WO2011125500A1 - Process for producing granules of fine particles containing sparingly water-soluble drug - Google Patents

Process for producing granules of fine particles containing sparingly water-soluble drug Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
water
soluble drug
soluble
weight
average particle
Prior art date
Application number
PCT/JP2011/057022
Other languages
French (fr)
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 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/en
Publication of WO2011125500A1 publication Critical patent/WO2011125500A1/en

Links

Images

Classifications

    • 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.

Abstract

A process for producing particles containing a sparingly water-soluble drug as an active ingredient is provided while minimizing the amounts of the additive ingredients other than the sparingly water-soluble drug, the drug-containing particles having improved water solubility and having been masked with respect to the bitterness or the like possessed by most sparingly water-soluble drugs. The process for producing granules of fine particles is characterized by spraying, in a fluidized bed granulator, an aqueous solution or hydrous-alcohol solution containing 1-10 wt.% water-soluble polymer over a mixture comprising 100 parts by weight of a sparingly water-soluble drug having an average particle diameter of 100 µm or less and 1-5 parts by weight of a fluidizing agent, at a spray air velocity of 300-900 m/sec to coat the mixture with 0.1-20 parts by weight of the solid matter contained in the water-soluble-polymer solution or hydrous-alcohol solution. The granules have an average particle diameter 0.2-5 times that of the sparingly water-soluble drug used as a starting material.

