JP4575654B2 - Pharmaceutical composition with improved solubility and fluidity - Google Patents

Pharmaceutical composition with improved solubility and fluidity Download PDF

Info

Publication number
JP4575654B2
JP4575654B2 JP2003313853A JP2003313853A JP4575654B2 JP 4575654 B2 JP4575654 B2 JP 4575654B2 JP 2003313853 A JP2003313853 A JP 2003313853A JP 2003313853 A JP2003313853 A JP 2003313853A JP 4575654 B2 JP4575654 B2 JP 4575654B2
Authority
JP
Japan
Prior art keywords
water
pharmaceutical composition
weight
soluble
poorly water
Prior art date
Legal status (The legal status 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 status listed.)
Expired - Lifetime
Application number
JP2003313853A
Other languages
Japanese (ja)
Other versions
JP2005082503A (en
JP2005082503A5 (en
Inventor
英芳 神戸
敏明 倉住
悌治 村田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SSP Co Ltd
Original Assignee
SSP Co Ltd
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
Priority to JP2003313853A priority Critical patent/JP4575654B2/en
Application filed by SSP Co Ltd filed Critical SSP Co Ltd
Priority to CNB2004800245287A priority patent/CN100389750C/en
Priority to KR1020067002247A priority patent/KR20060119860A/en
Priority to TW093126705A priority patent/TWI344376B/en
Priority to PCT/JP2004/012827 priority patent/WO2005023222A1/en
Publication of JP2005082503A publication Critical patent/JP2005082503A/en
Publication of JP2005082503A5 publication Critical patent/JP2005082503A5/ja
Priority to HK06113473A priority patent/HK1092711A1/en
Application granted granted Critical
Publication of JP4575654B2 publication Critical patent/JP4575654B2/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • 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
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/1611—Inorganic compounds

Description

本発明は、難水溶性薬物の溶解性と流動性が改善された医薬組成物に関する。   The present invention relates to a pharmaceutical composition having improved solubility and fluidity of a poorly water-soluble drug.

近年、医薬品として開発される薬物は、水に難溶性であることが多い。この難水溶性薬物は、バイオアベイラビリティーに問題があり、吸収性を向上させる必要がある。従来から、難水溶性薬物の溶解性は、微細化、非晶化、固体分散化、包接化等によって改善されていた。   In recent years, drugs developed as pharmaceuticals are often poorly soluble in water. This poorly water-soluble drug has a problem in bioavailability, and it is necessary to improve the absorbability. Conventionally, the solubility of poorly water-soluble drugs has been improved by miniaturization, amorphization, solid dispersion, inclusion, and the like.

難水溶性薬物を親水性高分子及び溶解性改善剤と共に水性溶媒の存在下で粉砕後水分を除去して得た固体分散体は、通常の固体分散体とは異なる溶解挙動を示すこと、すなわち、水中で難水溶性薬物を含む微細な液滴を生じて分散して急速に溶解することが知られている（特許文献１）。
また、難水溶性薬物の結晶粒子を気中に分散させ水溶性高分子溶液を噴霧しコーティングする方法が知られている（特許文献２）。しかし、この方法は、結晶薬物を気中に分散させた状態で噴霧処理を行う必要があり、実質的には噴霧機構として、中央に結晶薬物粒子の噴出部、その外側に水溶性高分子溶液の噴出部、さらにその外側に圧縮空気の噴出部を配置した同心3重構造のノズル(特許文献３)を装着したジェットコーティング装置という特殊な装置が必要であって、大量生産には対応し難いものである。
また、難水溶性のプロピオン酸系非ステロイド系抗炎症剤と水溶性高分子基材及び非イオン性界面活性剤を含有する易吸収性固形組成物が知られている（特許文献４）。 A solid dispersion obtained by removing water after pulverization of a poorly water-soluble drug with a hydrophilic polymer and a solubility improver in the presence of an aqueous solvent exhibits a dissolution behavior different from that of a normal solid dispersion, that is, It is known that fine droplets containing a poorly water-soluble drug are generated in water and dispersed and rapidly dissolved (Patent Document 1).
Further, a method is known in which crystal particles of a poorly water-soluble drug are dispersed in the air and sprayed with a water-soluble polymer solution for coating (Patent Document 2). However, in this method, it is necessary to perform the spray treatment in a state in which the crystalline drug is dispersed in the air. In practice, the spray mechanism is a spraying portion of the crystalline drug particles at the center and a water-soluble polymer solution at the outside. And a special device called a jet coating device equipped with a concentric triple structure nozzle (Patent Document 3) in which a compressed air ejection portion is arranged on the outside of the ejection portion is difficult, and it is difficult to cope with mass production. Is.
Further, an easily absorbable solid composition containing a hardly water-soluble propionic acid-based non-steroidal anti-inflammatory agent, a water-soluble polymer base material and a nonionic surfactant is known (Patent Document 4).

しかしながら、これらの方法では、適用可能な薬物が限定されることと、溶解性を改善した組成物は流動性が必ずしも良くない。その為、錠剤、カプセル剤、顆粒剤、散剤等の固形製剤を調製するにあたっては、再度造粒し流動性を上げる必要があり、複雑な工程になると同時に、溶解性を改善した難水溶性薬物を再び造粒することにより溶解性を低下させてしまう場合もあって、より広範囲にしかも簡単に難水溶性薬物の溶解性を改善すると同時に流動性を改善する方法の開発が強く望まれている。
特開平７−２９１８５４号公報 特開平６−１２８１４７号公報 特開平３−２７０５９８号公報 特開２０００−９５６８２号公報 However, in these methods, applicable drugs are limited, and a composition with improved solubility does not necessarily have good fluidity. Therefore, when preparing solid preparations such as tablets, capsules, granules, powders, etc., it is necessary to granulate again to increase fluidity, which is a complicated process and a poorly water-soluble drug with improved solubility It is strongly desired to develop a method that improves the solubility of poorly water-soluble drugs at the same time and improves the fluidity at the same time. .
JP 7-291854 A JP-A-6-128147 JP-A-3-270598 JP 2000-95682 A

すなわち、本発明の目的は、より広範囲な難水溶性薬物に適用でき、しかも簡単な製造法で得られる難水溶性薬物の溶解性と流動性が改善された医薬組成物を提供することにある。   That is, an object of the present invention is to provide a pharmaceutical composition which can be applied to a wider range of poorly water-soluble drugs and which has improved solubility and fluidity of the poorly water-soluble drugs obtained by a simple production method. .

