WO2013081044A1 - Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonic acid hydrate - Google Patents
Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonic acid hydrate Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
Abstract
Description
化合物Aのメタンスルホン酸塩水和物を含有する錠剤は、フィルムコーティング錠として市販されており(富山化学工業製 ジェニナック錠200mg)、1錠中に化合物A200mgを含有し、重量:約357mg、長径:約11.8mm、短径:約7.1mm、厚さ:約4.7mmである。この錠剤の化合物Aのメタンスルホン酸塩水和物の含有率は、錠剤質量の約72%である(質量百分率:以下、本明細書中に使用される%は、特に断らない限り、質量百分率を意味する。)。この錠剤は、通常1回あたり2錠を1日1回経口投与する。
このような比較的大きな錠剤は、成人患者であっても、服薬に抵抗感や圧迫感があり、小児および高齢者などの嚥下困難な患者においては、服薬が容易ではなく、服薬コンプライアンスの低下を引き起こすおそれがある。 1-cyclopropyl-8- (difluoromethoxy) -7-[(1R) -1-methyl-2,3-dihydro-1H-isoindol-5-yl] -4-oxo-1,4-dihydroquinoline- Methanesulfonate hydrate of 3-carboxylic acid (hereinafter referred to as Compound A) has a strong antibacterial action against Gram-positive and Gram-negative bacteria, especially MRSA, and is useful as a therapeutic agent for various infectious diseases [Patent Document 1].
Tablets containing Compound A methanesulfonate hydrate are commercially available as film-coated tablets (Geninac Tablets 200 mg, manufactured by Toyama Chemical Co., Ltd.), and each tablet contains Compound A 200 mg, weight: about 357 mg, major axis: About 11.8mm, short axis: about 7.1mm, thickness: about 4.7mm. The content of methanesulfonate hydrate of Compound A in this tablet is about 72% of the tablet weight (mass percentage: hereinafter,% used in the present specification means mass percentage unless otherwise specified. means.). In general, two tablets are orally administered once a day.
Such relatively large tablets have a sense of resistance and pressure even in adult patients, and in patients with difficulty in swallowing, such as children and the elderly, it is not easy to take drugs, resulting in decreased compliance. May cause.
しかし、錠剤に用いられる原薬のほとんどは、錠剤化する際に、それぞれの原薬物性により、キャッピング、硬度不足、脆弱性(高い摩損度)等の問題が起こるため、それ自体のみで、あるいは60%を超えるような高含量で錠剤化することは困難であるとされている[特許文献2]。 In order to reduce the size of the tablet, it is required to form a tablet with a high content.
However, since most of the drug substances used in tablets are tableted, problems such as capping, lack of hardness, and brittleness (high friability) occur due to the respective drug substances, so that they are used alone or It is said that it is difficult to tablet with a high content exceeding 60% [Patent Document 2].
(1)製剤あたりの化合物Aのメタンスルホン酸塩水和物の含有率が80~97.5質量%である。
(2)錠剤の大きさが、市販のジェニナック錠200mgよりも小さい。
(3)その結果、服薬コンプライアンスが改善される。
(4)溶出性が優れる。
(5)硬度および摩損度が優れる。
(6)その結果、フィルムコーティングおよび移送などに耐える。
本発明の錠剤は、化合物Aのメタンスルホン酸塩水和物の錠剤として有用である。 The tablet of the present invention has the following characteristics.
(1) The content of methanesulfonate hydrate of Compound A per formulation is 80-97.5% by mass.
(2) The tablet size is smaller than 200 mg of commercially available Geninac tablets.
(3) As a result, medication compliance is improved.
(4) Elution is excellent.
(5) Excellent hardness and friability.
(6) As a result, it withstands film coating and transfer.
The tablet of the present invention is useful as a tablet of Compound A methanesulfonate hydrate.
本発明に使用される化合物Aのメタンスルホン酸塩水和物は、たとえば、国際公開第99/21849号パンフレットに記載の方法により製造することができる。 Hereinafter, the present invention will be described in detail.
The methanesulfonate hydrate of Compound A used in the present invention can be produced, for example, by the method described in WO99 / 21849.
本発明の錠剤は、化合物Aのメタンスルホン酸塩水和物を含有する造粒末を製造し、所望により添加剤を加え、圧縮成形して得ることができる。また、必要に応じてフィルムコーティングすることができる。
本発明に使用される崩壊剤およびその他の添加剤は、造粒末内および/または造粒末外に配合することができる。 The tablet of the present invention contains methanesulfonate hydrate of Compound A. The methanesulfonate hydrate content of Compound A may be 80-97.5% by mass, preferably 80-95% by mass, based on the mass of the uncoated tablet. Moreover, the tablet of this invention can add a disintegrating agent as needed. Furthermore, a fluidizing agent, a lubricant and / or a coating agent can be added as necessary.
The tablet of the present invention can be obtained by producing a granulated powder containing the methanesulfonate hydrate of Compound A, adding an additive if desired, and compression molding. Moreover, it can be film-coated as necessary.
The disintegrant and other additives used in the present invention can be blended in and / or outside the granulated powder.
これらの崩壊剤は、1種または2種以上を組み合わせて使用してもよい。 Disintegrants used in the present invention include, for example, cellulose derivatives such as croscarmellose sodium, carmellose calcium, low substituted hydroxypropylcellulose and carmellose; starch derivatives such as sodium starch glycolate and partially pregelatinized starch; and And polyvinylpyrrolidone derivatives such as crospovidone. Preferred disintegrants include crospovidone, croscarmellose sodium and carmellose calcium, more preferably croscarmellose sodium and carmellose calcium.
These disintegrants may be used alone or in combination of two or more.
これらのコーティング剤は、1種または2種以上を組み合わせて使用してもよい。 Examples of the coating agent used in the present invention include hypromellose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer and polyvinyl alcohol / polyethylene glycol / graft copolymer. Preferably, hypromellose is more preferable.
These coating agents may be used alone or in combination of two or more.
滑沢剤としては、たとえば、フマル酸ステアリルナトリウム、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルクおよびショ糖脂肪酸エステルなどが挙げられる。好ましい滑沢剤としては、ステアリン酸マグネシウムおよびタルクが挙げられ、より好ましくは、ステアリン酸マグネシウムが挙げられる。
滑沢剤の含有率は、錠剤または造粒末質量の0.1~5%、好ましくは、0.2~4%、より好ましくは、0.5~3%である。 It is preferable to add a lubricant to the tablet and granulated powder of the present invention. The lubricant can be blended in and / or outside the granulated powder. As a preferable blending method, a method of blending outside the granulated powder, more preferably, a method of blending inside and outside the granulated powder can be mentioned.
Examples of the lubricant include sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, talc and sucrose fatty acid ester. Preferable lubricants include magnesium stearate and talc, and more preferably magnesium stearate.
The content of the lubricant is from 0.1 to 5%, preferably from 0.2 to 4%, more preferably from 0.5 to 3% of the mass of the tablet or granulated powder.