Description

難水溶性薬物含有微粒子造粒物の製造法Method for producing slightly water-soluble drug-containing fine particle granulated product
　本発明は、溶出性に優れた難水溶性薬物含有微粒子造粒物の製造法に関する。 The present invention relates to a process for producing a slightly water-soluble drug-containing fine particle granule having excellent dissolution properties.
　医薬品の有効成分の中には水に難溶性である薬物（難水溶性薬物）がある。当該難水溶性薬物は、製剤からの溶出性及び消化管からの吸収性が十分でない場合が多い。従って、難水溶性薬物の製剤からの溶出性を改善する目的で、微細化、非晶化、固体分散化、包接化等が行われている。また、難水溶性薬物の溶出性改良の技術として、親水性高分子及び溶解性改善剤を用いた固体分散体（特許文献１）、水溶性高分子溶液を噴霧してコーティングする技術（特許文献２）、水溶性高分子及び非イオン性界面活性剤を併用する技術（特許文献３）、難水溶性薬物と流動化剤の混合物を、水溶性高分子溶液を用いて造粒する技術（特許文献４）等が報告されている。 Among the active ingredients of pharmaceuticals, there are drugs that are sparingly soluble in water (poorly water-soluble drugs). In many cases, the poorly water-soluble drug is not sufficiently dissolved from the preparation and absorbed from the digestive tract. Therefore, in order to improve the dissolution property of a poorly water-soluble drug from a preparation, refinement, non-crystallization, solid dispersion, inclusion, and the like are performed. In addition, as a technique for improving the dissolution property of a poorly water-soluble drug, a solid dispersion using a hydrophilic polymer and a solubility improver (Patent Document 1) and a technique of coating by spraying a water-soluble polymer solution (Patent Document) 2) Technology that uses a water-soluble polymer and a nonionic surfactant in combination (Patent Document 3), Technology that granulates a mixture of a poorly water-soluble drug and a fluidizing agent using a water-soluble polymer solution (Patent) Reference 4) has been reported.
特開平７－２９１８５４号公報JP 7-291854 A 特開平６－１２８１４７号公報JP-A-6-128147 特開２０００－９５６８２号公報JP 2000-95682 A 特開２００５－８２５０３号公報JP 2005-82503 A
　しかしながら、これら従来の手段により得られた難水溶性薬物含有組成物の粒子径は、造粒化に用いる成分の使用量が多いことから数１００μｍ～数ｍｍにもなり、結果的に薬物の溶出性が十分でないものであった。
　従って、本発明の課題は、有効成分である難水溶性薬物以外の添加成分を極力少なくしつつ、かつ溶出性が改善されるとともに、難水溶性薬物の多くが有している苦味等がマスキングされた難水溶性薬物含有粒子の製造法を提供することにある。 However, the particle diameter of the poorly water-soluble drug-containing composition obtained by these conventional means is several hundred μm 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.
　そこで本発明者は、コーティングに用いる成分、その添加量及びコーティング条件について種々検討した結果、原料難水溶性薬物の粒子径、流動化剤、水溶性高分子及びそのコーティング速度を特定の範囲に設定することにより、原料難水溶性薬物の平均粒子径の５倍以下という微粒子が得られ、得られた微粒子は難水溶性薬物の溶出性に優れているだけでなく、苦味等を良好にマスキングできていることを見出し、本発明を完成した。 Therefore, as a result of various investigations regarding the components used for coating, the amount of addition, and the coating conditions, 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.
　すなわち、本発明は、流動層造粒装置において、平均粒子径が１００μｍ以下の難水溶性薬物１００重量部及び流動化剤１～５重量部を含有する混合物に、１～１０重量％の水溶性高分子を含有する水溶液又は含水アルコール溶液を３００～９００ｍ／ｓｅｃの噴霧空気速度で噴霧して、前記混合物に対して水溶性高分子溶液又は含水アルコール溶液中の固形分重量の０．１～２０重量部をコーティングすることを特徴とする、平均粒子径が原料難水溶性薬物の０．２～５倍である微粒子造粒物の製造法を提供することにある。
　また、本発明は、上記製法により得られる難水溶性薬物含有微粒子造粒物を提供するものである。 That is, 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 μm 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.
　本発明の製造法によれば、原料難水溶性薬物の平均粒子径の０．２～５倍という微粒子でありながら、水溶性高分子が均一かつ十分に難水溶性薬物粒子を被覆した微粒子造粒物が安定して得られる。本発明方法により得られた微粒子造粒物を用いれば、難水溶性薬物の溶出性に優れ、かつ苦味等も改善された医薬製剤を製造することができる。 According to the production method of the present invention, a fine particle structure in which the water-soluble polymer is uniformly and sufficiently coated with the poorly water-soluble drug particles while being fine particles having an average particle size of 0.2 to 5 times the average particle diameter of the raw material poorly water-soluble drug. 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.
実施例１で得られた微粒子のＳＥＭ観察像を示す。左側が微粒子の外観、右側が断面である。The SEM observation image of the microparticles | fine-particles obtained in Example 1 is shown. The left side is the appearance of the fine particles, and the right side is the cross section. 実施例１で得られた微粒子の溶出率曲線を示す。ＬＡＳＡは、軽質無水ケイ酸のことを示し、３％ＬＡＳＡは、イブプロフェンと軽質無水ケイ酸の物理的混合物（イブプロフェン：軽質無水ケイ酸＝９７：３）である。The elution rate curve of the microparticles | fine-particles obtained in Example 1 is shown. LASA indicates light anhydrous silicic acid, and 3% LASA is a physical mixture of ibuprofen and light anhydrous silicic acid (ibuprofen: light anhydrous silicic acid = 97: 3).