本発明者等は、この目的を達成する為に鋭意研究を重ねた結果、難水溶性薬物と流動化剤を予め混合し、これを水溶性高分子の水又は含水アルコール溶液を用いて造粒すると該薬物の溶解性と流動性が改善されることを見出し、本発明を完成した。
すなわち、本発明は、難水溶性薬物と流動化剤の混合物を、水溶性高分子の水又は含水アルコール溶液を用いて造粒することにより得られる造粒物を含有する医薬組成物を提供するものである。
また、本発明は上記医薬組成物を用いて得られる固形医薬製剤を提供するものである。 As a result of intensive research to achieve this object, the present inventors have mixed a poorly water-soluble drug and a fluidizing agent in advance, and granulated this using water or a hydrous alcohol solution of a water-soluble polymer. Then, it discovered that the solubility and fluidity | liquidity of this drug were improved, and completed this invention.
That is, the present invention provides a pharmaceutical composition containing a granulated product obtained by granulating a mixture of a poorly water-soluble drug and a fluidizing agent using water or a hydrous alcohol solution of a water-soluble polymer. Is.
Moreover, this invention provides the solid pharmaceutical formulation obtained using the said pharmaceutical composition.

本発明の医薬組成物は、難水溶性薬物の水への溶解性及び流動性が優れる。また、流動性に優れるので直接打錠が可能で、難水溶性薬物を含有する速溶性の錠剤等の固形医薬製剤が容易に得られる。   The pharmaceutical composition of the present invention is excellent in solubility and fluidity of a poorly water-soluble drug in water. Moreover, since it is excellent in fluidity | liquidity, direct tableting is possible and solid pharmaceutical preparations, such as a fast dissolving tablet containing a poorly water-soluble drug, are obtained easily.

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、難水溶性とは、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、末梢および脳血管拡張薬、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、鎮咳剤、鎮痰剤、粘液調整薬、制吐剤、尿酸排泄剤、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, poorly water-soluble is preferably one having a solubility in water at 36 ° C. of 1 g / 100 mL or less from the viewpoint of expression of 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 drug, 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 agents, expectorants, towns cough agent,鎮痰agents, mucus regulating agents, antiemetics, uricosuric agents, gout agents, antiarrhythmic agents, antihyperlipidemic agents, bronchodilators, antidiabetic agents, Oral contraceptives, motion sickness treatment, prostatic hypertrophy treatment, pancreatitis treatment, hypnosis induction agent, hypnosis Static 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。   Particularly preferred poorly water-soluble drugs include drugs such as ibuprofen, ketoprofen, spironolactone, furosemide, dipyridamole, mefenamic acid, piroxicam, trichlormethiazide, and pindolol.

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（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。
本発明の医薬組成物における流動化剤の配合量は、難水溶性薬物１００重量部に対して０．０１〜５重量部であるのが好ましく、更に０．０３〜４重量部、特に０．０５〜３重量部であるのが好ましい。 Examples of the fluidizing agent used in the present invention include light anhydrous silicic acid, hydrous silicic acid, talc, magnesium stearate, and lactose. 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 (manufactured by Nippon Aerosil Co., Ltd.), AdSolider 102 (manufactured by Freund Sangyo Co., Ltd.), Carplex # 67, # 80, # Hydrous silicon dioxide such as 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.
The blending amount of the fluidizing agent in the pharmaceutical composition of the present invention is preferably 0.01 to 5 parts by weight, more preferably 0.03 to 4 parts by weight, and particularly preferably 0. It is preferably from 05 to 3 parts by weight.

本発明で使用す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)、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。
本発明の医薬組成物における水溶性高分子の配合量は、難水溶性薬物１００重量部に対して好ましくは０．１〜５０重量部であって、更に０．３〜４０重量部、特に０．５〜３０重量部であるのが好ましい。 Examples of the water-soluble polymer used in the present invention include hydroxypropyl methylcellulose (hereinafter sometimes referred to as HPMC), hydroxypropylcellulose (hereinafter sometimes referred to as HPC), polyvinylpyrrolidone (hereinafter referred to as PVP). May be mentioned), 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- Hydroxypropylcellulose such as SL, HPC-SSL, HPC-M, HPC-H (manufactured by Nippon Soda Co., Ltd.); polyvinyl pyrrolidone 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.
The blending amount of the water-soluble polymer in the pharmaceutical composition of the present invention is preferably 0.1 to 50 parts by weight, more preferably 0.3 to 40 parts by weight, and particularly 0 to 100 parts by weight of the poorly water-soluble drug. It is preferably 5 to 30 parts by weight.

本発明の医薬組成物には、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、更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 pharmaceutical composition of the present invention, in addition to a poorly water-soluble drug, a fluidizing agent, and a water-soluble polymer, a drug other than the poorly water-soluble drug, and further components that are usually used in solid preparations are appropriately used depending on the purpose. You may mix | blend. 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, sweetening agents, and the like.

本発明の医薬組成物は、難水溶性薬物と流動化剤とを混合し、水溶性高分子を水又は含水アルコールに溶解した溶液を用いて造粒することにより製造される。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１０〜９０重量％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。この場合、水溶性高分子は１〜３０重量％溶液として使用するのが好ましく、更に５〜２０重量％溶液、特に５〜１５重量％溶液として使用するのが好ましい。   The pharmaceutical composition of the present invention is produced by mixing a poorly water-soluble drug and a fluidizing agent, and granulating using a solution obtained by dissolving a water-soluble polymer in water or a hydrous alcohol. As the water-containing alcohol used here, a water-containing alcohol containing 10 to 90% by weight of a lower alcohol such as ethanol or isopropanol is preferable, and water-containing ethanol is particularly preferable. In this case, the water-soluble polymer is preferably used as a 1 to 30% by weight solution, more preferably a 5 to 20% by weight solution, particularly preferably a 5 to 15% by weight solution.

