JP6509934B2 - Method for producing imidafenacin-containing tablets by direct compression method - Google Patents
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- 229950005396 imidafenacin Drugs 0.000 title claims description 111
- 238000000034 method Methods 0.000 title claims description 19
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- 238000007907 direct compression Methods 0.000 title 1
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- Medicinal Preparation (AREA)
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Description
本発明は、イミダフェナシンを含有する錠剤の新規製造方法に関する。 The present invention relates to a novel process for the preparation of tablets containing imidafenacin.
イミダフェナシンはムスカリンＭ１受容体及びＭ３受容体を選択的に阻害する抗コリン薬であり、過活動膀胱における尿意切迫感、頻尿及び切迫性尿失禁の治療薬として広く使用されている。現在、イミダフェナシンを有効成分とする医薬品としては、フィルムコーティング錠（ＦＣ錠）と口腔内崩壊錠（ＯＤ錠）が市販されている（非特許文献１）。 Imidafenacin is an anticholinergic that selectively inhibits muscarinic M1 and M3 receptors, and is widely used as a treatment for urinary urgency, frequent urination and urge incontinence in overactive bladder. At present, film-coated tablets (FC tablets) and orally disintegrating tablets (OD tablets) are commercially available as pharmaceuticals containing imidafenacin as an active ingredient (Non-patent Document 1).
特許文献１には、イミダフェナシンを有効成分とするＦＣ錠やその製造方法が開示されている。また、特許文献２〜８には、イミダフェナシンを有効成分とするＯＤ錠やその製造方法が開示されている。 Patent Document 1 discloses an FC tablet containing imidafenacin as an active ingredient and a method for producing the same. Further, Patent Documents 2 to 8 disclose OD tablets containing imidafenacin as an active ingredient and a method for producing the same.
しかしながら、特許文献１〜８には、イミダフェナシンを含有する錠剤の製造方法として、湿式顆粒圧縮法（湿式法）の例しか開示されておらず、その他の製造方法によりイミダフェナシンを含有する錠剤を製造した報告はない。 However, Patent Documents 1 to 8 disclose only an example of a wet granular compression method (wet method) as a method of producing a tablet containing imidafenacin, and produced a tablet containing imidafenacin by another production method. There is no report.
これまでに、イミダフェナシンを含有する錠剤の製造に、湿式顆粒圧縮法（湿式法）以外の製造方法が使用できるか否かについてはわかっていなかった。イミダフェナシンは薬理活性が高いため、錠剤中の含量が極めて少なく、例えば、市販されているＦＣ錠およびＯＤ錠に含まれるイミダフェナシンは０．１ｍｇにすぎない。本発明者らは、このような極微量のイミダフェナシンを含有する錠剤を直打法により製造する場合、イミダフェナシンと添加剤とを均一に混合することが難しく、錠剤ごとのイミダフェナシンの含量にばらつきが生じやすいという課題（含量均一性の課題）があることを見出した。そこで、製造工程が簡便な直打法を用いながら、イミダフェナシンの含量均一性が優れた錠剤の製造方法を提供することが、本発明が解決しようとする課題である。 So far, it has not been known whether manufacturing methods other than the wet granular compression method (wet method) can be used to manufacture tablets containing imidafenacin. Due to the high pharmacological activity of imidafenacin, the content in the tablet is extremely low, for example, imidafenacin contained in commercially available FC tablets and OD tablets is only 0.1 mg. The present inventors have difficulty in uniformly mixing the imidafenacin and the additive when producing a tablet containing such an extremely small amount of imidafenacin by the direct hitting method, and the content of imidafenacin varies from one tablet to another. It was found that there is a problem of being easy (a problem of content uniformity). Therefore, it is an object of the present invention to provide a method for producing a tablet having an excellent content uniformity of imidafenacin while using a direct hitting method in which the production process is simple.