　本発明で使用する難水溶性薬物は、水に溶け難い薬物であれば特に限定されない。ここで、難水溶性薬物としては、３６℃において水に対する溶解量が１ｇ／１００ｍＬ以下のものが溶解性改善効果の発現の点から好ましい。
　一般的に、難水溶性薬物としては胃腸鎮痛薬、制酸薬、鎮痛薬、抗炎症剤、抗炎症・鎮痛・解熱剤、消炎剤、抗菌剤、抗真菌剤、抗狭心症薬、無機質製剤、消化性潰瘍治療薬、冠状血管拡張薬、末梢及び脳血管拡張薬、抗感染剤、抗不安剤、神経弛緩薬、中枢神経系刺激薬、抗鬱薬、抗ヒスタミン剤、下痢止め剤、緩下薬、栄養補給剤、コレステロール低下剤、鎮徑剤、抗苦悶剤、心臓律動作動薬、動脈高血圧の治療薬、抗偏頭痛薬、血液凝固作用薬、甲状腺機能不全の治療薬、利尿剤、食欲抑制薬、抗ぜん息剤、去痰薬、鎮該剤、鎮痰剤、粘液調整薬、制吐剤、尿酸***剤、痛風治療剤、不整脈治療剤、高脂血症治療剤、気管支拡張剤、糖尿病用剤、経口避妊薬、乗り物酔い治療剤、前立腺肥大症治療剤、膵炎治療剤、催眠導入剤、催眠鎮静剤、抗リウマチ薬、抗てんかん薬、脳代謝改善剤、抗血小板剤、ビタミン剤等が挙げられる。難水溶性薬物は、単独で用いても良いが、必要により併用しても良い。 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. Here, as 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.
In general, 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, diabetes Oral contraceptives, motion sickness treatment, prostatic hypertrophy treatment, pancreatitis treatment, hypnosis induction agent, hypnosis Agents, antirheumatic agents, antiepileptics, cerebral metabolism improving agents, antiplatelet agents, vitamins and the like. The poorly water-soluble drug may be used alone or in combination as necessary.
　特に好ましい難水溶性薬物として、イブプロフェン、ケトプロフェン、スピロノラクトン、フロセミド、ジピリダモール、メフェナム酸、ピロキシカム、トリクロルメチアジド、ピンドロール等の薬物を挙げることができる。このうち、イブプロフェンを用いるのが特に好ましい。 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.
　本発明で使用する原料難水溶性薬物の平均粒子径は、造粒物からの溶出性、表面積を大きくすると言う観点から１００μｍ以下であるのが好ましく、１～１００μｍであるのが好ましく、１０～１００μｍであるのが特に好ましい。 The average particle size of the poorly water-soluble drug used in the present invention is preferably 100 μm or less, preferably 1 to 100 μm from the viewpoint of increasing the dissolution property from the granulated product and the surface area. A thickness of 100 μm is particularly preferable.
　本発明で使用する流動化剤としては、例えば、軽質無水ケイ酸、含水ケイ酸、タルク、ステアリン酸マグネシウム、乳糖等が挙げられる。これらの流動化剤は、市販のものを使用しても良い。例えば、アドソリダー１０１（フロイント産業（株）製）、アエロジル２００、アエロジル３００（日本アエロジル（株）製）等の軽質無水ケイ酸、アドソリダー１０２（フロイント産業（株）製）、カープレックス♯６７、♯８０、♯１００、♯１１２０（シオノギ製薬（株）製）等の含水二酸化ケイ素等が挙げられる。流動化剤としては、軽質無水ケイ酸、含水二酸化ケイ素が好ましく、特に軽質無水ケイ酸が好ましい。流動化剤は、単独で用いても良いが、必要により併用しても良い。 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. For example, 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.). As the fluidizing agent, 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.
　本発明の製造法においては、前記難水溶性薬物１００重量部及び流動化剤１～５重量部を含有する混合物を、流動層造粒装置に添加する。ここで流動化剤の含有量が多すぎる場合はコーティング層に取り込まれ、溶出の妨げとなり、また少なすぎる場合は、流動性が低下し、コーティングの均一性に問題が出るため、好ましくない。より好ましい流動化剤の使用量は難水溶性薬物１００重量部に対して１～４重量部であり、さらに好ましくは１～３重量部である。 In the production method of the present invention, 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. Here, when the content of the fluidizing agent is too large, it is taken into the coating layer and hinders elution, and when it is too small, the fluidity is lowered and there is a problem in the uniformity of the coating. A more preferable amount of the 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.
　また、難水溶性薬物及び流動化剤を含有する混合物には、さらに少量の滑沢剤を添加してもよいが、添加しないのが好ましい。 Further, 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.
　次に、流動層造粒装置で、１～１０重量％の水溶性高分子を含有する水溶液又は含水アルコール溶液を３００～９００ｍ／ｓｅｃの噴霧空気速度で噴霧してコーティングする。ここで用いられる水溶性高分子としては、ヒドロキシプロピルメチルセルロース（以下、ＨＰＭＣと記載することがある）、ヒドロキシプロピルセルロース（以下、ＨＰＣと記載することがある）、ボリビニルピロリドン（以下、ＰＶＰと記載することがある）、マクロゴール、メチルセルロース、プルラン、ポリビニルアルコール、カルボキシメチルセルロースナトリウム、ヒドロキシエチルセルロース、メチルヒドロキシエチルセルロース等が挙げられる。これらの水溶性高分子は、市販のものを使用しても良い。例えば、商品名（以下同様）ＴＣ－５Ｅ、ＴＣ－５Ｍ、ＴＣ－５Ｒ、ＴＣ－５Ｓ、メトローズ９０ＳＨ、メトローズ６５ＳＨ（信越化学工業（株）製）等のヒドロキシプロピルメチルセルロース；ＨＰＣ－Ｌ、ＨＰＣ－ＳＬ、ＨＰＣ－ＳＳＬ、ＨＰＣ－Ｍ、ＨＰＣ－Ｈ（日本曹達（株）製）等のヒドロキシプロピルセルロース；ＰＶＰ－Ｋ３０、ＰＶＰ－Ｋ９０（ビーエーエスエフ武田ビタミン（株）製）等のポリビニルピロリドン等が挙げられる。
　水溶性高分子としては、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドンが好ましく、特にヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロースが好ましい。水溶性高分子は、単独で用いても良いが、必要により併用しても良い。 Next, 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. Examples of 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). Macrogol, methylcellulose, pullulan, polyvinyl alcohol, sodium carboxymethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, and the like. Commercially available water-soluble polymers may be used. For example, 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.
