 m / sec for 280 to 1400 g, and the liquid speed was 1 g / min. Thereby, fine particles having an average particle diameter of about 50 ⁇ m were obtained.
  • Example 2 679 g of Ibuprofen (IBSFPROFEN 25 average particle diameter: about 26 ⁇ m) and 21 g of light anhydrous silicic acid (Freund Sangyo Co., Ltd. Adsolider 101) were mixed in a plastic bag, then passed through a 60M sieve and again in a plastic bag. Mixed. The mixed powder was coated with SFP.
  • the spraying air speed at this time was 300 m / sec, and the liquid speed was 1 g / min. Thereby, fine particles having an average particle diameter of about 120 ⁇ m were obtained.
  • Example 3 679 g of Ibuprofen (IBSFPROFEN 25 average particle diameter: about 26 ⁇ m) and 21 g of light anhydrous silicic acid (Freund Sangyo Co., Ltd. Adsolider 101) were mixed in a plastic bag, then passed through a 60M sieve and again in a plastic bag. Mixed. The mixed powder was coated with SFP.
  • the spraying air speed at this time was 450 m / sec, and the liquid speed was 1 g / min. Thereby, fine particles having an average particle diameter of about 50 ⁇ m were obtained.
  • Comparative Example 1 693 g of Ibuprofen (IBSF PROFEN 25 average particle size; approximately 26 ⁇ m) manufactured by BASF and 7 g of light anhydrous silicic acid (Adsolider 101 manufactured by Freund Sangyo Co., Ltd.) were mixed lightly in a plastic bag, then passed completely through a 60M sieve and again in a plastic bag. Mixed. The mixed powder was coated with SFP. As the coating solution, 1400 g of a 10 wt% HPMC (TC-5E manufactured by Shin-Etsu Chemical Co., Ltd.) aqueous solution was used. The spraying air velocity at this time was 900 m / sec, and the liquid velocity was 1 g / min.
  • IBSF PROFEN 25 average particle size; approximately 26 ⁇ m 693 g of Ibuprofen (IBSF PROFEN 25 average particle size; approximately 26 ⁇ m) manufactured by BASF and 7 g of light anhydrous silicic acid (Adsolider 101 manufactured by Freund San
  • Comparative Example 2 693 g of Ibuprofen (IBSF PROFEN 25 average particle size; approximately 26 ⁇ m) manufactured by BASF and 7 g of light anhydrous silicic acid (Adsolider 101 manufactured by Freund Sangyo Co., Ltd.) were mixed lightly in a plastic bag, then passed completely through a 60M sieve and again in a plastic bag. Mixed. The mixed powder was coated with a Wurster fluidized bed granulator (coating apparatus Small Particle Coater; hereinafter referred to as SPC) manufactured by POWREC. As the coating solution, 1400 g of a 10 wt% HPMC (TC-5E manufactured by Shin-Etsu Chemical Co., Ltd.) aqueous solution was used.
  • the spraying air velocity at this time was 900 m / sec, and the liquid velocity was 1 g / min. Thereby, particles having an average particle diameter of about 220 ⁇ m were obtained. When the obtained particles were observed with a scanning electron microscope, it was found that the ibuprofen particles were crushed and not uniformly coated, and the ibuprofen particles were present on the surface.
  • Test example 1 A cross-sectional photograph of the obtained particles was taken under the following conditions. After creating a section by Focused Ion beam (hereinafter referred to as FIB), the section was photographed with a scanning electron microscope (Dual Beam FIB Helios 600, FEI, USA). At this time, since sublimable ibuprofen was used as the core particle, a cross section was prepared using FIB after creating a condition of ⁇ 130 ° C. with liquid nitrogen. The results are shown in FIG. As is clear from FIG. 1, it was confirmed that the fine particles obtained in Example 1 were primary particles in which the surface of ibuprofen particles was coated with a water-soluble polymer.