本発明者らは鋭意検討した結果、イミダフェナシンの倍散粉末を直打法の製造工程に用いることで、イミダフェナシンの含量均一性が優れた錠剤を製造することができることを見出し、本発明を完成した。すなわち、本発明は以下の発明を包含する。
［１］（ｉ）イミダフェナシンと薬学的に許容される１または２以上の賦形剤とを混合し、イミダフェナシン倍散を製造する工程、
（ｉｉ）上記イミダフェナシン倍散と薬学的に許容される１または２以上の添加剤とを混合し、調整混合粉末を製造する工程、および
（ｉｉｉ）上記調整混合粉末を圧縮成型する工程
を含む、イミダフェナシンを含有する錠剤の製造方法。
［２］イミダフェナシン倍散が１０〜１６００倍散である、［１］に記載の製造方法。
［３］薬学的に許容される賦形剤が部分アルファー化デンプンおよび／または結晶セルロースである、［１］または［２］に記載の製造方法。
［４］薬学的に許容される添加剤が滑沢剤である、［１］〜［３］のいずれか一つに記載の製造方法。
［５］工程（ｉ）が、以下の（ｉ−１）および（ｉ−２）の工程を含む、［１］〜［４］のいずれか一つに記載の製造方法
（ｉ−１）イミダフェナシンと薬学的に許容される１または２以上の賦形剤とを混合し、１０〜２０％イミダフェナシン散を製造する工程
（ｉ−２）必要により、上記１０〜２０％イミダフェナシン散と薬学的に許容される１または２以上の賦形剤とを混合し、イミダフェナシン１０〜１６００倍散を製造する工程。
As a result of intensive investigations, the present inventors have found that use of imidafenacin powdered powder for the production step of the direct hitting method makes it possible to produce tablets excellent in imidafenacin content uniformity, and completed the present invention. . That is, the present invention includes the following inventions.
[1] (i) mixing imidafenacin with one or more pharmaceutically acceptable excipients to produce imidafenacin powder;
(Ii) mixing the imidafenacin powder with pharmaceutically acceptable one or more additives to produce a modified mixed powder, and (iii) compacting the modified mixed powder, Process for the preparation of tablets containing imidafenacin.
[2] The production method according to [1], wherein the imidafenacin rise is 10 to 1600 times.
[3] The production method according to [1] or [2], wherein the pharmaceutically acceptable excipient is partially pregelatinized starch and / or crystalline cellulose.
[4] The method according to any one of [1] to [3], wherein the pharmaceutically acceptable additive is a lubricant.
[5] The production method (i-1) imidafenacin according to any one of [1] to [4], wherein the step (i) comprises the following steps (i-1) and (i-2): And 10% 20% imidafenacin powder according to the step (i-2) of preparing 10-20% imidafenacin powder by mixing it with one or more pharmaceutically acceptable excipients, and pharmaceutically acceptable with the above 10-20% imidafenacin powder Mixing with one or more excipients to produce imidafenacin 10 to 1600 times the powder.
本発明によれば、イミダフェナシンの倍散粉末を直打法の製造工程に用いることで、錠剤中のイミダフェナシンの含量均一性が優れた錠剤を製造することができる。 According to the present invention, by using imidafenacin powdered powder in the production process of the direct-sticking method, it is possible to produce a tablet excellent in imidafenacin content uniformity in the tablet.
本発明において、イミダフェナシンとは４−（２−メチル−１Ｈ−イミダゾール−１−イル）−２，２−ジフェニルブタンアミドを表す。 In the present invention, imidafenacin represents 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide.
本発明において、錠剤中のイミダフェナシンの含量は０．０２５〜２ｍｇが好ましく、０．０５〜０．２５ｍｇが更に好ましく、０．１ｍｇが特に好ましい。 In the present invention, the content of imidafenacin in the tablet is preferably 0.025 to 2 mg, more preferably 0.05 to 0.25 mg, and particularly preferably 0.1 mg.
本発明の錠剤は、任意の薬学的に許容される添加剤を含むことができる。添加剤は有効成分（イミダフェナシン）以外の成分を表し、医薬品添加物事典［日本医薬品添加剤協会、薬事日報社（２０１６年）］に記載されているものを適宜使用できる。例えば、賦形剤、崩壊剤、結合剤、滑沢剤、コーティング剤、着色剤、光沢剤などが挙げられる。 The tablet of the present invention can contain any pharmaceutically acceptable additive. The additive represents a component other than the active ingredient (imidafenacin), and any of those described in the Pharmaceutical Additives Directory [Japan Pharmaceutical Additives Association, Pharmaceutical Daily News (2016)] can be used as appropriate. For example, excipients, disintegrants, binders, lubricants, coatings, colorants, brighteners and the like can be mentioned.