本発明に所望に応じて使用される賦形剤としては、たとえば、エリスリトール、マンニトール、キシリトールおよびソルビトールなどの糖アルコール類;白糖、粉糖、乳糖およびブドウ糖などの糖類;α-シクロデキストリン、β-シクロデキストリン、γ-シクロデキストリン、ヒドロキシプロピルβ-シクロデキストリンおよびスルホブチルエーテルβ-シクロデキストリンナトリウムなどのシクロデキストリン類;ならびに、粉末セルロースおよび結晶セルロースなどのセルロース類などが挙げられる。これらの賦形剤は、1種または2種以上を組み合わせて使用してもよい。
賦形剤の添加量は、特に限定されず、目的に応じて必要な量を適宜配合すればよい。 An excipient may be further added to the tablet and granulated powder of the present invention.
Excipients used as desired in the present invention include, for example, sugar alcohols such as erythritol, mannitol, xylitol and sorbitol; sugars such as sucrose, powdered sugar, lactose and glucose; α-cyclodextrin, β- And cyclodextrins such as cyclodextrin, γ-cyclodextrin, hydroxypropyl β-cyclodextrin and sulfobutyl ether β-cyclodextrin sodium; and celluloses such as powdered cellulose and crystalline cellulose. These excipients may be used alone or in combination of two or more.
The addition amount of the excipient is not particularly limited, and a necessary amount may be appropriately blended depending on the purpose.
結晶セルロースは、微結晶セルロースを含む。
結晶セルロースは、種々のグレードのものを用いることができる。好ましくは、平均重合度100~350、平均粒子径20~170μm、乾燥減量1.0~7.0%、かさ密度0.10~0.46g/cm3のものが挙げられ、より好ましくは、平均重合度100~350、平均粒子径50μm、乾燥減量2.0~6.0%、かさ密度0.10~0.31g/cm3のものが挙げられる。 Preferred excipients include crystalline cellulose.
Crystalline cellulose includes microcrystalline cellulose.
Crystalline cellulose of various grades can be used. Preferred examples include those having an average degree of polymerization of 100 to 350, an average particle size of 20 to 170 μm, a loss on drying of 1.0 to 7.0%, and a bulk density of 0.10 to 0.46 g / cm 3 , and more preferably an average degree of polymerization of 100 to 350, Examples include those having an average particle size of 50 μm, loss on drying of 2.0 to 6.0%, and bulk density of 0.10 to 0.31 g / cm 3 .
通常、薬剤に使用される添加物としては、矯味剤、着色剤、着香剤、界面活性剤、可塑剤および消泡剤などが挙げられる。
矯味剤としては、たとえば、アスパルテーム、サッカリン、ステビア、ソーマチンおよびアセスルファムカリウムなどが挙げられる。
着色剤としては、たとえば、二酸化チタン、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、食用赤色102号、食用黄色4号および食用黄色5号などが挙げられる。
着香剤としては、たとえば、オレンジ油、レモン油、ハッカ油およびパインオイルなどの精油;オレンジエッセンスおよびペパーミントエッセンスなどのエッセンス;チェリーフレーバー、バニラフレーバーおよびフルーツフレーバーなどのフレーバー;アップルミクロン、バナナミクロン、ピーチミクロン、ストロベリーミクロンおよびオレンジミクロンなどの粉末香料;バニリン;ならびにエチルバニリンなどが挙げられる。
界面活性剤としては、たとえば、ラウリル硫酸ナトリウム、スルホコハク酸ジオクチルナトリウム、ポリソルベート類およびポリオキシエチレン硬化ヒマシ油などが挙げられる。
可塑剤としては、たとえば、クエン酸トリエチル、フタル酸ジブチル、トリアセチンおよびプロピレングリコールなどが挙げられ、トリアセチンが好ましい。
消泡剤としては、たとえば、シリコン消泡剤およびシリコン樹脂エマルジョンなどが挙げられる。
これらの添加物は、1種または2種以上を組み合わせて使用してもよく、配合量は、特に限定されず、それぞれの目的に応じ、その効果が充分に発現されるよう適宜配合すればよい。 In the tablet and granulated powder of the present invention, additives usually used for drugs can be used within a range not impairing the effects of the present invention.
Additives that are usually used in medicines include flavoring agents, coloring agents, flavoring agents, surfactants, plasticizers and antifoaming agents.
Examples of the corrigent include aspartame, saccharin, stevia, thaumatin, and acesulfame potassium.
Examples of the colorant include titanium dioxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, edible red No. 102, edible yellow No. 4, and edible yellow No. 5.
Examples of flavoring agents include essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, And powder fragrances such as peach micron, strawberry micron and orange micron; vanillin; and ethyl vanillin.
Examples of the surfactant include sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbates, and polyoxyethylene hydrogenated castor oil.
Examples of the plasticizer include triethyl citrate, dibutyl phthalate, triacetin and propylene glycol, and triacetin is preferable.
Examples of the antifoaming agent include a silicon antifoaming agent and a silicon resin emulsion.
These additives may be used singly or in combination of two or more, and the blending amount is not particularly limited, and may be appropriately blended so that the effect is sufficiently exhibited according to each purpose. .
コンパクティング法としては、ローラーコンパクターを用いて圧縮成形物を製造し、それを破砕して造粒粒子を得る方法などが挙げられる。
ローラーコンパクターの圧力としては、使用する機種により異なるが、TF-LABO(フロイント産業製)を用いる場合、3~9MPaが好ましい。 Examples of the dry granulation method include a compacting method, a slugging method, and a briquetting method, and the compacting method is preferable.
Examples of the compacting method include a method of producing a compression molded product using a roller compactor and crushing it to obtain granulated particles.
The pressure of the roller compactor varies depending on the model used, but when using TF-LABO (manufactured by Freund Industries), 3 to 9 MPa is preferable.
素錠の摩損度としては、小さいほど好ましいが、錠剤摩損試験機を用いて、25rpmで750回転(30分)の条件で、0~4%が好ましく、0~2%がより好ましい。 The hardness of the uncoated tablet is preferably 50 to 200N, more preferably 60 to 200N.
The friability of the uncoated tablet is preferably as small as possible, but is preferably 0 to 4% and more preferably 0 to 2% under the condition of 750 revolutions (30 minutes) at 25 rpm using a tablet friability tester.
日本薬局方溶出試験法の試験液第1液は、塩化ナトリウム2.0gを塩酸7.0mLおよび水に溶かして1000mLにした試験液である。
また、85%溶出時間とは、錠剤に含まれる化合物Aのうち、85質量%の化合物Aが溶出する時間である。 The tablets of the present invention are the 16th revised Japanese Pharmacopoeia Dissolution Test Method (Paddle Method), and the 85% dissolution time in a dissolution test where the first solution of the Japanese Pharmacopoeia Dissolution Test is the test solution and the rotation speed is 50 times / min. May be 30 minutes or less, but is preferably 15 minutes or less.
The test liquid No. 1 in the Japanese Pharmacopoeia dissolution test method is a test liquid prepared by dissolving 2.0 g of sodium chloride in 7.0 mL of hydrochloric acid and water to make 1000 mL.
The 85% dissolution time is the time for 85% by weight of Compound A out of Compound A contained in the tablet.