使用する造粒装置としては、特に限定はないが、例えば、攪拌型造粒装置（バーチカルグラニュレター）、流動層装置、転動流動装置等が挙げられる。特に、流動層造粒装置が好ましく、例えば、流動層造粒機（マルチプレックス 微粒子コーティング装置ＳＰＣ−０１型）が挙げられる。   The granulating device to be used is not particularly limited, and examples thereof include a stirring granulator (vertical granulator), a fluidized bed device, a rolling fluidizing device, and the like. In particular, a fluidized bed granulator is preferable, and examples thereof include a fluidized bed granulator (multiplex fine particle coating apparatus SPC-01 type).

造粒物は、粒径６３〜５００μｍの粒子が８５重量％以上の微粒子であるのが溶解性及び流動性の改善の点で好ましい。なお、粒子の粒径はふるい分け試験法で測定する。   The granulated product is preferably a fine particle having a particle size of 63 to 500 μm of 85% by weight or more from the viewpoint of improvement of solubility and fluidity. The particle size of the particles is measured by a screening test method.

このようにして製造された粒子状の医薬組成物は、流動性が良く、しかも溶解性が改善されているので、粒子状医薬組成物を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。従って、本発明の医薬組成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、更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 pharmaceutical composition produced in this way has good fluidity and improved solubility, so that the particulate pharmaceutical composition can be used as a powder as it is, but granules, capsules, etc. In addition, it is possible to easily produce tablet-type pharmaceutical preparations that are rapidly dissolved by direct tableting. Accordingly, examples of solid pharmaceutical preparations obtained using the pharmaceutical composition 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, corrigents, 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 粒径：２０〜３３μｍ）１０００ｇと軽質無水ケイ酸（フロイント産業(株)製 アドソリダー１０１）１０ｇを、バーチカルグラニュレーターＶＧ−１０（パウレック製）で混合後、流動層造粒機（マルチプレックス製：微粒子コーティング装置ＳＰＣ−０１型）で１０重量％ＨＰＭＣ（信越化学工業(株)製 ＴＣ−５Ｅ）水溶液５０ｇで造粒し、６３〜５００μｍの粒子が９９．６重量％の微粒子の造粒物を得た。 Example 1
After mixing 1000 g of ibuprofen (BASF IBUPROFEN25 particle size: 20 to 33 μm) and 10 g of light anhydrous silicic acid (Freund Sangyo Co., Ltd. Adsolider 101) with a vertical granulator VG-10 (Pauleck), a fluidized bed granulator Granulated with 50 g of 10 wt% HPMC (TC-5E manufactured by Shin-Etsu Chemical Co., Ltd.) aqueous solution (manufactured by multiplex: fine particle coating apparatus SPC-01 type), and particles of 63 to 500 μm are fine particles of 99.6 wt% A granulated product was obtained.

実施例２
実施例１と同様に、１０重量％ＨＰＭＣ水溶液４００ｇで造粒し、６３〜５００μｍの粒子が９６．２重量％の微粒子の造粒物を得た。 Example 2
In the same manner as in Example 1, granulation was performed with 400 g of a 10 wt% aqueous HPMC solution to obtain a granulated product of 96.2 wt% of 63-500 μm particles.

実施例３
実施例１と同様に、１０重量％ＨＰＭＣ水溶液１０００ｇで造粒し、６３〜５００μｍの粒子が９８．２重量％の微粒子の造粒物を得た。 Example 3
In the same manner as in Example 1, granulation was performed with 1000 g of a 10 wt% aqueous HPMC solution to obtain a granulated product of 98.2 wt% of 63 to 500 μm particles.

比較例１
イブプロフェン１０００ｇ（BASF製 IBUPROFEN25 粒径：２０〜３０μｍ）とアドソリダー１０１ １０ｇを、バーチカルグラニュレーターＶＧ−１０で混合し、粒径６３μｍ以下が９９．７重量％の造粒物を得た。 Comparative Example 1
1000 g of ibuprofen (BASF IBUPROFEN25 particle size: 20 to 30 μm) and Adsolider 101 10 g were mixed with a vertical granulator VG-10 to obtain a granulated product having a particle size of 63 μm or less of 99.7% by weight.

試験例１
実施例１〜３及び比較例１で製造した医薬組成物の難水溶性薬物の溶出量を次の試験法に従って行った。
溶出試験法：日局 溶出試験法（２）第２法（パドル法）試験液：水９００ｍＬにイブプロフェンとして６５ｍｇ含有量の医薬組成物を入れ、１００ｒ／ｍｉｎの回転数で攪拌したとき、難水溶性薬物の溶出量をＵＶ法で測定した。医薬組成物に配合した難水溶性薬物量に対する溶出量の百分率で評価を行った。 Test example 1
The elution amount of the poorly water-soluble drug of the pharmaceutical composition produced in Examples 1 to 3 and Comparative Example 1 was performed according to the following test method.
Dissolution test method: JP Dissolution test method (2) Second method (paddle method) Test solution: When a pharmaceutical composition with a content of 65 mg as ibuprofen is placed in 900 mL of water and stirred at a rotational speed of 100 r / min, it is poorly water-soluble. The elution amount of the sex drug was measured by the UV method. Evaluation was carried out as a percentage of the amount of elution with respect to the amount of poorly water-soluble drug compounded in the pharmaceutical composition.

測定結果を図１に示す。
本発明の医薬組成物（実施例１〜３）はイブプロフェン（難水溶性薬物）の溶出速度が速く、３０分で８０％以上が溶出し溶出性が優れたものであった。 The measurement results are shown in FIG.
The pharmaceutical composition (Examples 1 to 3) of the present invention had a high elution rate of ibuprofen (a poorly water-soluble drug), and 80% or more eluted in 30 minutes and was excellent in elution.