本発明において、薬学的に許容される賦形剤としては、乳糖および白糖などの糖類、Ｄ−ソルビトールおよびマンニトールなどの糖アルコール類、結晶セルロース、カルメロース、カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、カルボキシメチルセルロースカルシウムおよび低置換度ヒドロキシプロピルセルロースなどのセルロース類、部分アルファー化デンプンおよびトウモロコシデンプンなどのデンプン類などが挙げられる。本発明においては、結晶セルロースおよび／または部分アルファー化デンプンが好ましく、結晶セルロースと部分アルファー化デンプンの両方を配合する場合、結晶セルロースと部分アルファー化デンプンの配合比率は流動性と成形性の観点から４：１が好ましい。 In the present invention, pharmaceutically acceptable excipients include saccharides such as lactose and sucrose, sugar alcohols such as D-sorbitol and mannitol, crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose Examples thereof include sodium, celluloses such as calcium carboxymethylcellulose and low substituted hydroxypropylcellulose, starches such as partially pregelatinized starch and corn starch, and the like. In the present invention, microcrystalline cellulose and / or partially pregelatinized starch are preferred, and when both microcrystalline cellulose and partially pregelatinized starch are blended, the blending ratio of microcrystalline cellulose and partially pregelatinized starch is from the viewpoint of flowability and formability 4: 1 is preferred.
本発明において、薬学的に許容される崩壊剤としては、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウムおよびメチルセルロースなどのセルロース類、部分アルファー化デンプンおよびトウモロコシデンプンなどのデンプン類、クロスポビドンなどが挙げられる。 In the present invention, pharmaceutically acceptable disintegrants include carboxymethyl cellulose, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, celluloses such as croscarmellose sodium and methyl cellulose, starches such as partially pregelatinized starch and corn starch And crospovidone.
本発明において、薬学的に許容される結合剤としては、結晶セルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルメチルセルロース、エチルセルロースおよびメチルセルロースなどのセルロース類、ポビドン、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール完全けん化物、ポリビニルアルコール部分けん化物、カルボキシビニルポリマー、ポリ塩化ビニルなどのビニル系高分子物質、アミノアルキルメタクリレートコポリマー（Ｅ、ＲＳ）、メタクリル酸コポリマー（Ｌ、Ｓ、ＬＤ）、アクリル酸エチル・メタクリル酸メチルコポリマー分散液などのアクリル系高分子物質、ステアリルアルコール、ゼラチン、デキストリン、アラビアゴム、プルラン、マクロゴール、デンプン、などが挙げられる。 In the present invention, pharmaceutically acceptable binders include crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, ethyl cellulose and celluloses such as methyl cellulose, povidone, polyvinyl acetal diethyl amino acetate, polyvinyl alcohol completely saponified , Polyvinyl alcohol partial saponification, carboxy vinyl polymer, vinyl polymer such as polyvinyl chloride, aminoalkyl methacrylate copolymer (E, RS), methacrylic acid copolymer (L, S, LD), ethyl acrylate, methyl methacrylate, methyl methacrylate Acrylic polymer substances such as copolymer dispersion, stearyl alcohol, gelatin, dextrin, gum arabic, pullulan, macrogow , Starch, and the like.
本発明において、薬学的に許容される滑沢剤としては、ステアリン酸およびその金属塩類、タルク、硬化油、軽質無水ケイ酸、含水二酸化ケイ素、ショ糖脂肪酸エステルなどが挙げられる。本発明においては、ステアリン酸マグネシウムが好ましい。 In the present invention, pharmaceutically acceptable lubricants include stearic acid and metal salts thereof, talc, hydrogenated oil, light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid ester and the like. In the present invention, magnesium stearate is preferred.
本発明において、薬学的に許容されるコーティング剤としては、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、エチルセルロース、メチルセルロース、カルメロースカルシウム、カルメロースナトリウム、カルボキシメチルエチルセルロース、結晶セルロース、ヒドロキシプロピルメチルセルロースアセテートサクシネートおよびヒドロキシプロピルメチルセルロースフタレートなどのセルロース類、アミノアルキルメタクリレートコポリマー（Ｅ、ＲＳ）、メタクリル酸コポリマー（Ｌ、Ｓ、ＬＤ）、アクリル酸エチル・メタクリル酸メチルコポリマー分散液などのアクリル系高分子物質、ポビドン、ステアリルアルコール、ポリビニルアセタールジエチルアミノアセテートなどが挙げられる。本発明においては、ヒドロキシプロピルメチルセルロースが好ましい。 In the present invention, as pharmaceutically acceptable coating agents, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, carmellose calcium, carmellose sodium, carboxymethyl ethyl cellulose, crystalline cellulose, hydroxypropyl methyl cellulose acetate succinate and hydroxy Cellulose such as propyl methyl cellulose phthalate, amino alkyl methacrylate copolymer (E, RS), methacrylic acid copolymer (L, S, LD), acrylic polymer such as ethyl acrylate / methyl methacrylate copolymer dispersion, povidone, stearyl Alcohol, polyvinylacetal diethylaminoacetate and the like can be mentioned. In the present invention, hydroxypropyl methylcellulose is preferred.