試料として、実施例1~4、9~10および参考例1~2のフィルムコーティング錠を使用した。
溶出試験は、日本薬局方溶出試験(パドル法)によって行った。パドルの回転数は、50rpmとした。日本薬局方溶出試験第1液900mLに試料を投入し、30分後に試験溶液を採取し、化合物Aの溶出率(%)を吸光度法により求めた。なお、溶出試験第1液は、塩化ナトリウム2.0gを塩酸(JIS K 8180、特級)7.0mLおよび水に溶かして1000mLとして調製した。
結果を表1に示す。 Test example 1
As samples, the film-coated tablets of Examples 1 to 4, 9 to 10 and Reference Examples 1 to 2 were used.
The dissolution test was conducted by the Japanese Pharmacopoeia dissolution test (paddle method). The rotation speed of the paddle was 50 rpm. A sample was put into 900 mL of the first solution of the Japanese Pharmacopoeia dissolution test, and after 30 minutes, the test solution was collected, and the dissolution rate (%) of Compound A was determined by the absorbance method. The first dissolution test solution was prepared as 1000 mL by dissolving 2.0 g of sodium chloride in 7.0 mL of hydrochloric acid (JIS K 8180, special grade) and water.
The results are shown in Table 1.
一方、崩壊剤として、低置換度ヒドロキシプロピルセルロース(実施例1)、カルメロースカルシウム(実施例2)、クロスカルメロースナトリウム(実施例3)、デンプングリコール酸ナトリウム(実施例4)、カルメロース(実施例9)および部分アルファ化デンプン(実施例10)を使用したフィルムコーティング錠は、化合物Aのメタンスルホン酸塩水和物の素錠中含有率が85%と高含量であるにもかかわらず、30分後の溶出率が85%以上であり、優れた溶出性を示した。 Film-coated tablets using corn starch (Reference Example 1) and hydroxypropyl starch (Reference Example 2) as disintegrants had an elution rate of less than 85% after 30 minutes and exhibited low elution properties.
On the other hand, as a disintegrant, low-substituted hydroxypropylcellulose (Example 1), carmellose calcium (Example 2), croscarmellose sodium (Example 3), sodium starch glycolate (Example 4), carmellose (implemented) A film-coated tablet using Example 9) and partially pregelatinized starch (Example 10) had a high content of 85% of the methanesulfonate hydrate of Compound A in the uncoated tablet. The elution rate after a minute was 85% or more, and an excellent elution property was shown.
試料として、実施例1~8のフィルムコーティング錠および素錠を使用した。
フィルムコーティング錠の溶出試験は、試験例1と同様に行った。
素錠の硬度は、錠剤硬度計(錠剤硬度計8M、シュロイニゲル製)を用いて、3回測定して求めた。
素錠の摩損度は、日本薬局方参考情報「錠剤の摩損度試験法」に従い、錠剤摩損度試験器(PTF1ER、PHARMATEST製)を用いて、22錠につき、25rpmで750回転(30分)の条件により求めた。
結果を表2に示す。 Test example 2
As samples, the film-coated tablets and uncoated tablets of Examples 1 to 8 were used.
The dissolution test of the film-coated tablet was carried out in the same manner as in Test Example 1.
The hardness of the uncoated tablet was determined by measuring three times using a tablet hardness meter (tablet hardness meter 8M, manufactured by Schleunigel).
The friability of the uncoated tablets is 750 rotations (30 minutes) at 25 rpm for 22 tablets using a tablet friability tester (PTF1ER, manufactured by PHARMATE) according to the Japanese Pharmacopoeia reference information “Table friability test method”. Obtained according to conditions.
The results are shown in Table 2.
軽質無水ケイ酸を含有しないフィルムコーティング錠(実施例1~4)および軽質無水ケイ酸を含有するフィルムコーティング錠(実施例5~8)とも、30分後の溶出率が85%以上であり、優れた溶出性を示した。 The hardness of uncoated tablets containing no light anhydrous silicic acid (Examples 1 to 4) is 58 to 86 N, while the hardness of uncoated tablets containing light anhydrous silicic acid (Examples 5 to 8) is 88 to 86 N. It was greatly improved to 132N. In addition, the uncoated tablet containing light anhydrous silicic acid (Examples 5 to 8) has a friability of 1.1 to 1.7% compared to the uncoated tablet containing light anhydrous silicic acid (Examples 1 to 4). The degree was 0.4-0.7%. The uncoated tablets of Examples 1 to 4 were excellent as tablets having necessary hardness and friability, and the uncoated tablets of Examples 5 to 8 were excellent as tablets having further improved hardness and friability.
Both the film-coated tablets not containing light anhydrous silicic acid (Examples 1 to 4) and the film-coated tablets containing light anhydrous silicic acid (Examples 5 to 8) had an elution rate of 85% or more after 30 minutes, Excellent elution was exhibited.
試料として、実施例11および12のフィルムコーティング錠および素錠を使用した。
フィルムコーティング錠の溶出試験は、試験例1と同様に行った。また、素錠の硬度および素錠の摩損度は、試験例2と同様に行った。なお、素錠の硬度は、10回測定して求めた。
結果を表3に示す。 Test example 3
The film-coated tablets and uncoated tablets of Examples 11 and 12 were used as samples.
The dissolution test of the film-coated tablet was carried out in the same manner as in Test Example 1. The hardness of the uncoated tablet and the friability of the uncoated tablet were the same as in Test Example 2. The hardness of the uncoated tablet was determined by measuring 10 times.
The results are shown in Table 3.
試料として、実施例6、13および14のフィルムコーティング錠および素錠を使用した。
フィルムコーティング錠の溶出試験は、試験例1と同様に行った。また、素錠の硬度および素錠の摩損度は、試験例2と同様に行った。なお、素錠の硬度は、実施例6で3回、実施例13で6回、実施例14で10回測定して求めた。
結果を表4に示す。 Test example 4
The film-coated tablets and uncoated tablets of Examples 6, 13 and 14 were used as samples.
The dissolution test of the film-coated tablet was carried out in the same manner as in Test Example 1. The hardness of the uncoated tablet and the friability of the uncoated tablet were the same as in Test Example 2. The hardness of the uncoated tablet was determined by measuring 3 times in Example 6, 6 times in Example 13, and 10 times in Example 14.
The results are shown in Table 4.
軽質無水ケイ酸を含有するフィルムコーティング錠(実施例13)および含水二酸化ケイ素を含有するフィルムコーティング錠(実施例14)は、二酸化ケイ素の種類にかかわらず、30分後の溶出率が85%以上であり、優れた溶出性を示し、その素錠は、必要な硬度および摩損度を有する錠剤として優れていた。 A film-coated tablet (Example 6) having a light silicic acid content of 0.9% and a film-coated tablet (Example 13) having a 3% light anhydrous silicic acid content of 30% regardless of the amount of light silicic acid added. The dissolution rate after a minute was 85% or more, showing excellent dissolution, and the uncoated tablet was excellent as a tablet having the required hardness and friability.