実施例４
イブプロフェン（BASF製 IBUPROFEN50 粒径：４５〜６０μｍ）１０００ｇとアドソリダー１０１ １０ｇを、バーチカルグラニュレーターＶＧ−１０で混合後、微粒子コーティング装置（ＳＰＣ−０１型）で１０重量％ＨＰＭＣ（ＴＣ−５Ｅ）水溶液１０００ｇで微粒子造粒し、６３〜５００μｍの粒子が９７．７重量％の微粒子の造粒物を得た。 Example 4
1000 g of ibuprofen (BASF IBUPROFEN50 particle size: 45 to 60 μm) and Adsolider 101 10 g were mixed with a vertical granulator VG-10, and then 10 g HPMC (TC-5E) aqueous solution 1000 g with a fine particle coating apparatus (SPC-01 type). To obtain a granulated product of 97.7% by weight of 63-500 μm particles.

実施例５
実施例４の１０重量％ＨＰＭＣ（ＴＣ−5Ｅ）水溶液１０００ｇを１０重量％ＨＰＣ（ＨＰＣ−ＳＳＬ）水溶液１０００ｇに代えた他は実施例４と同様にして、６３〜５００μｍの粒子が９８．７重量％の微粒子の造粒物を得た。 Example 5
In the same manner as in Example 4 except that 1000 g of the 10 wt% HPMC (TC-5E) aqueous solution in Example 4 was replaced with 1000 g of the 10 wt% HPC (HPC-SSL) aqueous solution, particles of 63 to 500 μm were 98.7 wt%. % Granulated product was obtained.

比較例２
イブプロフェン（BASF製 IBUPROFEN50 粒径：４５〜６０μｍ）１０００ｇとアドソリダー１０１ １０ｇを、バーチカルグラニュレーターＶＧ−１０で混合し、粒径６３μｍ以下が９７．５重量％の造粒物を得た。 Comparative Example 2
1000 g of ibuprofen (BASF IBUPROFEN50 particle size: 45-60 μm) and Adsolider 101 10 g were mixed with a vertical granulator VG-10 to obtain a granulated product having a particle size of 63 μm or less of 97.5 wt%.

比較例３
実施例４の１０重量％ＨＰＭＣ（ＴＣ−５Ｅ）水溶液１０００ｇを１０重量％乳糖水溶液１０００ｇに代えた他は実施例４と同様にして、６３〜５００μｍの粒子が９７．２重量％の微粒子の造粒物を得た。 Comparative Example 3
In the same manner as in Example 4 except that 1000 g of the 10 wt% HPMC (TC-5E) aqueous solution in Example 4 was replaced with 1000 g of the 10 wt% lactose aqueous solution, 63 to 500 μm particles were produced as 97.2 wt% fine particles. Grains were obtained.

試験例２
試験例１と同様にして実施例４、５及び比較例２、３医薬組成物の溶出試験を行った結果を図２に示す。
本発明の医薬組成物（実施例４、５）は、イブプロフェンの溶出性が顕著に改善されていた。 Test example 2
The results of conducting dissolution tests of Examples 4, 5 and Comparative Examples 2 and 3 pharmaceutical compositions in the same manner as in Test Example 1 are shown in FIG.
In the pharmaceutical composition of the present invention (Examples 4 and 5), the dissolution property of ibuprofen was remarkably improved.

実施例６
ケトプロフェン（米沢浜理薬品工業(株)製）１０００ｇとアドソリダー１０１ １０ｇを、バーチカルグラニュレーターＶＧ−１０で混合後、微粒子コーティング装置（ＳＰＣ−０１型）で１０重量％ＨＰＭＣ（ＴＣ−５Ｅ）水溶液 １０００ｇで微粒子造粒し、６３〜５００μｍの粒子が９７．４重量％の微粒子の造粒物を得た。
比較例４
ケトプロフェン１０００ｇとアドソリダー１０１ １０ｇを、バーチカルグラニュレーターＶＧ−１０（パウレック製）で混合して造粒物を得た。 Example 6
After mixing 1000 g of ketoprofen (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd.) and 10 g of Adsolider 101 with a vertical granulator VG-10, a 10 wt% HPMC (TC-5E) aqueous solution 1000 g with a fine particle coating device (SPC-01 type). To obtain a granulated product of 97.4% by weight of 63-500 μm particles.
Comparative Example 4
A granulated product was obtained by mixing 1000 g of ketoprofen and 10 g of Adsolider 101 with a vertical granulator VG-10 (manufactured by Paulek).

実施例７
スピロノラクトン（コーア商事(株)製）１０００ｇ、アドソリダー１０１ ５ｇ及び１０重量％ＨＰＭＣ（ＴＣ−５Ｅ）水溶液１０００ｇを用い、実施例６と同様にして６３〜５００μｍの粒子が９５．７重量％の微粒子の造粒物を得た。
比較例５
スピロノラクトン１０００ｇとアドソリダー１０１ ５ｇを用い、比較例４と同様にして造粒物を得た。 Example 7
Using spironolactone (manufactured by Koa Shoji Co., Ltd.) 1000 g, Adsolider 1015 g, and 10 wt% HPMC (TC-5E) aqueous solution 1000 g, 63 to 500 μm particles were 95.7 wt% fine particles in the same manner as in Example 6. A granulated product was obtained.
Comparative Example 5
A granulated product was obtained in the same manner as in Comparative Example 4 using 1000 g of spironolactone and 15 g of Adsolider 101.

実施例８
フロセミド（(株)静岡カフェイン工業所製）１０００ｇ、アドソリダー１０１ ５ｇ及び１０重量％ＨＰＭＣ（ＴＣ−５Ｅ）水溶液１０００ｇを用い、実施例６と同様にして６３〜５００μｍの粒子が９６．３重量％の微粒子の造粒物を得た。
比較例６
フロセミド１０００ｇとアドソリダー１０１ ５ｇを用い、比較例４と同様にして造粒物を得た。 Example 8
Using 1000 g of furosemide (manufactured by Shizuoka Caffeine Kogyo Co., Ltd.), Adsolider 1015 g and 1000 g of 10 wt% HPMC (TC-5E) aqueous solution, 63 to 500 μm particles were 96.3% by weight in the same manner as in Example 6. Granules of fine particles were obtained.
Comparative Example 6
A granulated product was obtained in the same manner as in Comparative Example 4 using 1000 g of furosemide and 15 g of Adsolider 101.