本発明において、薬学的に許容される着色剤としては、酸化チタン、三二酸化鉄、黄色三二酸化鉄などが挙げられる。 In the present invention, pharmaceutically acceptable coloring agents include titanium oxide, ferric oxide, yellow ferric oxide and the like.
本発明において、薬学的に許容される光沢剤としては、カルナウバロウなどが挙げられる。 In the present invention, pharmaceutically acceptable brighteners include carnauba wax and the like.
本発明は、製造工程中にイミダフェナシン倍散を用いることで、イミダフェナシンの含量均一性が良好な錠剤を製造することができる。本発明のイミダフェナシン倍散は、最終的な錠剤中のイミダフェナシンの含量を考慮して、任意の濃度とすることができる。例えば、イミダフェナシンの含量が低い錠剤を製造する場合はイミダフェナシンの濃度が低いイミダフェナシン倍散とし、イミダフェナシンの含量が高い錠剤を製造する場合はイミダフェナシンの濃度が高いイミダフェナシン倍散とすることが好ましい。本発明においては、１０〜１６００倍散が好ましい。 The present invention can produce tablets with good content uniformity of imidafenacin by using imidafenacin powder during the manufacturing process. The imidafenacin double powder of the present invention can be any concentration in consideration of the content of imidafenacin in the final tablet. For example, when producing a tablet having a low content of imidafenacin, it is preferable to use imidafenacin at a low concentration of imidafenacin, and when producing a tablet having a high content of imidafenacin, to use imidafenacin at a high concentration of imidafenacin. In the present invention, 10 to 1600 times the amount is preferable.
本発明のイミダフェナシン倍散は、例えば、イミダフェナシンと薬学的に許容される賦形剤とを乳鉢または任意の混合機を用いて混合し製造することができる。本発明においては、任意の混合機を用いて混合することが人為的な誤差の少ないことから好ましく、Ｖ型混合機または擂潰機を用いて混合することが更に好ましく、擂潰機を用いて混合することが錠剤中のイミダフェナシンの含量均一性が良好なことから特に好ましい。 The imidafenacin double powder of the present invention can be produced, for example, by mixing imidafenacin and a pharmaceutically acceptable excipient with a mortar or any mixer. In the present invention, mixing using any mixer is preferable because of less artificial error, mixing using a V-type mixer or a grinder is more preferable, and using a grinder Mixing is particularly preferable because the content uniformity of imidafenacin in the tablet is good.
イミダフェナシンの濃度が低いイミダフェナシン倍散を製造する場合は、イミダフェナシンの濃度が高いイミダフェナシン倍散を製造した後、それを薬学的に許容される賦形剤で段階的に希釈し、イミダフェナシンの濃度が低いイミダフェナシン倍散とすることが含量均一性の確保の点から好ましい。例えば、イミダフェナシンと薬学的に許容される賦形剤とを混合して１０〜２０％イミダフェナシン散（イミダフェナシン５〜１０倍散）を製造した後、それと薬学的に許容される賦形剤とを混合してより濃度が低いイミダフェナシン倍散とする工程を繰り返すことにより、イミダフェナシン１０〜１６００倍散とすることが好ましい。 When producing imidafenacin at a low concentration of imidafenacin, after producing imidafenacin at a high concentration of imidafenacin, it is serially diluted with a pharmaceutically acceptable excipient and the concentration of imidafenacin is low. It is preferable to use imidafenacin double powder from the viewpoint of securing the content uniformity. For example, imidafenacin and a pharmaceutically acceptable excipient are mixed to produce 10-20% imidafenacin powder (imidafenacin 5 to 10 times powder), and then it is mixed with a pharmaceutically acceptable excipient The imidafenacin concentration is preferably 10 to 1600 times by repeating the process of reducing the concentration to imidafenacin double powder.
本発明の調整混合粉末は、例えば、上記の方法により製造したイミダフェナシン倍散と薬学的に許容される添加剤とを乳鉢または任意の混合機を用いて混合することで製造することができる。本発明においては、任意の混合機を用いて混合することが好ましく、Ｖ型混合機または擂潰機を用いて混合することが更に好ましく、Ｖ型混合機を用いて混合することが特に好ましい。 The modified mixed powder of the present invention can be produced, for example, by mixing the imidafenacin powder powder prepared by the above-mentioned method and a pharmaceutically acceptable additive with a mortar or any mixer. In the present invention, mixing is preferably performed using any mixer, more preferably using a V-type mixer or a grinder, and particularly preferably using a V-type mixer.