The film-coated tablet containing light anhydrous silicic acid (Example 13) and the film-coated tablet containing hydrous silicon dioxide (Example 14) had an elution rate of 85% or more after 30 minutes regardless of the type of silicon dioxide. And showed excellent dissolution properties, and the uncoated tablet was excellent as a tablet having the required hardness and friability.
試料として、実施例15~29のフィルムコーティング錠および素錠を使用した。
フィルムコーティング錠の溶出試験は、試験例1と同様に行った。また、素錠の硬度および素錠の摩損度は、試験例2と同様に行った。なお、素錠の硬度は、10回測定して求めた。
結果を表5に示す。 Test Example 5
The film-coated tablets and uncoated tablets of Examples 15 to 29 were used as samples.
The dissolution test of the film-coated tablet was carried out in the same manner as in Test Example 1. The hardness of the uncoated tablet and the friability of the uncoated tablet were the same as in Test Example 2. The hardness of the uncoated tablet was determined by measuring 10 times.
The results are shown in Table 5.
また、化合物Aのメタンスルホン酸塩水和物の素錠中含有率が97.5%とさらに高い、フィルムコーティング錠(実施例24~29)も、30分後の溶出率が85%以上と優れた溶出性を示した。それらの素錠は必要な硬度および摩損度を有する錠剤として優れていた。 Film coated tablets (Examples 15 to 23) with 95% content of methanesulfonate hydrate of Compound A in the uncoated tablets have an elution rate of 85% or more after 30 minutes and show excellent dissolution properties. It was. Moreover, those uncoated tablets had sufficient hardness. In particular, the uncoated tablet containing light anhydrous silicic acid and / or hydrous silicon dioxide (Examples 15, 17, 19-22) had an excellent friability of 1-2%.
In addition, the content of methanesulfonate hydrate of Compound A in the uncoated tablet is as high as 97.5%, and the film-coated tablets (Examples 24 to 29) also have an excellent dissolution rate of 85% or more after 30 minutes. Showed sex. Those uncoated tablets were excellent as tablets having the required hardness and friability.
コーティング剤は、特に断らない限り、オパドライ00K43069(ヒプロメロース2910 66.588%、酸化チタン24.847%、トリアセチン7.951%、三二酸化鉄0.102%、黄色三二酸化鉄0.512%、日本カラコン製)を使用した。
なお、以下の実施例および参考例で製造された製剤は、直径:約8.6mm、厚さ:約4.8mmの円形の錠剤である。 The present invention will be described with reference to examples and comparative examples, but the present invention is not limited thereby.
Unless otherwise specified, Opadry 00K43069 (hypromellose 2910 66.588%, titanium oxide 24.847%, triacetin 7.951%, iron sesquioxide 0.102%, yellow iron sesquioxide 0.512%, manufactured by Nippon Colorcon) was used unless otherwise specified.
The preparations produced in the following examples and reference examples are round tablets having a diameter of about 8.6 mm and a thickness of about 4.8 mm.
化合物Aのメタンスルホン酸塩水和物122.91g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)13.81gおよび低置換度ヒドロキシプロピルセルロース(L-HPC LH-11、信越化学製)7.1gを混合し、目開き850μmの篩で2回篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)1.31gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.5mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤はオパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Example 1
122.91 g of methanesulfonate hydrate of Compound A, 13.81 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) and 7.1 g of low-substituted hydroxypropylcellulose (L-HPC LH-11, manufactured by Shin-Etsu Chemical) Sieve twice with an open 850 μm sieve. To this mixed powder, 1.31 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm, and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.5 mg per tablet to obtain film-coated tablets. The coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
化合物Aのメタンスルホン酸塩水和物122.92g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)13.81gおよびカルメロースカルシウム(E.C.G-505、ニチリン化学製)7.1gを混合し、目開き850μmの篩で2回篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)1.31gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧10kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.5mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤はオパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Example 2
122.92 g of methanesulfonate hydrate of Compound A, 13.81 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals Co., Ltd.) and 7.1 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Co., Ltd.) are mixed and mixed with a sieve having an opening of 850 μm. Sifted through. To this mixed powder, 1.31 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm, and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 10 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.5 mg per tablet to obtain film-coated tablets. The coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
化合物Aのメタンスルホン酸塩水和物122.92g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)13.81gおよびクロスカルメロースナトリウム(プリメロース、DMV製)7.1gを混合し、目開き850μmの篩で2回篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)1.31gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.5mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤はオパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Example 3
122.92 g of methanesulfonate hydrate of Compound A, 13.81 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) and 7.1 g of croscarmellose sodium (Primellose, manufactured by DMV) are mixed and sieved twice with a sieve having an opening of 850 μm I had. To this mixed powder, 1.31 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm, and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.5 mg per tablet to obtain film-coated tablets. The coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
化合物Aのメタンスルホン酸塩水和物122.92g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)13.81gおよびデンプングリコール酸ナトリウム(プリモジェル、DMV製)7.11gを混合し、目開き850μmの篩で2回篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)1.31gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.5mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤はオパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Example 4
122.92g of methanesulfonate hydrate of Compound A, 13.81g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) and 7.11g of sodium starch glycolate (Primogel, manufactured by DMV) were mixed and twice with a sieve having an opening of 850µm Sifted. To this mixed powder, 1.31 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm, and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.5 mg per tablet to obtain film-coated tablets. The coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
化合物Aのメタンスルホン酸塩水和物122.9g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)12.4g、軽質無水ケイ酸(エロジール200、日本アエロジル製)1.41gおよび低置換度ヒドロキシプロピルセルロース(L-HPC LH-11、信越化学製)7.11gを混合し、目開き850μmの篩で2回篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)1.3gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.7mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤はオパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Example 5
122.9 g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 12.4 g, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) and low-substituted hydroxypropylcellulose (L-HPC) (LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) 7.11 g was mixed and sieved twice with a sieve having an opening of 850 μm. To this mixed powder, 1.3 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm, and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.7 mg per tablet to obtain film-coated tablets. The coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
化合物Aのメタンスルホン酸塩水和物122.9g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)12.4g、軽質無水ケイ酸(エロジール200、日本アエロジル製)1.4gおよびカルメロースカルシウム(E.C.G-505、ニチリン化学製)7.1gを混合し、目開き850μmの篩で2回篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)1.3gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.7mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤はオパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Example 6
122.9 g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 12.4 g, 1.4 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) and carmellose calcium (ECG-505, Nichirin Chemical) 7.1 g) was mixed and sieved twice with a sieve having an opening of 850 μm. To this mixed powder, 1.3 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm, and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.7 mg per tablet to obtain film-coated tablets. The coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
化合物Aのメタンスルホン酸塩水和物122.91g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)12.4g、軽質無水ケイ酸(エロジール200、日本アエロジル製)1.4gおよびクロスカルメロースナトリウム(プリメロース、DMV製)7.1gを混合し、目開き850μmの篩で2回篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)1.31gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.2mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤はオパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Example 7
122.91 g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 12.4 g, 1.4 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) and croscarmellose sodium (Primelose, manufactured by DMV) 7.1 g was mixed and sieved twice with a sieve having an opening of 850 μm. To this mixed powder, 1.31 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm, and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets. The coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
化合物Aのメタンスルホン酸塩水和物122.91g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)12.4g、軽質無水ケイ酸(エロジール200、日本アエロジル製)1.4gおよびデンプングリコール酸ナトリウム(プリモジェル、DMV製)7.1gを混合し、目開き850μmの篩で2回篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)1.3gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.2mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤はオパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Example 8
122.91 g of methanesulfonate hydrate of Compound A, 12.4 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals), 1.4 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) and sodium starch glycolate (Primogel, manufactured by DMV) ) 7.1 g was mixed and sieved twice with a sieve having an opening of 850 μm. To this mixed powder, 1.3 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm, and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets. The coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
化合物Aのメタンスルホン酸塩水和物44.07g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)4.44g、軽質無水ケイ酸(エロジール200、日本アエロジル製)0.5g、カルメロース(NS-300、ニチリン化学製)2.54gおよび目開き500μmの篩を通したステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.46gを混合し、目開き850μmの篩で2回篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.3mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤はオパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Example 9
44.07 g of methane sulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 4.44 g, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) 0.5 g, carmellose (NS-300, manufactured by Nichirin Chemical) 0.44 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) passed through a sieve having 2.54 g and an opening of 500 μm was mixed, and sieved twice with a sieve having an opening of 850 μm. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.3 mg per tablet to obtain film-coated tablets. The coating agent used was a small amount of silicon defoamer (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) added to Opadry 00K43069.