As the 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.
　ここで使用する含水アルコールとしては、エタノール、イソプロパノール等の低級アルコールを９０重量％以下含有する含水アルコールが好ましく、特に含水エタノールが好ましい。この水溶液又は含水アルコール溶液中の水溶性高分子濃度は１～１０重量％が好ましく、さらに２．５～１０重量％、特に２．５～５重量％が好ましい。 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. The 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.
　これらの水溶液又は含水アルコール溶液の使用量は、難水溶性薬物１００重量部に対し０．９～２０００重量部、さらに２～１０００重量部、特に２～５００重量部であるのが、生産効率の点で好ましい。 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.
　また、水溶性高分子の使用量は、難水溶性薬物１００重量部に対し、０．１～２０重量部、さらに０．１～１５重量部、特に０．５～１１重量部が、生産効率の点で好ましい。 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.
　本発明においては、コーティングするための前記水溶液又は含水アルコール溶液の噴霧空気速度が、３００～９００ｍ／ｓｅｃであることが、難水溶性薬物粒子に少ない量の水溶性高分子を均一にコーティングするうえで重要である。９００ｍ／ｓｅｃよりも速度が高くなると、難水溶性薬物粒子が壊れてしまい、結果として凝集などを生起し、所望の微粒子造粒物が得られない。また、３００ｍ／ｓｅｃよりも速度が低くなると、凝集、付着、過度な造粒等が起こり、所望の微粒子造粒物が得られない。例えばイブプロフェンの場合、平均粒子径約２６μｍの粒子が、平均約５μｍまで破砕が進み、流動性が著しく阻害されたが、３００～９００ｍ／ｓｅｃの噴霧空気速度でコーティング液を噴霧し続けると造粒が始まり、１０～１５μｍまで造粒されると流動性を回復する現象が認められた。より好ましい噴霧空気速度は、３００～７５０ｍ／ｓｅｃ、さらに好ましくは３００～６００ｍ／ｓｅｃである。また、この時、微弱噴霧空気速度でも微細ミストを発生するノズルを使用し、薬物の平均粒子径よりも小さなミストを発生する液速度に調整することが好ましい。
　ここで、噴霧空気速度は、単位時間当たりの噴霧空気量をノズル先端の空気噴出口の断面積で除したものである。例えば、噴霧空気量が１５Ｌ／ｍｉｎで断面積が０．５平方ｍｍであった場合、１５００万立方ｍｍ／ｍｉｎ÷０．５平方ｍｍ＝３０００万ｍｍ／ｍｉｎ＝３万ｍ／ｍｉｎ＝５００ｍ／ｓｅｃとなる。 In the present invention, 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. Is important. When 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. On the other hand, when 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. For example, in the case of ibuprofen, particles having an average particle size of about 26 μm were crushed to an average of about 5 μm, and the fluidity was remarkably impaired. However, if the coating liquid is continuously sprayed at a spray air velocity of 300 to 900 m / sec, granulation is performed. The phenomenon that fluidity was restored when granulation was performed up to 10 to 15 μm was observed. 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.
Here, the atomizing air velocity is obtained by dividing the amount of atomizing air per unit time by the cross-sectional area of the air outlet at the nozzle tip. For example, when the spray air amount is 15 L / min and the cross-sectional area is 0.5 square mm, 15 million cubic mm / min ÷ 0.5 square mm = 30 million mm / min = 30,000 m / min = 500 m / sec.
　また、この噴霧空気速度は、最初３００～４５０ｍ／ｓｅｃとし、次いで４５０～６００ｍ／ｓｅｃとするのがさらに好ましい。このように噴霧空気速度を最初低速とし、次いで高速とすることにより、難水溶性薬物粒子に均一に少量の水溶性高分子を被覆することができる。低速噴霧と高速噴霧の時間の比（低速：高速）は、１：２０～５：５、特に１：１０～３：７が好ましい。 Further, it is more preferable that the atomizing air speed is initially 300 to 450 m / sec and then 450 to 600 m / sec. Thus, by setting the spraying air speed to a low speed first and then to a high speed, the slightly water-soluble polymer particles can be uniformly coated on the poorly water-soluble drug particles. The ratio of the time of the low speed spray to the high speed spray (low speed: high speed) is preferably 1:20 to 5: 5, particularly 1:10 to 3: 7.
　なお、本発明の造粒は、噴霧空気量を前記のように低速に調節することができる流動層造粒装置を用いて行うのが好ましい。このような流動層造粒装置としては、処理容器と、該処理容器の内部に配設されたドラフトチューブと、粉粒体粒子の凝集を機械的な解砕力によって分散する解砕機構とを備え、
　前記処理容器の底部から導入された流動化気体によって、該処理容器内の粉粒体粒子に、該処理容器の内壁と前記ドラフトチューブとの間の空間部を上昇し、前記ドラフトチューブの内部を下降する方向に循環する流動層を形成し、
　前記ドラフトチューブの内部に沿って下降する前記粉粒体粒子の凝集を前記解砕機構によって分散することを特徴とする流動層装置（特開２００４－１４８２９１号公報）、例えばパウレック社製　微粒子コーティング装置（Ｓｕｐｅｒ　Ｆｉｎｅ　Ｐｒｏｃｅｓｓｏｒ；以下ＳＦＰ）が挙げられる。
　また、前記解砕機構であるが、必要に応じて、一部を取り外して使用することもできる。例えば、イブプロフェンの様に低融点の薬物を扱う場合、スクリーンを外し、流動をスムーズにして、操作した方が、所望の微粒子を得られることもある。 In addition, it is preferable to perform the granulation of this invention using the fluidized-bed granulation apparatus which can adjust the amount of spraying air to low speed as mentioned above. 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).
Moreover, although it is the said crushing mechanism, 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.