本発明の錠剤は、例えば、上記の方法で製造した調整混合粉末を任意の打錠機を用いて圧縮成型することで製造することができる。 The tablet of the present invention can be produced, for example, by compression molding the prepared mixed powder produced by the above method using any tableting machine.
本発明の錠剤をフィルムコーティング錠とする場合は、例えば、国際公開ＷＯ２００１／０３４１４７に記載の方法により行うことができる。 When making the tablet of this invention into a film coating tablet, it can carry out by the method of international publication WO2001 / 034147, for example.
以下、実施例により本発明を説明するが、本発明はこれらの実施例によって限定されるものではない。 Hereinafter, the present invention will be described by way of examples, but the present invention is not limited by these examples.
（実施例１）
イミダフェナシン０．０５ｍｇ素錠の製造
Example 1
Manufacture of imidafenacin 0.05 mg plain tablet
（工程１）１０％イミダフェナシン散（イミダフェナシン１０倍散）の製造
イミダフェナシン１５．０ｇと部分アルファー化デンプン（スターチ１５００）６０．０ｇを、乳棒回転数１０７ｍｉｎ−１、乳鉢回転数７ｍｉｎ−１、混合時間２０分間の条件下、擂潰機（ラボミルＵＴ‐２１）を用いて混合し、２０％イミダフェナシン散を得た。これに部分アルファー化デンプン（スターチ１５００）７５．０ｇを加え、乳棒回転数１０７ｍｉｎ−１、乳鉢回転数７ｍｉｎ−１、混合時間２０分間の条件下、擂潰機（ラボミルＵＴ‐２１）を用いて混合し、１０％イミダフェナシン散を得た（バッチ１）。同様にして同量の１０％イミダフェナシン散を得た（バッチ２）。バッチ１とバッチ２を合わせ、乳棒回転数１０７ｍｉｎ−１、乳鉢回転数７ｍｉｎ−１、混合時間２０分間の条件下、擂潰機（ラボミルＵＴ‐２１）を用いて混合し、１０％イミダフェナシン散を２９７．８ｇ得た（定量結果：平均含量９７．８％、レンジ１．４％）。
(Step 1) Preparation of 10% imidafenacin powder (imidaphenacin 10 times powder) 15.0 g of imidafenacin and 60.0 g of partially pregelatinized starch (starch 1500), pestle rotation speed 107 min -1 , mortar rotation speed 7 min -1 , mixing time The mixture was mixed using a grinder (Labor Mill UT-21) for 20 minutes to obtain 20% imidafenacin powder. To this, 75.0 g of partially pregelatinized starch (starch 1500) is added, pestle rotation speed 107 min -1 , mortar rotation speed 7 min -1 , mixing time 20 minutes, using crushing machine (Rabomill UT-21) Mix to obtain 10% imidafenacin powder (batch 1). The same amount of 10% imidafenacin powder was obtained in the same manner (batch 2). Batch 1 and batch 2 are combined and mixed using a grinder (Labor Mill UT-21) under conditions of pestle rotation speed 107 min -1 , mortar rotation speed 7 min -1 , mixing time 20 minutes, and 10% imidafenacin powder 297.8 g were obtained (quantitative result: average content 97.8%, range 1.4%).