実施例９
ジピリダモール（日本シィベルヘグナー(株)製）１０００ｇ、アエロジル２００ １０ｇ及び１０重量％ＨＰＭＣ（ＴＣ−５Ｅ）水溶液１０００ｇを用い、実施例６と同様にして６３〜５００μｍの粒子が９４．２重量％の微粒子の造粒物を得た。
比較例７
ジピリダモール１０００ｇとアエロジル２００ １０ｇを用い、比較例４と同様にして造粒物を得た。 Example 9
Using 1000 g of dipyridamole (manufactured by Nippon Siebel Hegner Co., Ltd.), 10 g of Aerosil 200, and 1000 g of a 10 wt% HPMC (TC-5E) aqueous solution, 63 to 500 μm particles were 94.2 wt% in the same manner as in Example 6. A granulated product of fine particles was obtained.
Comparative Example 7
A granulated product was obtained in the same manner as in Comparative Example 4 using 1000 g of dipyridamole and 10 g of Aerosil 200.

実施例１０
メフェナム酸（(株)静岡カフェイン工業所製）１０００ｇ、アドソリダー１０１ ３ｇ及び１０重量％ＨＰＭＣ（ＴＣ−５Ｅ）水溶液１０００ｇを用い、実施例６と同様にして６３〜５００μｍの粒子が９９．６重量％の微粒子の造粒物を得た。
比較例８
メフェナム酸１０００ｇとアドソリダー１０１ ３ｇを用い、比較例４と同様にして造粒物を得た。 Example 10
1000 g of mefenamic acid (manufactured by Shizuoka Caffeine Kogyo Co., Ltd.), 1313 g of Adsolider 101 and 1000 g of 10 wt% HPMC (TC-5E) aqueous solution were used, and particles of 63 to 500 μm were 99.6 wt. % Granulated product was obtained.
Comparative Example 8
A granulated product was obtained in the same manner as in Comparative Example 4 using 1000 g of mefenamic acid and 13 g of Adsolider 101.

実施例１１
ピロキシカム（尼崎化学合成(株)製）１０００ｇ、アドソリダー１０１ １．０ｇ及び１０重量％ＨＰＭＣ（ＴＣ−５Ｅ）水溶液１０００ｇを用い、実施例６と同様にして６３〜５００μｍの粒子が９６．２重量％の微粒子の造粒物を得た。
比較例９
ピロキシカム１０００ｇとアドソリダー１０１ 1ｇを用い、比較例４と同様にして造粒物を得た。 Example 11
Using 1000 g of piroxicam (manufactured by Amagasaki Chemical Synthesis Co., Ltd.), 1.0 g of Adsolider 101 and 1000 g of a 10 wt% HPMC (TC-5E) aqueous solution, 63 to 500 μm particles were 96.2 wt% in the same manner as in Example 6. Granules of fine particles were obtained.
Comparative Example 9
A granulated product was obtained in the same manner as in Comparative Example 4 using 1000 g of piroxicam and 1101 g of Adsolider 101.

実施例１２
トリクロルメチアジド（日本シィベルヘグナー(株)製）１０００ｇ、アドソリダー１０１ ０．５ｇ及び１０重量％ＨＰＭＣ（ＴＣ−５Ｅ）水溶液１０００ｇを用い、実施例６と同様にして６３〜５００μｍの粒子が９７．９重量％の微粒子の造粒物を得た。
比較例１０
トリクロルメチアジド１０００ｇとアドソリダー１０１ ０．５ｇを用い、比較例４と同様にして造粒物を得た。 Example 12
Using 1000 g of trichloromethiazide (manufactured by Nippon Siebel Hegner Co., Ltd.), 0.5 g of Adsolider 101 and 1000 g of 10 wt% HPMC (TC-5E) aqueous solution, particles of 63 to 500 μm were 97. A granulated product of 9% by weight of fine particles was obtained.
Comparative Example 10
A granulated product was obtained in the same manner as in Comparative Example 4 using 1000 g of trichloromethiazide and 0.5 g of Adsolider 101.

実施例１３
ピンドロール（ダイト(株)製）１０００ｇ、アドソリダー１０１ １０ｇ及び１０重量％ＨＰＭＣ（ＴＣ−５Ｅ）水溶液１０００ｇを用い、実施例６と同様にして６３〜５００μｍの粒子が９７．２重量％の微粒子の造粒物を得た。
比較例11
ピンドロール１０００ｇとアドソリダー１０１ １０ｇを、比較例４と同様にして造粒物を得た。 Example 13
Using Pindolol (manufactured by Daito Co., Ltd.) 1000 g, Adsolider 101 10 g and 10 wt% HPMC (TC-5E) 1000 g aqueous solution, 63 to 500 μm particles were produced as 97.2 wt% fine particles in the same manner as in Example 6. Grains were obtained.
Comparative Example 11
In the same manner as in Comparative Example 4, a granulated product was obtained using 1000 g of pindolol and 10 g of Adsolider 101.

試験例３
本発明の医薬組成物（実施例６〜１３）の難水溶性薬物の溶出性を試験例１と同様にして測定した結果を表１に示す。
本発明の医薬組成物は、比較例に比していずれも顕著に改善された溶出性を有していた。 Test example 3
Table 1 shows the results of measuring the dissolution properties of the poorly water-soluble drugs of the pharmaceutical compositions of the present invention (Examples 6 to 13) in the same manner as in Test Example 1.
The pharmaceutical composition of the present invention had significantly improved dissolution properties as compared with the comparative example.

Figure 0004575654
Figure 0004575654

試験例４
実施例１〜１３及び比較例１〜１１で製造された医薬組成物の１〜１１のオリフィス径（ｍｍ）及び粒度分布の測定結果を表２に示す。 Test example 4
Table 2 shows the measurement results of the orifice diameter (mm) and the particle size distribution of 1 to 11 of the pharmaceutical compositions produced in Examples 1 to 13 and Comparative Examples 1 to 11.