化合物Aのメタンスルホン酸塩水和物44.07g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)4.43g、軽質無水ケイ酸(エロジール200、日本アエロジル製)0.49g、部分アルファ化デンプン(PCS、旭化成ケミカルズ製)2.54gおよび目開き500μmの篩を通したステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.46gを混合し、目開き850μmの篩で2回篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.3mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤として、オパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Example 10
44.07 g of methane sulfonate hydrate of Compound A, 4.43 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals), 0.49 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil), partially pregelatinized starch (PCS, manufactured by Asahi Kasei Chemicals) ) 0.44 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) passed through a sieve having 2.54 g and an opening of 500 μm was mixed and sieved twice with a sieve having an opening of 850 μm. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.3 mg per tablet to obtain film-coated tablets. As a coating agent, a material obtained by adding a small amount of a silicon antifoaming agent (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) to Opadry 00K43069 was used.
化合物Aのメタンスルホン酸塩水和物47.32g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)2.43g、カルメロースカルシウム(E.C.G-505、ニチリン化学製)1.89gおよび目開き500μmの篩を通したステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.35gを混合し、目開き850μmの篩で2回篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して1.1%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.9mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 11
Methanesulfonate hydrate 47.32g of compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 2.43g, carmellose calcium (ECG-505, manufactured by Nichirin Chemical) 1.89g, and stearic acid passed through a sieve with an opening of 500μm Magnesium (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) (0.35 g) was mixed and sieved twice with a sieve having an aperture of 850 μm. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.9 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物47.31g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)1.91g、軽質無水ケイ酸(エロジール200、日本アエロジル製)0.52g、カルメロースカルシウム(E.C.G-505、ニチリン化学製)1.9gおよび目開き500μmの篩を通したステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.35gを混合し、目開き850μmの篩で2回篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して1.1%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.9mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 12
47.31g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 1.91g, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) 0.52g, carmellose calcium (ECG-505, Nichirin Chemical) (Manufactured) 1.9 g and 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) passed through a sieve having an opening of 500 μm were mixed, and sieved twice with a sieve having an opening of 850 μm. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.9 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物59.83gおよび軽質無水ケイ酸(エロジール200、日本アエロジル製)2.14gを混合し、整粒機(コーミル、スクリーン径1.143mm)にて篩過した。篩過した末を混合容器に入れた。次にカルメロースカルシウム(E.C.G-505、ニチリン化学製)3.56g、さらに結晶セルロース(セオラス PH101、旭化成ケミカルズ製)3.9gを整粒機(コーミル、スクリーン径1.143mm)にて篩過し、篩過した末を混合容器に入れた。篩過した末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.65gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して1.1%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧11kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.8mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 13
59.83 g of methanesulfonate hydrate of Compound A and 2.14 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil Co., Ltd.) were mixed and sieved with a granulator (Comil, screen diameter 1.143 mm). The sieved powder was placed in a mixing container. Next, 3.56 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Co., Ltd.) and 3.9 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals Co., Ltd.) are sifted with a granulator (Comil, screen diameter 1.143 mm). The finished powder was placed in a mixing container. After sieving, 0.65 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 11 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.8 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物44.42g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)2.89g、含水二酸化ケイ素(カープレックス#80、DSLジャパン製)1.58g、カルメロースカルシウム(E.C.G-505、ニチリン化学製)2.63gおよび目開き500μmの篩を通したステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.47gを混合し、目開き850μmの篩で2回篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して1.1%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.9mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 14
44.42 g of methanesulfonate hydrate of Compound A, 2.89 g of crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals), 1.58 g of hydrous silicon dioxide (Carplex # 80, manufactured by DSL Japan), carmellose calcium (ECG-505, Nichirin) Chemical) (2.63 g) and 0.47 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Sangyo) passed through a sieve with an opening of 500 μm were mixed, and sieved twice with an sieve of an opening of 850 μm. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.9 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物49.97g、軽質無水ケイ酸(エロジール200、日本アエロジル製)0.53gおよびカルメロースカルシウム(E.C.G-505、ニチリン化学製)1.17gを混合し、目開き850μmの篩で篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.35gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して1.1%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.2mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 15
49.97g of methane sulfonate hydrate of Compound A, 0.53g of light anhydrous silicic acid (Erogil 200, manufactured by Nippon Aerosil) and 1.17g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical) are mixed and sieved with 850μm mesh And sieved. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物49.95gおよびカルメロースカルシウム(E.C.G-505、ニチリン化学製)1.69gを混合し、目開き850μmの篩で篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.35gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して1.1%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.2mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 16
49.95 g of methanesulfonate hydrate of Compound A and 1.69 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical) were mixed and sieved with a sieve having an opening of 850 μm. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物49.94g、軽質無水ケイ酸(エロジール200、日本アエロジル製)0.53gおよびクロスカルメロースナトリウム(キッコレートND-2HS、旭化成ケミカルズ製)1.17gを混合し、目開き850μmの篩で篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.35gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して1.1%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.2mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 17
49.94 g of methanesulfonate hydrate of Compound A, 0.53 g of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil Co., Ltd.) and 1.17 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals Co., Ltd.) are mixed. And sieved with a sieve. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物49.99gおよびクロスカルメロースナトリウム(キッコレートND-2HS、旭化成ケミカルズ製)1.70gを混合し、目開き850μmの篩で篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.35gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して1.1%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.2mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 18
49.99 g of methanesulfonate hydrate of Compound A and 1.70 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals) were mixed and sieved with a sieve having an opening of 850 μm. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.1% of the magnesium stearate equivalent to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物50.22g、軽質無水ケイ酸(エロジール200、日本アエロジル製)0.26gおよびカルメロースカルシウム(E.C.G-505、ニチリン化学製)1.18gを混合し、目開き850μmの篩で篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.35gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.5%相当量の含水二酸化ケイ素(カープレックス#80、DSLジャパン製)および1.1%相当量の500μmの篩を通したステアリン酸マグネシウムを加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.2mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 19