（工程２）イミダフェナシン０．０５ｍｇ素錠の製造
工程１で得られた１０％イミダフェナシン散１０．２０ｇおよび部分アルファー化デンプン（スターチ１５００）５０．０ｇを、回転数３１ｍｉｎ−1、混合時間２０分間の条件下、Ｖ型混合機（小型Ｖ混１５）を用いて混合し、イミダフェナシン６０倍散を得た。これに結晶セルロース（アビセルＰＨ−３０１）３９．０ｇおよび部分アルファー化デンプン（スターチ１５００）２６１．０ｇを加え、回転数３１ｍｉｎ−１、混合時間２０分間の条件下、Ｖ型混合機（小型Ｖ混１５）を用いて混合し、イミダフェナシン３６０倍散を得た。これに結晶セルロース（アビセルＰＨ−３０１）１２３５．０ｇを加え、回転数３１ｍｉｎ−１、混合時間２０分間の条件下、Ｖ型混合機（小型Ｖ混１５）を用いて混合し、イミダフェナシン１５９５．２倍散を得た。これにステアリン酸マグネシウム４．８ｇを加え、回転数３１ｍｉｎ−1、混合時間１０分間の条件下、Ｖ型混合機（小型Ｖ混１５）で調整混合し、調整混合粉末を１５９８．２ｇ得た（含量均一性試験結果：平均含量９９．７％、判定値１．８％）。
得られた調整混合粉末１３４０．１ｇを、下杵圧７７４〜８２５ｋｇの条件下、小型高速打錠機（ＨＴ−ＡＰ１８−ＳＳ−ＩＩ）を用いて圧縮成型し、イミダフェナシン０．０５ｍｇ素錠を５７８．４ｇ（８０．０２ｍｇ／錠）得た。
(Step 2) Preparation of imidafenacin 0.05 mg plain tablet 10.20 g of the 10% imidafenacin powder obtained in Step 1 and 50.0 g of partially pregelatinized starch (starch 1500) at a rotation speed of 31 min −1 and a mixing time of 20 minutes Under the conditions, mixing was carried out using a V-type mixer (small V mixing 15) to obtain imidafenacin 60 fold powder. To this, 39.0 g of crystalline cellulose (Avicel PH-301) and 261.0 g of partially pregelatinized starch (starch 1500) were added, and the V-type mixer (small V-blender) was operated under the conditions of rotation speed 31 min -1 and mixing time 20 minutes. The mixture was mixed using 15) to obtain imidafenacin 360-fold powder. To this, 1235.0 g of crystalline cellulose (Avicel PH-301) is added, and mixed using a V-type mixer (small V mixing 15) under the conditions of a rotation speed of 31 min -1 and a mixing time of 20 minutes. I got a double shot. To this, 4.8 g of magnesium stearate was added, and the mixture was adjusted and mixed by a V-type mixer (small V mixture 15) under the conditions of a rotation number of 31 min -1 and a mixing time of 10 minutes to obtain 1598.2 g of adjusted mixed powder ( Content uniformity test result: Average content 99.7%, judgment value 1.8%).
The prepared mixed powder 1340.1 g was compression molded using a small high-speed tableting machine (HT-AP18-SS-II) under a lower punch pressure of 774 to 825 kg to obtain imidafenacin 0.05 mg plain tablet 578 It obtained .4 g (80.02 mg / tablet).
（実施例２）
イミダフェナシン０．０５ｍｇＦＣ錠の製造
(Example 2)
Manufacture of imidafenacin 0.05 mg FC tablets
（工程１）コーティング液の調整
１Ｌのステンレス容器に精製水５７５ｇを採取し、これにヒドロキシプロピルメチルセルロース（ＴＣ−５ＲＷ）５０ｇを徐々に加えて攪拌し、分散・溶解させた。
(Step 1) Preparation of Coating Solution 575 g of purified water was collected in a 1 L stainless steel container, 50 g of hydroxypropyl methylcellulose (TC-5RW) was gradually added to this, and the mixture was stirred, dispersed and dissolved.
（工程２）イミダフェナシン０．０５ｍｇＦＣ錠の製造
実施例１で得られたイミダフェナシン０．０５ｍｇ素錠５０００錠（４００．２ｇ）に、ハイコーター試験機（ＨＣＴ−ＭＩＮＩ）を用いてコーティング液２５０．０ｇをコーティングし、イミダフェナシン０．０５ｍｇコーティング錠を４１５．６ｇ（８３．１５ｍｇ／錠）得た。
得られたイミダフェナシン０．０５ｍｇコーティング錠４９９８錠に、カルナウバロウ（ポリシングワックス−１０３）１０．０２ｍｇを添加、混合し、イミダフェナシン０．０５ｍｇＦＣ錠を４１５．７ｇ（８３．１５ｍｇ／錠）得た。
(Step 2) Preparation of imidafenacin 0.05 mg FC tablet The imidafenacin 0.05 mg plain tablet 5000 tablet (400.2 g) obtained in Example 1 was coated with 250.0 g of a coating solution using a high coater tester (HCT-MINI). Were coated to give 415.6 g (83.15 mg / tablet) of imidafenacin 0.05 mg-coated tablet.
To the obtained imidafenacin 0.05 mg coated tablet 4998 tablets was added 10.02 mg carnauba wax (Policing Wax-103) and mixed to obtain 415.7 g (83.15 mg / tablet) imidafenacin 0.05 mg FC tablet.