　このような噴霧速度でコーティングすることにより、平均粒子径が原料難水溶性薬物の０．２～５倍である微粒子造粒物が得られる。得られる微粒子造粒物には、難水溶性薬物粒子上に均一に少量の水溶性高分子が被覆されているため、難水溶性薬物の溶出性が良好であり、苦味などのマスキング効果にも優れている。また、難水溶性薬物に昇華作用がある場合（例えば、イブプロフェン）には、昇華が抑制できる。より好ましい平均粒子径は、原料難水溶性薬物の０．２～５倍であり、さらに好ましくは０．２～３倍である。 By coating at such a spraying rate, 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. Are better. Moreover, when 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.
　得られる微粒子造粒物の平均粒子径は、前記の如く、原料難水溶性薬物の０．２～５倍であればよいが、１５～２００μｍ、さらに１５～１５０μｍ、特に１５～１００μｍであるのが好ましい。 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 μm, more preferably 15 to 150 μm, particularly 15 to 100 μm. Is preferred.
　なお、本発明において平均粒子径は、篩分け法、もしくはレーザー回折式粒度分布測定装置などによって測定することができる。 In the present invention, the average particle diameter can be measured by a sieving method or a laser diffraction particle size distribution measuring apparatus.
　本発明により得られる微粒子造粒物の形態は、難水溶性薬物の溶出性、表面積を大きくすると言う観点から、一次粒子、すなわち、難水溶性薬物粒子１個に水溶性高分子が被覆した形態であるのが好ましい。 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.
　本発明の微粒子造粒物には、難水溶性薬物、流動化剤及び水溶性高分子の他に、難水溶性薬物以外の薬物、さらに固形製剤に通常使用される成分を適宜その目的に応じて配合してもよい。例えば、デンプン、炭酸カルシウム、硫酸カルシウム、結晶セルロース、植物末等の賦形剤、着色剤、矯味剤、矯臭剤、光線遮断剤、香味剤、甘味剤等が挙げられる。 In the fine particle granule of the present invention, in addition to the poorly water-soluble drug, the fluidizing agent and the water-soluble polymer, 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.
　このようにして製造された微粒子状造粒物は、流動性が良く、しかも溶出性が改善されているので、そのまま散剤等として使用できるが、顆粒剤、カプセル剤等にできる他、直接打錠して速溶性の錠剤型医薬製剤を容易に製造することができる。本発明の微粒子状造粒物を用いて得られる固形医薬製剤としては、顆粒剤、散剤、錠剤、カプセル剤等が挙げられる。これらの固形医薬製剤を調製するにあたっては、さらに固形製剤に通常使用される成分、例えば、デンプン、炭酸カルシウム、硫酸カルシウム、結晶セルロース、植物末等の賦形剤、着色剤、矯味剤、矯臭剤、光線遮断剤、香味剤、甘味剤等を配合しても良い。 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. Thus, a fast-dissolving tablet-type pharmaceutical preparation can be easily produced. Examples of solid pharmaceutical preparations obtained using the fine granulated product of the present invention include granules, powders, tablets, capsules and the like. In preparing these solid pharmaceutical preparations, 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.
　次に、実施例を挙げて本発明を具体的に説明するが、本発明はこれに限定されるものではない。 Next, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
実施例１
　イブプロフェン（ＢＡＳＦ製　ＩＢＵＰＲＯＦＥＮ２５　平均粒径；約２６μｍ）６７９ｇと軽質無水ケイ酸（フロイント産業株式会社製　アドソリダー１０１）２１ｇを、ビニール袋にて軽く混合した後、６０Ｍ篩に全通し、ビニール袋にて再度混合した。その混合末をＳＦＰの１型（以下ＳＦＰ－０１）でコーティングを行った。コーティング液は、５重量％（ＨＰＭＣ（信越化学工業（株）製　ＴＣ－５Ｅ）：マクロゴール６０００（日本油脂（株）ＰＥＧ＃６０００）＝１：１）水溶液１４００ｇを用いた。この時の噴霧空気速度は、コーティング液量０～２８０ｇの時、３００ｍ／ｓｅｃ、２８０～１４００ｇは４５０ｍ／ｓｅｃとし、液速度は、１ｇ／ｍｉｎとした。これにより、平均粒子径約５０μｍの微粒子を得た。 Example 1
679 g of Ibuprofen (IBSF PROFEN 25 average particle size; about 26 μm) manufactured by BASF and 21 g of light anhydrous silicic acid (Adsolider 101 manufactured by Freund Sangyo Co., Ltd.) were lightly mixed in a plastic bag, then passed through a 60M sieve and again in a plastic bag. Mixed. The mixed powder was coated with an SFP type 1 (hereinafter SFP-01). The coating solution used was 1400 g of a 5% by weight (HPMC (TC-5E manufactured by Shin-Etsu Chemical Co., Ltd.): Macrogol 6000 (Nippon Yushi Co., Ltd. PEG # 6000) = 1: 1) aqueous solution. 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 μm were obtained.
実施例２
　イブプロフェン（ＢＡＳＦ製　ＩＢＵＰＲＯＦＥＮ２５　平均粒径：約２６μｍ）６７９ｇと軽質無水ケイ酸（フロイント産業株式会社製　アドソリダー１０１）２１ｇを、ビニール袋にて軽く混合した後、６０Ｍ篩に全通し、ビニール袋にて再度混合した。その混合末をＳＦＰでコーティングを行った。コーティング液は、５重量％（ＨＰＭＣ（信越化学工業（株）製　ＴＣ－５Ｅ）：マクロゴール６０００（日本油脂（株）ＰＥＧ＃６０００）＝１：１）水溶液１４００ｇを用いた。この時の噴霧空気速度は、３００ｍ／ｓｅｃとし、液速度は、１ｇ／ｍｉｎとした。これにより、平均粒子径約１２０μｍの微粒子を得た。 Example 2
679 g of Ibuprofen (IBSFPROFEN 25 average particle diameter: about 26 μm) 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 coating solution used was 1400 g of a 5% by weight (HPMC (TC-5E manufactured by Shin-Etsu Chemical Co., Ltd.): Macrogol 6000 (Nippon Yushi Co., Ltd. PEG # 6000) = 1: 1) aqueous solution. 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 μm were obtained.
実施例３
　イブプロフェン（ＢＡＳＦ製　ＩＢＵＰＲＯＦＥＮ２５　平均粒径：約２６μｍ）６７９ｇと軽質無水ケイ酸（フロイント産業株式会社製　アドソリダー１０１）２１ｇを、ビニール袋にて軽く混合した後、６０Ｍ篩に全通し、ビニール袋にて再度混合した。その混合末をＳＦＰでコーティングを行った。コーティング液は、５重量％（ＨＰＭＣ（信越化学工業（株）製　ＴＣ－５Ｅ）：マクロゴール６０００（日本油脂（株）ＰＥＧ＃６０００）＝１：１）水溶液１４００ｇを用いた。この時の噴霧空気速度は、４５０ｍ／ｓｅｃとし、液速度は、１ｇ／ｍｉｎとした。これにより、平均粒子径約５０μｍの微粒子を得た。 Example 3