Figure 0004575654
Figure 0004575654

なお、測定は次の方法に従った。
オリフィス径：オリフィス径測定器（小西医療器(株)製）を用いて粉体の流れ出る穴の径（ｍｍ）を測定した。
粒度分布：５００、３５５、３００、２５０、１７７、１５０、１２５、７５、６３μｍのふるいを用いて、ミクロ型電磁振動ふるい器（Ｍ−２型、筒井理化学器(株)製）で測定した。 In addition, the measurement followed the following method.
Orifice diameter: The diameter (mm) of the hole through which the powder flows was measured using an orifice diameter measuring device (manufactured by Konishi Medical Instrument Co., Ltd.).
Particle size distribution: Measured with a micro type electromagnetic vibration sieve (M-2 type, manufactured by Tsutsui Rikagaku Co., Ltd.) using sieves of 500, 355, 300, 250, 177, 150, 125, 75, 63 μm.

本発明の医薬品組成物（実施例１〜１３）は、比較例１〜１１で製造した医薬品組成物よりオリフィス径が小さく、流動性が優れていた。また、本発明の医薬組成物は、いずれも６３〜５００μｍの粒径範囲に８５重量％以上が入っていた。   The pharmaceutical composition (Examples 1 to 13) of the present invention had a smaller orifice diameter and excellent fluidity than the pharmaceutical compositions produced in Comparative Examples 1 to 11. Moreover, as for the pharmaceutical composition of this invention, all contained 85 weight% or more in the particle size range of 63-500 micrometers.

実施例１４
実施例３の造粒物１９９８ｇ、クロスポピドンＣＬ（商品名：コリドンＣＬ、ビーエーエスエフ(株)製）７２０ｇをＶ型混合機（Ｖ−１０型、徳寿製作所製）を用いて１５分混合し、タルク２８ｇとステアリン酸マグネシウム１４ｇを添加しさらに３分混合し、ロータリー打錠機（ＲＴ−Ｓ１５−Ｔ３５、菊水製作所(株)製）で、直径８．５ｍｍ、１錠２３０ｍｇの錠剤を得た。 Example 14
1998 g of the granulated product of Example 3 and 720 g of crospovidone CL (trade name: Kollidon CL, manufactured by BASF Corporation) were mixed for 15 minutes using a V-type mixer (V-10, manufactured by Tokusu Seisakusho) 28 g of talc and 14 g of magnesium stearate were added and further mixed for 3 minutes, and tablets with a diameter of 8.5 mm and one tablet of 230 mg were obtained with a rotary tableting machine (RT-S15-T35, manufactured by Kikusui Seisakusho Co., Ltd.).

実施例１５
実施例６の造粒物１９９８ｇ、クロスポピドンＣＬ７２０ｇをＶ型混合機（Ｖ−１０型）を用いて１５分混合し、タルク２８ｇとステアリン酸マグネシウム１４ｇを添加しさらに３分混合し、ロータリー打錠機（ＲＴ−Ｓ１５−Ｔ３５）で、直径８．５ｍｍ、１錠２３０ｍｇの錠剤を得た。 Example 15
The granulated product of Example 6 (1998 g) and crospovidone CL (720 g) were mixed for 15 minutes using a V-type mixer (type V-10), talc (28 g) and magnesium stearate (14 g) were added, and the mixture was further mixed for 3 minutes. With a machine (RT-S15-T35), tablets with a diameter of 8.5 mm and one tablet of 230 mg were obtained.

試験例５
実施例１４及び１５で製造した錠剤の試験例１と同じ試験法での溶出試験結果（表３）及び錠剤の物性（表４）を示す。 Test Example 5
The dissolution test result (Table 3) and the physical property of a tablet (Table 4) by the same test method as the test example 1 of the tablet manufactured in Example 14 and 15 are shown.

Figure 0004575654
Figure 0004575654

実施例１４及び１５で製造した錠剤は、いずれも難水溶性薬物の溶出性が優れていた。   The tablets produced in Examples 14 and 15 were all excellent in the solubility of poorly water-soluble drugs.

Figure 0004575654
Figure 0004575654

なお、測定は次の方法に従った。
硬度：錠剤硬度計（ＴＨ−３０３ＲＰ、富山産業(株)製）を用いて測定した。なお、値は１０回の平均値を示す。
崩壊時間：崩壊試験器（ＮＴ−６Ｈ、富山産業(株)製）を用いて測定した。なお、値は６回の平均値で示す（試験液：水）。 In addition, the measurement followed the following method.
Hardness: Measured using a tablet hardness meter (TH-303RP, manufactured by Toyama Sangyo Co., Ltd.). In addition, a value shows the average value of 10 times.
Disintegration time: measured using a disintegration tester (NT-6H, manufactured by Toyama Sangyo Co., Ltd.). In addition, a value is shown by the average value of 6 times (test liquid: water).

実施例１６
イブプロフェン１０００ｇ（BASF製 IBUPROFEN50 粒径：４５〜６０μｍ）と含水二酸化ケイ素（フロイント産業(株)製 アドソリダー１０２）１０ｇを、バーチカルグラニュレーターＶＧ−１０で混合後、微粒子コーティング装置（ＳＰＣ−０１型）で１０重量％ＰＶＰ（ビーエーエスエフ武田ビタミン(株)製 ＰＶＰ−Ｋ３０）水溶液１０００ｇで微粒子造粒し、６３〜５００μｍの粒子が８５％以上の微粒子の造粒物を得た。 Example 16
After mixing 1000 g of ibuprofen (BASF IBUPROFEN50 particle size: 45 to 60 μm) and hydrous silicon dioxide (Freund Sangyo Co., Ltd. Adsolider 102) with a vertical granulator VG-10, fine particle coating device (SPC-01 type) Fine particles were granulated with 1000 g of an aqueous solution of 10% by weight PVP (PVP-K30 manufactured by BASF Takeda Vitamin Co., Ltd.) to obtain a granulated product of fine particles having a particle size of 63 to 500 μm of 85% or more.

比較例１２
イブプロフェン１０００ｇ（BASF製 IBUPROFEN50 粒径：４５〜６０μｍ）とアドソリダー１０２ １０ｇを、バーチカルグラニュレーターＶＧ−１０で混合し、混合物を得た。 Comparative Example 12
1000 g of ibuprofen (IBUPROFEN50 particle size: 45-60 μm manufactured by BASF) and 10 g of Adsolider 102 were mixed with a vertical granulator VG-10 to obtain a mixture.