実施例１で得られた素錠および実施例２で得られたＦＣ錠の処方（各成分の量の単位：ｍｇ／錠）と物性を表１に示す。なお、表中、ＨＰＭＣはヒドロキシプロピルメチルセルロースを表す。 Table 1 shows the formulations (unit of amount of each component: mg / tablet) and physical properties of the core tablet obtained in Example 1 and the FC tablet obtained in Example 2. In the table, HPMC represents hydroxypropyl methylcellulose.
得られた錠剤は、含量均一性、硬度、摩損度のいずれも良好な物性を示した。 The obtained tablets exhibited good physical properties in all of content uniformity, hardness and friability.
（実施例３）
イミダフェナシン０．２５ｍｇ素錠の製造
(Example 3)
Production of imidafenacin 0.25 mg plain tablet
実施例１の工程１で得られた１０％イミダフェナシン散３０．７０ｇおよび部分アルファー化デンプン（スターチ１５００）１８０．０ｇを、回転数３１ｍｉｎ−1、混合時間２０分間の条件下、Ｖ型混合機（小型Ｖ混１５）を用いて混合し、イミダフェナシン７０倍散を得た。これに結晶セルロース（アビセルＰＨ−３０１）１１０８．７ｇおよび部分アルファー化デンプン（スターチ１５００）６９．０ｇを加え、回転数３１ｍｉｎ−１、混合時間２０分間の条件下、Ｖ型混合機（小型Ｖ混１５）を用いて混合し、イミダフェナシン４６２．８倍散を得た。これにステアリン酸マグネシウム３．６ｇを加え、回転数３１ｍｉｎ−1、混合時間１０分間の条件下、Ｖ型混合機（小型Ｖ混１５）で調整混合し、調整混合粉末を１３９０．５ｇ得た（含量均一性試験結果：平均含量１００．４％、判定値１．９％）。
得られた調整混合粉末１１４２．６ｇを、下杵圧５１０〜５３１ｋｇの条件下、小型高速打錠機（ＨＴ−ＡＰ１８−ＳＳ−ＩＩ）を用いて圧縮成型し、イミダフェナシン０．２５ｍｇ素錠を５１８．７ｇ（１１５．８７ｍｇ／錠）得た。
30.70 g of 10% imidafenacin powder obtained in step 1 of Example 1 and 180.0 g of partially pregelatinized starch (starch 1500) were mixed with a V-type mixer (rotation speed: 31 min −1 , mixing time: 20 minutes) The mixture was mixed using a small V mixture 15) to obtain imidafenacin 70-fold powder. This crystalline cellulose (Avicel PH-301) 1108.7g and partially pregelatinized starch (Starch 1500) 69.0 g was added, rotating speed 31Min -1, under the conditions of mixing time 20 min, V-type mixer (small V mixed The mixture was mixed using 15) to obtain imidafenacin 462.8 times powder. To this, 3.6 g of magnesium stearate was added, and the mixture was adjusted and mixed by a V-type mixer (small V mixing 15) under the conditions of a rotation number of 31 min -1 and a mixing time of 10 minutes to obtain 1390.5 g of adjusted mixed powder ( Content uniformity test result: Average content 100.4%, judged value 1.9%).
1142.6 g of the prepared mixed powder obtained was compression-molded using a small high-speed tableting machine (HT-AP18-SS-II) under conditions of a lower pressure of 510 to 531 kg, and imidafenacin 0.25 mg plain tablet 518 .7 g (115.87 mg / tablet) were obtained.
（実施例４）
イミダフェナシン０．２５ｍｇＦＣ錠の製造
(Example 4)
Manufacture of imidafenacin 0.25 mg FC tablets
実施例３で得られたイミダフェナシン０．２５ｍｇ素錠３６００錠（４１７．２ｇ）に、ハイコーター試験機（ＨＣＴ−ＭＩＮＩ）を用いて実施例２の工程１で得られたコーティング液１８０．０ｇをコーティングし、イミダフェナシン０．２５ｍｇコーティング錠を４２４．６ｇ（１１７．９ｍｇ／錠）得た。
得られたイミダフェナシン０．２５ｍｇコーティング錠３６０１錠に、カルナウバロウ（ポリシングワックス−１０３）７．２０ｍｇを添加、混合し、イミダフェナシン０．２５ｍｇＦＣ錠を４２４．７５ｇ（１１７．９ｍｇ／錠）得た。
The imidafenacin 0.25 mg plain tablet 3600 tablet (417.2 g) obtained in Example 3 was treated with 180.0 g of the coating solution obtained in step 1 of Example 2 using a high coater tester (HCT-MINI). It coated and obtained 424.6 g (117.9 mg / tablet) of the imidafenacin 0.25 mg coated tablet.