Mix methanesulfonate hydrate 50.22g of compound A, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil Co., Ltd.) 0.26g and carmellose calcium (ECG-505, manufactured by Nichirin Chemical) 1.18g sieve And sieved. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.5% equivalent amount of hydrous silicon dioxide (Carplex # 80, manufactured by DSL Japan) and 1.1% equivalent amount of magnesium stearate passed through a 500 μm sieve are added to the uncoated tablet weight, Mix for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物50.20g、含水二酸化ケイ素(カープレックス#80、DSLジャパン製)0.26gおよびカルメロースカルシウム(E.C.G-505、ニチリン化学製)1.18gを混合し、目開き850μmの篩で篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.35gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.5%相当量の軽質無水ケイ酸(エロジール200、日本アエロジル製)および1.1%相当量の500μmの篩を通したステアリン酸マグネシウムを加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.2mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 20
Compound A 50.20 g of methanesulfonate hydrate, 0.26 g of hydrous silicon dioxide (Carplex # 80, manufactured by DSL Japan) and 1.18 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Co., Ltd.) were mixed, and the mesh opening was 850 μm. Sieving with a sieve. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.5% equivalent amount of light anhydrous silicic acid (Erogil 200, manufactured by Nippon Aerosil Co., Ltd.) and 1.1% equivalent amount of magnesium stearate passed through a 500 μm sieve were added. Mixed for minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物50.48gおよびカルメロースカルシウム(E.C.G-505、ニチリン化学製)1.19gを混合し、目開き850μmの篩で篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.35gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して1.0%相当量の含水二酸化ケイ素(カープレックス#80、DSLジャパン製)および1.1%相当量の500μmの篩を通したステアリン酸マグネシウムを加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.2mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 21
50.48 g of methanesulfonate hydrate of Compound A and 1.19 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Co., Ltd.) were mixed and sieved with a sieve having an opening of 850 μm. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.0% equivalent of hydrous silicon dioxide (Carplex # 80, manufactured by DSL Japan) and 1.1% equivalent of magnesium stearate passed through a 500 μm sieve are added to the uncoated tablet weight, Mix for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物49.96g、軽質無水ケイ酸(エロジール200、日本アエロジル製)0.53g、カルメロースカルシウム(E.C.G-505、ニチリン化学製)0.60gおよびクロスポビドン(ポリプラスドンXL-10,ISPジャパン)0.60gを混合し、目開き850μmの篩で篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.35gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して1.1%相当量のステアリン酸マグネシウムを500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.2mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 22
49.96 g of methanesulfonate hydrate of Compound A, 0.53 g of light anhydrous silicic acid (Erogil 200, manufactured by Nippon Aerosil), 0.60 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical) and crospovidone (Polyplastone XL- (10, ISP Japan) 0.60 g was mixed and sieved with a sieve having an opening of 850 μm. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.1% of magnesium stearate equivalent to the weight of the uncoated tablet was added through a 500 μm sieve and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物49.96g、カルメロースカルシウム(E.C.G-505、ニチリン化学製)0.85gおよびクロスポビドン(ポリプラスドンXL-10,ISPジャパン)0.85gを混合し、目開き850μmの篩で篩過した。この混合末に、ステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.35gを目開き500μmの篩を通して加え、30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して1.1%相当量のステアリン酸マグネシウムを500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.2mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 23
49.96g of Compound A methanesulfonate hydrate, 0.85g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical Co., Ltd.) and 0.85g of crospovidone (Polyplastidone XL-10, ISP Japan) were mixed, and the mesh opening was 850μm. Sieving with a sieve. To this mixed powder, 0.35 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industry) was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 1.1% of magnesium stearate equivalent to the weight of the uncoated tablet was added through a 500 μm sieve and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.2 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物48.99g、軽質無水ケイ酸(エロジール200、日本アエロジル製)0.25gおよびクロスカルメロースナトリウム(キッコレートND-2HS、旭化成ケミカルズ製)0.75gを混合し、目開き850μmの篩で篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.5%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.6mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 24
48.99g of Compound A methanesulfonate hydrate, 0.25g of light anhydrous silicic acid (Erogil 200, manufactured by Nippon Aerosil Co., Ltd.) and 0.75g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals Co., Ltd.) are mixed. And sieved with a sieve. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, magnesium stearate equivalent to 0.5% based on the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物48.99g、含水二酸化ケイ素(カープレックス#80、DSLジャパン製)0.25gおよびクロスカルメロースナトリウム(キッコレートND-2HS、旭化成ケミカルズ製)0.75gを混合し、目開き850μmの篩で篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.5%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.6mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 25
48.99 g of methanesulfonate hydrate of Compound A, 0.25 g of hydrous silicon dioxide (Carplex # 80, manufactured by DSL Japan) and 0.75 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals) are mixed. Sieving with an 850 μm sieve. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, magnesium stearate equivalent to 0.5% based on the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物49.24gおよびクロスカルメロースナトリウム(キッコレートND-2HS、旭化成ケミカルズ製)0.76gを混合し、目開き850μmの篩で篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.5%相当量の軽質無水ケイ酸(エロジール200、日本アエロジル製)および0.5%相当量の500μmの篩を通したステアリン酸マグネシウムを加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.6mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 26
49.24 g of methanesulfonate hydrate of Compound A and 0.76 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals) were mixed and sieved with a sieve having an opening of 850 μm. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.5% equivalent amount of light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil Co., Ltd.) and 0.5% equivalent amount of magnesium stearate passed through a 500 μm sieve were added. Mixed for minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物49.24gおよびクロスカルメロースナトリウム(キッコレートND-2HS、旭化成ケミカルズ製)0.76gを混合し、目開き850μmの篩で篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.5%相当量の含水二酸化ケイ素(カープレックス#80、DSLジャパン製)および0.5%相当量の500μmの篩を通したステアリン酸マグネシウムを加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.6mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 27
49.24 g of methanesulfonate hydrate of Compound A and 0.76 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals) were mixed and sieved with a sieve having an opening of 850 μm. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.5% equivalent amount of hydrous silicon dioxide (Carplex # 80, manufactured by DSL Japan) and 0.5% equivalent amount of magnesium stearate passed through a 500 μm sieve are added to the uncoated tablet weight, Mix for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物48.99gおよびカルメロースカルシウム(E.C.G-505、ニチリン化学製)1.01gを混合し、目開き850μmの篩で篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.5%相当量のステアリン酸マグネシウムを500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.6mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 28
48.99 g of methanesulfonate hydrate of Compound A and 1.01 g of carmellose calcium (ECG-505, manufactured by Nichirin Chemical) were mixed and sieved with a sieve having an opening of 850 μm. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, magnesium stearate equivalent to 0.5% based on the weight of the uncoated tablet was added through a 500 μm sieve and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物48.99gおよびクロスカルメロースナトリウム(キッコレートND-2HS、旭化成ケミカルズ製)1.01gを混合し、目開き850μmの篩で篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.5%相当量のステアリン酸マグネシウムを500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり6.6mgの割合でコーティングし、フィルムコーティング錠を得た。 Example 29
48.99 g of methanesulfonate hydrate of Compound A and 1.01 g of croscarmellose sodium (Kickolate ND-2HS, manufactured by Asahi Kasei Chemicals) were mixed and sieved with a sieve having an opening of 850 μm. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, magnesium stearate equivalent to 0.5% based on the weight of the uncoated tablet was added through a 500 μm sieve and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 6.6 mg per tablet to obtain film-coated tablets.