679 g of Ibuprofen (IBSFPROFEN 25 average particle diameter: about 26 μm) 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 coating solution used was 1400 g of a 5% by weight (HPMC (TC-5E manufactured by Shin-Etsu Chemical Co., Ltd.): Macrogol 6000 (Nippon Yushi Co., Ltd. PEG # 6000) = 1: 1) aqueous solution. 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 μm were obtained.
比較例１
　イブプロフェン（ＢＡＳＦ製　ＩＢＵＰＲＯＦＥＮ２５　平均粒径；約２６μｍ）６９３ｇと軽質無水ケイ酸（フロイント産業株式会社製　アドソリダー１０１）７ｇを、ビニール袋にて軽く混合した後、６０Ｍ篩に全通し、ビニール袋にて再度混合した。その混合末をＳＦＰでコーティングを行った。コーティング液は、１０重量％ＨＰＭＣ（信越化学工業（株）製　ＴＣ－５Ｅ）水溶液１４００ｇを用いた。この時の噴霧空気速度は、９００ｍ／ｓｅｃとし、液速度は、１ｇ／ｍｉｎとした。これにより、平均粒子径約１６０μｍの粒子を得た。
　得られた粒子を走査電顕観察したところ、イブプロフェン粒子が破砕されており、均一にコーティングされず、表面にイブプロフェン粒子が存在することがわかった。 Comparative Example 1
693 g of Ibuprofen (IBSF PROFEN 25 average particle size; approximately 26 μm) 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. Thereby, particles having an average particle diameter of about 160 μm 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.
比較例２
　イブプロフェン（ＢＡＳＦ製　ＩＢＵＰＲＯＦＥＮ２５　平均粒径；約２６μｍ）６９３ｇと軽質無水ケイ酸（フロイント産業株式会社製　アドソリダー１０１）７ｇを、ビニール袋にて軽く混合した後、６０Ｍ篩に全通し、ビニール袋にて再度混合した。その混合末をワースター式流動層造粒機（パウレック社製　コーティング装置Ｓｍａｌｌ　Ｐａｒｔｉｃｌｅ　Ｃｏａｔｅｒ；以下ＳＰＣ）でコーティングを行った。コーティング液は、１０重量％ＨＰＭＣ（信越化学工業（株）製　ＴＣ－５Ｅ）水溶液１４００ｇを用いた。この時の噴霧空気速度は、９００ｍ／ｓｅｃとし、液速度は、１ｇ／ｍｉｎとした。これにより、平均粒子径約２２０μｍの粒子を得た。
　得られた粒子を走査電顕観察したところ、イブプロフェン粒子が破砕されており、均一にコーティングされず、表面にイブプロフェン粒子が存在することがわかった。 Comparative Example 2
693 g of Ibuprofen (IBSF PROFEN 25 average particle size; approximately 26 μm) 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 μm 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.
試験例１
　得られた粒子の断面写真の撮影を以下の条件で行った。Ｆｏｃｕｓｅｄ　Ｉｏｎ　ｂｅａｍ（以下ＦＩＢ）によって断面を作製した後、走査型電子顕微鏡（Ｄｕａｌ　Ｂｅａｍ　ＦＩＢ　Ｈｅｌｉｏｓ６００、ＦＥＩ、ＵＳＡ）で、断面撮影を行った。なお、この時、昇華性のあるイブプロフェンを核粒子としたため、液体窒素にて－１３０℃の条件を作り出した上で、ＦＩＢを用いて断面を作成した。
　結果を図１に示す。図１から明らかなように、実施例１で得られた微粒子は、イブプロフェン粒子の表面を水溶性高分子が被覆した一次粒子であることが確認された。 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.
試験例２
　実施例１で得られた微粒子の溶出試験を以下の条件で行った。パドル法５０ｒｐｍ、試験液（９００ｍＬ）は、精製水を用いた。イブプロフェンと軽質無水ケイ酸の物理的混合物重量に対して、噴霧した水溶性高分子溶液又は含水アルコール溶液中の固形分重量の比率をパーセンテージで示した。また、３％ＬＡＳＡは、イブプロフェンと軽質無水ケイ酸の物理的混合物（イブプロフェン：軽質無水ケイ酸＝９７：３）である。
　結果を図２に示す。図２に示すように、実施例１で得られた微粒子は、良好な溶出性を示した。 Test example 2
The dissolution test of the fine particles obtained in Example 1 was performed under the following conditions. The paddle method 50 rpm and the test liquid (900 mL) used purified water. The ratio of the solid content weight in the sprayed water-soluble polymer solution or hydrous alcohol solution to the physical mixture weight of ibuprofen and light anhydrous silicic acid was shown as a percentage. 3% LASA is a physical mixture of ibuprofen and light anhydrous silicic acid (ibuprofen: light anhydrous silicic acid = 97: 3).
The results are shown in FIG. As shown in FIG. 2, the fine particles obtained in Example 1 showed good elution properties.
試験例３
　実施例１～３、比較例１、２を５０ｍｇずつ秤量し、口腔内にて苦味を感じるまでの時間を測定した。なお、試験終了後、３回以上口腔内を水ですすぎ、試験と試験の間は、１５分以上開けて行った。 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.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　　○・・・１分以上苦味を感じなかった。
　　△・・・３０秒～１分の間に苦味を感じた。
　　×・・・３０秒以内に苦みを感じた。 ○ ... I did not feel bitterness for more than 1 minute.
Δ: Bitterness was felt between 30 seconds and 1 minute.
X: I felt bitter within 30 seconds.
　実施例１～３は、比較例１、２と比較して明らかに苦みに対するマスキング効果が高くなった。 Examples 1 to 3 clearly had a higher masking effect on bitterness than Comparative Examples 1 and 2.
試験例４
　実施例１～３、比較例１、２を５００ｍｇずつ秤量し、透明１号規格ビンの底面に均一に広げ、金属キャップにて栓をした。５０℃恒温室にて３日間保管後、ビンの壁面の曇りの程度を比較した。 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.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　　－・・・・・全く曇りを認めなかった。
　　±・・・・・ほとんど曇りを認めなかった。
　　＋・・・・・わずかに曇りを認めた。
　　＋＋・・・・曇りを認めた。
　　＋＋＋・・・著しい曇りを認めた。 -... No cloudiness was observed.
±: Almost no cloudiness was observed.
+: Slightly cloudy was observed.
++ ... Cloudiness was recognized.
++++ Significant cloudiness was observed.
　イブプロフェンは、昇華性を有しており、通常、高い温度で保存するとガラス瓶の内壁などを白く曇らせる原因となっている。以上の条件で、実施例１～３の検体は、ガラス瓶の内壁を曇らせることはなかった。 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.