試験例６
難水溶性薬物の溶出性を試験例１と同様にして測定した結果を表５に示す。本発明の医薬組成物は、比較例に比して顕著に改善された溶出性を有していた。 Test Example 6
Table 5 shows the results of measuring the dissolution property of the poorly water-soluble drug in the same manner as in Test Example 1. The pharmaceutical composition of the present invention had significantly improved dissolution compared to the comparative example.

Figure 0004575654
Figure 0004575654

医薬組成物の溶出試験結果を示す図である。It is a figure which shows the elution test result of a pharmaceutical composition. 医薬組成物の溶出試験結果を示す図である。It is a figure which shows the elution test result of a pharmaceutical composition.

Claims (3)

（Ａ）イブプロフェン、ケトプロフェン、フロセミド、スピロノラクトン、ジピリダモール、ピロキシカム、メフェナム酸、トリクロルメチアジド及びピンドロールから選ばれる難水溶性薬物、
（Ｂ）軽質無水ケイ酸及び含水二酸化ケイ素から選ばれる流動化剤、並びに
（Ｃ）ヒドロキシプロピルメチルセルロース及びヒドロキシプロピルセルロースから選ばれる水溶性高分子、
からなる造粒物を含有する医薬組成物であって、該造粒物が、難水溶性薬物１００重量部と流動化剤０．０１〜５重量部の混合物を水溶性高分子０．１〜５０重量部を含有する水又は含水アルコール溶液を用いて造粒することにより得られるものである医薬組成物。 (A) a poorly water-soluble drug selected from ibuprofen, ketoprofen, furosemide, spironolactone, dipyridamole, piroxicam, mefenamic acid, trichlormethiazide and pindolol,
(B) fluidizing agent selected from light anhydrous silicic acid and hydrated silicon dioxide, and (C) hydroxypropylmethyl cellulose and hydroxypropyl cell row scan or found water-soluble polymer selected,
The granule comprises a mixture of 100 parts by weight of a poorly water-soluble drug and 0.01 to 5 parts by weight of a fluidizing agent. The pharmaceutical composition which is obtained by granulating using the water or hydrous alcohol solution containing 50 weight part. 造粒物の８５重量％以上が粒子径６３〜５００μｍである請求項１記載の医薬組成物。   The pharmaceutical composition according to claim 1, wherein 85% by weight or more of the granulated product has a particle size of 63 to 500 µm. 請求項１又は２記載の医薬組成物を用いて得られる固形医薬製剤。   A solid pharmaceutical preparation obtained using the pharmaceutical composition according to claim 1 or 2.
JP2003313853A 2003-09-05 2003-09-05 Pharmaceutical composition with improved solubility and fluidity Expired - Lifetime JP4575654B2 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP2003313853A JP4575654B2 (en) 2003-09-05 2003-09-05 Pharmaceutical composition with improved solubility and fluidity
KR1020067002247A KR20060119860A (en) 2003-09-05 2004-09-03 Pharmaceutical composition with improved solubility and fluidity
TW093126705A TWI344376B (en) 2003-09-05 2004-09-03 Pharmaceutical composition having improved solubility and fluidity
PCT/JP2004/012827 WO2005023222A1 (en) 2003-09-05 2004-09-03 Pharmaceutical composition with improved solubility and fluidity
CNB2004800245287A CN100389750C (en) 2003-09-05 2004-09-03 Pharmaceutical composition with improved solubility and fluidity
HK06113473A HK1092711A1 (en) 2003-09-05 2006-12-07 Pharmeceutical composition with improved solubility and fluidity

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2003313853A JP4575654B2 (en) 2003-09-05 2003-09-05 Pharmaceutical composition with improved solubility and fluidity

Publications (3)

Publication Number Publication Date
JP2005082503A JP2005082503A (en) 2005-03-31
JP2005082503A5 JP2005082503A5 (en) 2006-07-06
JP4575654B2 true JP4575654B2 (en) 2010-11-04

Family

ID=34269778

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2003313853A Expired - Lifetime JP4575654B2 (en) 2003-09-05 2003-09-05 Pharmaceutical composition with improved solubility and fluidity

Country Status (6)

Country Link
JP (1) JP4575654B2 (en)
KR (1) KR20060119860A (en)
CN (1) CN100389750C (en)
HK (1) HK1092711A1 (en)
TW (1) TWI344376B (en)
WO (1) WO2005023222A1 (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007001066A1 (en) * 2005-06-27 2007-01-04 Daiichi Sankyo Company, Limited Pharmaceutical preparation containing an angiotensin ii receptor antagonist and a calcium channel blocker
ES2524443T3 (en) * 2006-11-13 2014-12-09 DePuy Synthes Products, LLC In vitro expansion of postpartum cells using microcarriers
JP5201819B2 (en) * 2006-11-22 2013-06-05 エスエス製薬株式会社 Solid composition
JP5817715B2 (en) * 2010-03-03 2015-11-18 ライオン株式会社 Solid pharmaceutical composition, pharmaceutical preparation and method for producing solid pharmaceutical composition
CN105343006B (en) * 2015-12-02 2019-05-14 北京大学 A kind of nanometer shell system and its preparation method and application carrying insoluble drug
CN105832680B (en) * 2016-05-12 2018-12-25 沈阳药科大学 A kind of pharmaceutical composition improving spirolactone In Vitro Dissolution and mobility
JP6918392B2 (en) * 2021-01-13 2021-08-11 築野食品工業株式会社 Yield improvement in powder production or generation, scattering or solidification inhibitor of fine powder in powder use

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04159222A (en) * 1990-10-22 1992-06-02 Taisho Yakuhin Kogyo Kk Production of solid preparation for oral administration
WO1992009275A1 (en) * 1990-11-30 1992-06-11 Yamanouchi Pharmaceutical Co., Ltd. Quick release coated preparation
JPH10298111A (en) * 1997-03-10 1998-11-10 Basf Ag Use of re-dispersible polymeric powder or polymeric granule as binder and solid pharmaceutical dosage form
JP2000026292A (en) * 1998-01-29 2000-01-25 Kissei Pharmaceut Co Ltd Rapid release oral pharmaceutical composition
WO2000078292A1 (en) * 1999-06-18 2000-12-28 Takeda Chemical Industries, Ltd. Quickly disintegrating solid preparations