化合物Aのメタンスルホン酸塩水和物44.05g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)4.43g、軽質無水ケイ酸(エロジール200、日本アエロジル製)0.49g、トウモロコシデンプン(日食コーンスターチW、日本食品化工製)2.53gおよび目開き500μmの篩を通したステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.46gを混合し、目開き850μmの篩で2回篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.3mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤として、オパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Reference example 1
44.05g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 4.43g, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil Co., Ltd.) 0.49g, corn starch (eclipse corn starch W, Japanese food) (Kako) (2.53 g) and 0.46 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) passed through a sieve having an opening of 500 μm were mixed, and sieved twice with a sieve having an opening of 850 μm. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.3 mg per tablet to obtain film-coated tablets. As a coating agent, a material obtained by adding a small amount of a silicon antifoaming agent (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) to Opadry 00K43069 was used.
化合物Aのメタンスルホン酸塩水和物44.07g、結晶セルロース(セオラス PH101、旭化成ケミカルズ製)4.45g、軽質無水ケイ酸(エロジール200、日本アエロジル製)0.49g、ヒドロキシプロピルスターチ(HPS101、日澱化学製)2.53gおよび目開き500μmの篩を通したステアリン酸マグネシウム(ステアリン酸マグネシウム、太平化学産業製)0.46gを混合し、目開き850μmの篩で2回篩過した。この混合末を30分間混合した。この混合末を乾式造粒機にて圧縮成形し、成形された固形物を整粒した。得られた整粒末に、素錠重量に対して0.3%相当量のステアリン酸マグネシウムを目開き500μmの篩を通して加え、30分間混合した。この混合末を錠剤径8.5mmでダブルアール面の杵を用い、打錠圧12kNで打錠し、1錠300mgの円形の素錠を得た。素錠にコーティング剤を1錠あたり5.3mgの割合でコーティングし、フィルムコーティング錠を得た。なお、コーティング剤として、オパドライ00K43069にシリコン消泡剤(KM72、信越化学製)を微量添加したものを使用した。 Reference example 2
44.07 g of methanesulfonate hydrate of Compound A, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) 4.45 g, light anhydrous silicic acid (Erogyl 200, manufactured by Nippon Aerosil) 0.49 g, hydroxypropyl starch (HPS101, manufactured by Nissho Chemical Co., Ltd.) ) 0.46 g of magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) passed through a sieve having 2.53 g and an opening of 500 μm was mixed and sieved twice with a sieve having an opening of 850 μm. This mixed powder was mixed for 30 minutes. This mixed powder was compression-molded with a dry granulator, and the formed solid was sized. To the obtained sized powder, 0.3% of magnesium stearate relative to the weight of the uncoated tablet was added through a sieve having an opening of 500 μm and mixed for 30 minutes. This mixed powder was tableted with a tablet diameter of 8.5 mm and a double round face with a tableting pressure of 12 kN to obtain a round uncoated tablet of 300 mg per tablet. The uncoated tablets were coated with a coating agent at a rate of 5.3 mg per tablet to obtain film-coated tablets. As a coating agent, a material obtained by adding a small amount of a silicon antifoaming agent (KM72, manufactured by Shin-Etsu Chemical Co., Ltd.) to Opadry 00K43069 was used.
Claims (8)
- 1-シクロプロピル-8-(ジフルオロメトキシ)-7-[(1R)-1-メチル-2,3-ジヒドロ-1H-イソインドール-5-イル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸のメタンスルホン酸塩水和物の含有率が80~97.5質量%である錠剤。 1-cyclopropyl-8- (difluoromethoxy) -7-[(1R) -1-methyl-2,3-dihydro-1H-isoindol-5-yl] -4-oxo-1,4-dihydroquinoline- A tablet having a methanesulfonate hydrate content of 3-carboxylic acid of 80 to 97.5% by mass.
- 含有率が80~95質量%である、請求項1に記載の錠剤。 The tablet according to claim 1, wherein the content is 80 to 95% by mass.
- 日本薬局方溶出試験第1液を試験液とし、回転数を50rpmとした日本薬局方溶出試験法第2法(パドル法)において、1-シクロプロピル-8-(ジフルオロメトキシ)-7-[(1R)-1-メチル-2,3-ジヒドロ-1H-イソインドール-5-イル]-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸のメタンスルホン酸塩水和物の85%溶出時間が30分以内である、請求項1または2に記載の錠剤。 In the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method) using the first solution of the Japanese Pharmacopoeia Dissolution Test as the test solution and rotating at 50 rpm, 1-cyclopropyl-8- (difluoromethoxy) -7-[( 1R) -1-Methyl-2,3-dihydro-1H-isoindol-5-yl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid methanesulfonate hydrate 85% elution time The tablet according to claim 1 or 2, wherein is within 30 minutes.
- さらに崩壊剤を含有する請求項1~3のいずれか一項に記載の錠剤。 The tablet according to any one of claims 1 to 3, further comprising a disintegrant.
- 崩壊剤がセルロース誘導体、デンプン誘導体およびポリビニルピロリドン誘導体から選ばれる1種以上である請求項4に記載の錠剤。 The tablet according to claim 4, wherein the disintegrant is at least one selected from cellulose derivatives, starch derivatives and polyvinylpyrrolidone derivatives.
- セルロース誘導体がクロスカルメロースナトリウム、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロースおよびカルメロース;デンプン誘導体がデンプングリコール酸ナトリウムおよび部分アルファ化デンプン;ポリビニルピロリドン誘導体がクロスポビドンである請求項5に記載の錠剤。 The tablet according to claim 5, wherein the cellulose derivative is croscarmellose sodium, carmellose calcium, low-substituted hydroxypropylcellulose and carmellose; the starch derivative is sodium starch glycolate and partially pregelatinized starch; and the polyvinylpyrrolidone derivative is crospovidone.
- さらに流動化剤を含有する請求項1~6のいずれか一項に記載の錠剤。 The tablet according to any one of claims 1 to 6, further comprising a fluidizing agent.
- 流動化剤が二酸化ケイ素である請求項7に記載の錠剤。
The tablet according to claim 7, wherein the fluidizing agent is silicon dioxide.