Claims (4)

  1. 　流動層造粒装置において、平均粒子径が１００μｍ以下の難水溶性薬物１００重量部及び流動化剤１～５重量部を含有する混合物に、１～１０重量％の水溶性高分子を含有する水溶液又は含水アルコール溶液を３００～９００ｍ／ｓｅｃの噴霧空気速度で噴霧して、前記混合物に対して水溶性高分子溶液又は含水アルコール溶液中の固形分重量の０．１～２０重量部コーティングすることを特徴とし、平均粒子径が原料難水溶性薬物の０．２～５倍である微粒子造粒物の製造法。 In a fluidized bed granulator, an aqueous solution containing 1 to 10% by weight of a water-soluble polymer in a mixture containing 100 parts by weight of a poorly water-soluble drug having an average particle size of 100 μm or less and 1 to 5 parts by weight of a fluidizing agent Alternatively, the water-containing alcohol solution is sprayed at a spray air velocity of 300 to 900 m / sec, and the mixture is coated with 0.1 to 20 parts by weight of the solid content in the water-soluble polymer solution or the water-containing alcohol solution. A process for producing a granulated fine particle characterized in that the average particle size is 0.2 to 5 times that of a raw material poorly water-soluble drug.
  2. 　噴霧条件が、最初３００～４５０ｍ／ｓｅｃの速度、次いで４５０～６００ｍ／ｓｅｃの速度で噴霧するものである請求項１記載の微粒子造粒物の製造法。 2. The method for producing a granulated granule according to claim 1, wherein the spraying condition is that spraying is initially performed at a speed of 300 to 450 m / sec and then at a speed of 450 to 600 m / sec.
  3. 　原料難水溶性薬物の平均粒子径が１０～１００μｍであり、得られる微粒子造粒物の平均粒子径が１５～２００μｍである請求項１又は２記載の製造法。 3. The production method according to claim 1, wherein the raw material poorly water-soluble drug has an average particle size of 10 to 100 μm, and the fine particle granule obtained has an average particle size of 15 to 200 μm.
  4. 　請求項１～３のいずれか１項記載の方法によって得られる難水溶性薬物含有微粒子造粒物。 A slightly water-soluble drug-containing fine particle granulated product obtained by the method according to any one of claims 1 to 3.
PCT/JP2011/057022 2010-03-31 2011-03-23 Process for producing granules of fine particles containing sparingly water-soluble drug WO2011125500A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2012509421A JP5825686B2 (en) 2010-03-31 2011-03-23 Method for producing slightly water-soluble drug-containing fine particle granulated product