  • Test example 3 50 mg of each of Examples 1 to 3 and Comparative Examples 1 and 2 were weighed, and the time until bitterness was felt in the oral cavity was measured. In addition, after the test was completed, the oral cavity was rinsed with water three times or more, and between the tests, the test was opened for 15 minutes or more.
  • Test example 4 500 mg each of Examples 1 to 3 and Comparative Examples 1 and 2 were weighed, spread evenly on the bottom of a transparent No. 1 standard bottle, and stoppered with a metal cap. After storing in a 50 ° C. constant temperature room for 3 days, the degree of cloudiness on the wall of the bottle was compared.
  • Ibuprofen has a sublimation property, and when it is stored at a high temperature, it usually causes the inner wall of the glass bottle to become cloudy white. Under the above conditions, the samples of Examples 1 to 3 did not cloud the inner wall of the glass bottle.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un procédé pour produire des particules contenant un médicament faiblement hydrosoluble en tant que substance active tout en réduisant au minimum les quantités des composants additifs autres que le médicament faiblement hydrosoluble, les particules contenant le médicament ayant une hydrosolubilité améliorée et ayant été masquées en terme d'amertume ou similaire possédée par la plupart des médicaments faiblement hydrosolubles. Le procédé pour produire des granules de particules fines est caractérisé par la pulvérisation, dans un granulateur à lit fluidisé, d'une solution aqueuse ou d'une solution hydroalcoolique contenant de 1 à 10 % en poids de polymère hydrosoluble par rapport à un mélange comprenant 100 parties en poids d'un médicament faiblement hydrosoluble ayant un diamètre de particule moyen de 100 µm ou moins et de 1 à 5 parties en poids d'un agent fluidisant, à une vitesse d'air de pulvérisation de 300 à 900 m/s pour enrober le mélange avec 0,1 à 20 parties en poids de la matière solide contenue dans la solution de polymère hydrosoluble ou solution hydroalcoolique. Les granules ont un diamètre de particule moyen de 0,2 à 5 fois celui du médicament faiblement hydrosoluble utilisé en tant que matériau de départ.
PCT/JP2011/057022 2010-03-31 2011-03-23 Procédé pour produire des granules de particules fines contenant un médicament faiblement hydrosoluble WO2011125500A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013231091A (ja) * 2013-08-23 2013-11-14 Toyama Chem Co Ltd トスフロキサシンを含有する粒状固形製剤
JP2013231090A (ja) * 2013-08-23 2013-11-14 Toyama Chem Co Ltd トスフロキサシンおよびポリビニルピロリドンを含有する粒状固形製剤

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008709A1 (fr) * 1992-10-09 1994-04-28 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Procede de production de granules fins
JP2001019635A (ja) * 1999-07-07 2001-01-23 Nitto Yakuhin Kogyo Kk 苦味を有する難水溶性粉粒体を核物質として含むマイクロカプセルおよびその製造方法、ならびに係るマイクロカプセルを含有する固形製剤
JP2006507036A (ja) * 2002-08-14 2006-03-02 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー 薬剤粒子のコーティング方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008709A1 (fr) * 1992-10-09 1994-04-28 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Procede de production de granules fins
JP2001019635A (ja) * 1999-07-07 2001-01-23 Nitto Yakuhin Kogyo Kk 苦味を有する難水溶性粉粒体を核物質として含むマイクロカプセルおよびその製造方法、ならびに係るマイクロカプセルを含有する固形製剤
JP2006507036A (ja) * 2002-08-14 2006-03-02 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー 薬剤粒子のコーティング方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013231091A (ja) * 2013-08-23 2013-11-14 Toyama Chem Co Ltd トスフロキサシンを含有する粒状固形製剤
JP2013231090A (ja) * 2013-08-23 2013-11-14 Toyama Chem Co Ltd トスフロキサシンおよびポリビニルピロリドンを含有する粒状固形製剤

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