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR112014012994A BR112014012994A2 (en) | 2011-11-30 | 2012-11-29 | tablet containing 1-cyclopropyl-8- (difluoromethoxy) -7 - [(1r) -1-methyl-2,3-dihydro-1h-isoindol-5-yl] -4-oxo-1,4-methanesulfonate hydrate -dihydroquinoline-3-carboxylic acid |
RU2014126094A RU2633477C2 (en) | 2011-11-30 | 2012-11-29 | Pill containing methanesulfonate hydrate of 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2,3-dihydro-1h-isoindole-5-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid |
SG11201402597WA SG11201402597WA (en) | 2011-11-30 | 2012-11-29 | Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonic acid hydrate |
CN201280066321.0A CN104039322A (en) | 2011-11-30 | 2012-11-29 | Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonic acid hydrate |
JP2013547208A JP6117112B2 (en) | 2011-11-30 | 2012-11-29 | 1-cyclopropyl-8- (difluoromethoxy) -7-[(1R) -1-methyl-2,3-dihydro-1H-isoindol-5-yl] -4-oxo-1,4-dihydroquinoline- Tablets containing 3-carboxylic acid methanesulfonate hydrate |
MX2014006378A MX350659B (en) | 2011-11-30 | 2012-11-29 | Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-met hyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3 -carboxylic acid methanesulfonic acid hydrate. |
ZA2014/03942A ZA201403942B (en) | 2011-11-30 | 2014-05-29 | Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindol-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonate hydrate |
PH12014501224A PH12014501224B1 (en) | 2011-11-30 | 2014-05-30 | Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonate hydrate |
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JP2011261727 | 2011-11-30 | ||
JP2011-261727 | 2011-11-30 |
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PCT/JP2012/080887 WO2013081044A1 (en) | 2011-11-30 | 2012-11-29 | Tablet containing 1-cyclopropyl-8-(difluoromethoxy)-7-[(1r)-1-methyl-2, 3-dihydro-1h-isoindole-5-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methanesulfonic acid hydrate |
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JP (1) | JP6117112B2 (en) |
CN (2) | CN109662952A (en) |
BR (1) | BR112014012994A2 (en) |
MX (1) | MX350659B (en) |
MY (1) | MY169750A (en) |
PH (1) | PH12014501224B1 (en) |
RU (1) | RU2633477C2 (en) |
SG (1) | SG11201402597WA (en) |
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Cited By (3)
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WO2017073738A1 (en) * | 2015-10-29 | 2017-05-04 | 日本臓器製薬株式会社 | Tablet having fexofenadine as effective component thereof |
WO2017188362A1 (en) * | 2016-04-27 | 2017-11-02 | 富山化学工業株式会社 | Tablet containing tosufloxacin tosilate, disintegrator and acidic amino acid |
JP2019073488A (en) * | 2017-10-19 | 2019-05-16 | 日本化薬株式会社 | Pharmaceutical tablets containing aprepitant as active ingredient |
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JP2005047861A (en) * | 2003-07-30 | 2005-02-24 | Shionogi & Co Ltd | Stable tablet containing crystalline cellulose |
JP2011068647A (en) * | 2009-08-31 | 2011-04-07 | Kowa Co | Solid formulation containing aspartic acid or salt thereof |
WO2011059075A1 (en) * | 2009-11-13 | 2011-05-19 | 味の素株式会社 | Glutamic acid-rich and arginine-rich preparation |
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JP4370050B2 (en) * | 2000-12-04 | 2009-11-25 | 大正製薬株式会社 | Clarithromycin tablets and method for producing the same |
DE60318384T2 (en) * | 2003-03-19 | 2009-02-19 | The Jordanian Pharmaceutical Manufacturing Co. Ltd. | Non-hygroscopic pharmaceutical compositions containing non-hydrated quinolone carboxylic acids |
DE602005012107D1 (en) * | 2004-08-13 | 2009-02-12 | Schering Plough Ltd | PHARMACEUTICAL FORMULATIONS WITH AN ANTIBIOTI |
US20070249577A1 (en) * | 2005-05-10 | 2007-10-25 | Hopkins Scott J | Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures |
FI20080352A0 (en) * | 2008-05-09 | 2008-05-09 | Atacama Labs Oy | Process for preparing a tablet with high drug content |
FI20080353A0 (en) * | 2008-05-09 | 2008-05-09 | Atacama Labs Oy | Process for preparing a tablet with extra high drug content |
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2012
- 2012-11-29 MY MYPI2014701375A patent/MY169750A/en unknown
- 2012-11-29 CN CN201910108608.9A patent/CN109662952A/en active Pending
- 2012-11-29 WO PCT/JP2012/080887 patent/WO2013081044A1/en active Application Filing
- 2012-11-29 RU RU2014126094A patent/RU2633477C2/en active
- 2012-11-29 SG SG11201402597WA patent/SG11201402597WA/en unknown
- 2012-11-29 JP JP2013547208A patent/JP6117112B2/en active Active
- 2012-11-29 CN CN201280066321.0A patent/CN104039322A/en active Pending
- 2012-11-29 BR BR112014012994A patent/BR112014012994A2/en not_active Application Discontinuation
- 2012-11-29 MX MX2014006378A patent/MX350659B/en active IP Right Grant
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JP2005047861A (en) * | 2003-07-30 | 2005-02-24 | Shionogi & Co Ltd | Stable tablet containing crystalline cellulose |
JP2011068647A (en) * | 2009-08-31 | 2011-04-07 | Kowa Co | Solid formulation containing aspartic acid or salt thereof |
WO2011059075A1 (en) * | 2009-11-13 | 2011-05-19 | 味の素株式会社 | Glutamic acid-rich and arginine-rich preparation |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017073738A1 (en) * | 2015-10-29 | 2017-05-04 | 日本臓器製薬株式会社 | Tablet having fexofenadine as effective component thereof |
WO2017188362A1 (en) * | 2016-04-27 | 2017-11-02 | 富山化学工業株式会社 | Tablet containing tosufloxacin tosilate, disintegrator and acidic amino acid |
JPWO2017188362A1 (en) * | 2016-04-27 | 2019-02-28 | 富士フイルム富山化学株式会社 | Tablets containing tosufloxacin tosylate, disintegrant and acidic amino acid |
JP2019073488A (en) * | 2017-10-19 | 2019-05-16 | 日本化薬株式会社 | Pharmaceutical tablets containing aprepitant as active ingredient |
JP7058104B2 (en) | 2017-10-19 | 2022-04-21 | 日本化薬株式会社 | Pharmaceutical tablets containing aprepitant as an active ingredient |
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CN104039322A (en) | 2014-09-10 |
MY169750A (en) | 2019-05-15 |
JPWO2013081044A1 (en) | 2015-04-27 |
BR112014012994A2 (en) | 2017-06-13 |
MX350659B (en) | 2017-09-13 |
RU2633477C2 (en) | 2017-10-12 |
MX2014006378A (en) | 2014-10-13 |
PH12014501224A1 (en) | 2014-09-08 |
SG11201402597WA (en) | 2014-09-26 |
ZA201403942B (en) | 2015-08-26 |
CN109662952A (en) | 2019-04-23 |
RU2014126094A (en) | 2016-01-27 |
PH12014501224B1 (en) | 2014-09-08 |
JP6117112B2 (en) | 2017-04-19 |
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