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2010-083100 2010-03-31
JP2010083100 2010-03-31

Publications (1)

Publication Number Publication Date
WO2011125500A1 true WO2011125500A1 (en) 2011-10-13

Family

ID=44762454

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2011/057022 WO2011125500A1 (en) 2010-03-31 2011-03-23 Process for producing granules of fine particles containing sparingly water-soluble drug

Country Status (2)

Country Link
JP (1) JP5825686B2 (en)
WO (1) WO2011125500A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013231091A (en) * 2013-08-23 2013-11-14 Toyama Chem Co Ltd Granular solid preparation containing tosufloxacin
JP2013231090A (en) * 2013-08-23 2013-11-14 Toyama Chem Co Ltd Granular solid preparation containing tosufloxacin and polyvinylpyrrolidone

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008709A1 (en) * 1992-10-09 1994-04-28 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Production method for fine granulate
JP2001019635A (en) * 1999-07-07 2001-01-23 Nitto Yakuhin Kogyo Kk Microcapsule containing sparingly water-soluble granule with bitterness as core substance and its production, and solid preparation containing such microcapsule
JP2006507036A (en) * 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 Method for coating drug particles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008709A1 (en) * 1992-10-09 1994-04-28 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Production method for fine granulate
JP2001019635A (en) * 1999-07-07 2001-01-23 Nitto Yakuhin Kogyo Kk Microcapsule containing sparingly water-soluble granule with bitterness as core substance and its production, and solid preparation containing such microcapsule
JP2006507036A (en) * 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 Method for coating drug particles

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013231091A (en) * 2013-08-23 2013-11-14 Toyama Chem Co Ltd Granular solid preparation containing tosufloxacin
JP2013231090A (en) * 2013-08-23 2013-11-14 Toyama Chem Co Ltd Granular solid preparation containing tosufloxacin and polyvinylpyrrolidone

Also Published As

Publication number Publication date
JP5825686B2 (en) 2015-12-02
JPWO2011125500A1 (en) 2013-07-08

Similar Documents

Publication Publication Date Title
JP4219988B2 (en) Fenofibrate pharmaceutical composition having high bioavailability and method for preparing the same
TWI422375B (en) Medicinal preparation having a superior light stability
JP7124107B2 (en) Porous silica particle composition
JP2002524413A (en) A novel solid dosage form of nanoparticulate naproxen
JPH07508509A (en) Gastroprotected stable omeprazole composition in the form of microgranules and method for producing the same
US5965167A (en) Dosage units
JP5160423B2 (en) Method for producing spherical elementary granules containing readily water-soluble drug
WO2012005359A1 (en) Orally disintegrating tablet
WO2009101656A1 (en) Delayed release preparation
JP2008231029A (en) Bitter taste-masking preparation
JP5825686B2 (en) Method for producing slightly water-soluble drug-containing fine particle granulated product
JPH0776517A (en) Composition for medicine
WO2012036078A1 (en) Drug-containing film-coated particles in which unpleasant taste is masked
WO2009101658A1 (en) Timed-release pharmaceutical preparation
JP4575654B2 (en) Pharmaceutical composition with improved solubility and fluidity
JP4716063B2 (en) Unpleasant taste masking particles and oral preparations containing the same
JP4999297B2 (en) High content terbinafine hydrochloride small tablets
FI95776C (en) Method for preparing low dose controlled release aspirin tablets
JP2006206449A (en) Powder for coating, method for producing the same and preparation containing powder for coating
JP2006327943A (en) Taste-masked tablet suppressed with delay of elution over time
JP2011225468A (en) Solid formulation
JP2020180101A (en) Method for Producing Levetiracetam-Containing Pharmaceutical Composition
JP2947841B2 (en) Sustained-release solid preparation
JP2022103591A (en) Timed-releasable granules and applications thereof
EP1438960B2 (en) Compostion of itraconazole dispersed in a hydrophilic polymer having enhanced bioavailability

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11765401

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2012509421

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11765401

Country of ref document: EP

Kind code of ref document: A1