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LU84875A1 (en) * 1983-06-27 1985-03-29 Oreal TINCTORIAL COMPOSITIONS FOR KERATINIC FIBERS BASED ON DIRECT DYES AND XANTHANE GUM
DE3720757A1 (en) * 1987-06-24 1989-01-05 Bayer Ag DHP COAT TABLET
CH675537A5 (en) * 1988-03-25 1990-10-15 Ciba Geigy Ag
US5656290A (en) * 1993-02-26 1997-08-12 The Procter & Gamble Company Bisacodyl dosage form with multiple enteric polymer coatings for colonic delivery
US5651983A (en) * 1993-02-26 1997-07-29 The Procter & Gamble Company Bisacodyl dosage form for colonic delivery
JP3247511B2 (en) * 1993-09-07 2002-01-15 山之内製薬株式会社 Pharmaceutical composition
JP3096666B2 (en) * 1996-11-01 2000-10-10 藤崎電機株式会社 Method and apparatus for granulating powder
JP3870470B2 (en) * 1997-02-07 2007-01-17 大正製薬株式会社 Multiple unit type sustained release tablets
JP4438121B2 (en) * 1998-04-27 2010-03-24 大正製薬株式会社 Intraoral rapidly disintegrating tablet and method for producing the same
GB9816899D0 (en) * 1998-08-05 1998-09-30 Boots Co Plc Therapeutic agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04159222A (en) * 1990-10-22 1992-06-02 Taisho Yakuhin Kogyo Kk Production of solid preparation for oral administration
WO1992009275A1 (en) * 1990-11-30 1992-06-11 Yamanouchi Pharmaceutical Co., Ltd. Quick release coated preparation
JPH10298111A (en) * 1997-03-10 1998-11-10 Basf Ag Use of re-dispersible polymeric powder or polymeric granule as binder and solid pharmaceutical dosage form
JP2000026292A (en) * 1998-01-29 2000-01-25 Kissei Pharmaceut Co Ltd Rapid release oral pharmaceutical composition
WO2000078292A1 (en) * 1999-06-18 2000-12-28 Takeda Chemical Industries, Ltd. Quickly disintegrating solid preparations

Also Published As

Publication number Publication date
CN100389750C (en) 2008-05-28
HK1092711A1 (en) 2007-02-16
JP2005082503A (en) 2005-03-31
KR20060119860A (en) 2006-11-24
CN1842324A (en) 2006-10-04
TWI344376B (en) 2011-07-01
TW200514571A (en) 2005-05-01
WO2005023222A1 (en) 2005-03-17

Similar Documents

Publication Publication Date Title
JP5285105B2 (en) Pharmaceutical composition
JP4868695B2 (en) Oral preparation with good disintegration
JP4920798B2 (en) Intraoral quick disintegrating tablet containing two or more kinds of particles
JP5278708B2 (en) Nateglinide-containing hydrophilic pharmaceutical formulation
JP7124107B2 (en) Porous silica particle composition
US6048547A (en) Process for manufacturing solid compositions containing polyethylene oxide and an active ingredient
KR20100012867A (en) Solid dosage forms comprising tadalafil
TWI229603B (en) Beta-lactam compositions
JP2015063521A (en) Tablet with high drug content and production method thereof
RU2300368C2 (en) Ibuprofen-containing composition
JPH09208458A (en) Offensive taste-masked preparation
JPH0717866A (en) Medicinal composition
JP4575654B2 (en) Pharmaceutical composition with improved solubility and fluidity
JP6630229B2 (en) Levetiracetam-containing pharmaceutical composition and method for producing the same
JP2010120872A (en) Method for producing orally rapidly disintegrable tablet
JP5275815B2 (en) Orally disintegrating tablets and bitterness-suppressing preparations containing risperidone
JP6328138B2 (en) Of N- [5- [2- (3,5-dimethoxyphenyl) ethyl] -2H-pyrazol-3-yl] -4-[(3R, 5S) -3,5-dimethylpiperazin-1-yl] benzamide Pharmaceutical formulation
JP5825686B2 (en) Method for producing slightly water-soluble drug-containing fine particle granulated product
EP1729735B1 (en) Compressed solid dosage form manufacturing process well-suited for use with drugs of low aqueous solubility and compressed solid dosage forms made thereby
JP2006257068A (en) High content terbinafine hydrochloride tablet and method for producing the same
JP2002037727A (en) Lipid-soluble medicine-formulated rapid disintegrable solid pharmaceutical preparation and method for producing the same
JP2004161653A (en) Multiple unit type sustained-release preparation
CA2174538A1 (en) Base for sustained-release preparation, sustained-release preparation, and process for producing the preparation
KR100454499B1 (en) Pharmaceutical excipients with excellent compressibility
WO2014157603A1 (en) Pharmaceutical composition for oral administration

Legal Events

Date Code Title Description
A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20060522

A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20060522

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20091013

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20091214

A02 Decision of refusal

Free format text: JAPANESE INTERMEDIATE CODE: A02

Effective date: 20100330

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20100629

A911 Transfer to examiner for re-examination before appeal (zenchi)

Free format text: JAPANESE INTERMEDIATE CODE: A911

Effective date: 20100722

TRDD Decision of grant or rejection written
A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

Effective date: 20100817

A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20100820

R150 Certificate of patent or registration of utility model

Ref document number: 4575654

Country of ref document: JP

Free format text: JAPANESE INTERMEDIATE CODE: R150

Free format text: JAPANESE INTERMEDIATE CODE: R150

FPAY Renewal fee payment (event date is renewal date of database)

Free format text: PAYMENT UNTIL: 20130827

Year of fee payment: 3

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

S531 Written request for registration of change of domicile

Free format text: JAPANESE INTERMEDIATE CODE: R313531

R350 Written notification of registration of transfer

Free format text: JAPANESE INTERMEDIATE CODE: R350

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

EXPY Cancellation because of completion of term