To the obtained imidafenacin 0.25 mg coated tablet 3601 tablets, 7.20 mg of carnauba wax (Policing Wax-103) was added and mixed to obtain 424.75 g (117.9 mg / tablet) of imidafenacin 0.25 mg FC tablet.
実施例３で得られた素錠および実施例４で得られたＦＣ錠の処方（各成分の量の単位：ｍｇ／錠）と物性を表２に示す。なお、表中、ＨＰＭＣはヒドロキシプロピルメチルセルロースを表す。 Table 2 shows the formulations (unit of amount of each component: mg / tablet) and physical properties of the core tablet obtained in Example 3 and the FC tablet obtained in Example 4. In the table, HPMC represents hydroxypropyl methylcellulose.
得られた錠剤は、含量均一性、硬度、摩損度のいずれも良好な物性を示した。 The obtained tablets exhibited good physical properties in all of content uniformity, hardness and friability.
（実施例５）
イミダフェナシン２ｍｇ素錠の製造
(Example 5)
Production of imidafenacin 2 mg plain tablet
（工程１）１０％イミダフェナシン散（イミダフェナシン１０倍散）の製造
イミダフェナシン１２．００ｇと部分アルファー化デンプン（スターチ１５００）４８．００ｇを、乳棒回転数１０６ｍｉｎ−１、乳鉢回転数７ｍｉｎ−１、混合時間２０分間の条件下、擂潰機（ラボミルＵＴ‐２１）を用いて混合し、２０％イミダフェナシン散を得た。これに部分アルファー化デンプン（スターチ１５００）６０．００ｇを加え、乳棒回転数１０６ｍｉｎ−１、乳鉢回転数７ｍｉｎ−１、混合時間２０分間の条件下、擂潰機（ラボミルＵＴ‐２１）を用いて混合し、１０％イミダフェナシン散を得た（バッチ１）。同様にして同量の１０％イミダフェナシン散を得た（バッチ２）。バッチ１とバッチ２を合わせ、乳棒回転数１０６ｍｉｎ−１、乳鉢回転数７ｍｉｎ−１、混合時間２０分間の条件下、擂潰機（ラボミルＵＴ‐２１）を用いて混合し、１０％イミダフェナシン散を２３８．５０ｇ得た（定量結果：平均含量９８．９％、レンジ２．２％）。
(Step 1) Preparation of 10% imidafenacin powder (imidafenacin 10 times powder) 12.00 g of imidafenacin and 48.00 g of partially pregelatinized starch (starch 1500), pestle rotation number 106 min -1 , mortar rotation number 7 min -1 , mixing time The mixture was mixed using a grinder (Labor Mill UT-21) for 20 minutes to obtain 20% imidafenacin powder. To this, 60.00 g of partially pregelatinized starch (starch 1500) is added, pestle rotation speed 106 min -1 , mortar rotation speed 7 min -1 , mixing time 20 minutes, using crushing machine (Rabomill UT-21) Mix to obtain 10% imidafenacin powder (batch 1). The same amount of 10% imidafenacin powder was obtained in the same manner (batch 2). Batch 1 and batch 2 are combined and mixed using a grinder (Labor Mill UT-21) under conditions of pestle rotation speed 106 min -1 , mortar rotation speed 7 min -1 , mixing time 20 minutes, and 10% imidafenacin powder 238.50 g were obtained (quantitative result: average content 98.9%, range 2.2%).
（工程２）イミダフェナシン２ｍｇ素錠の製造
工程１で得られた１０％イミダフェナシン散２０２．２ｇ、結晶セルロース（アビセルＰＨ−３０１）１０７７．８ｇおよび部分アルファー化デンプン（スターチ１５００）６６．０ｇを、回転数３１ｍｉｎ−1、混合時間２０分間の条件下、Ｖ型混合機（小型Ｖ混１５）を用いて混合した。これにステアリン酸マグネシウム４．００ｇを加え、回転数３１ｍｉｎ−1、混合時間２０分間の条件下、Ｖ型混合機（小型Ｖ混１５）で調整混合し、調整混合粉末を１３４９．０ｇ得た（含量均一性試験結果：平均含量１００．３％、判定値１．０％）。
得られた調整混合粉末１０４５．０ｇを、下杵圧５３８〜５６９ｋｇの条件下、小型高速打錠機（ＨＴ−ＡＰ１８−ＳＳ−ＩＩ）を用いて圧縮成型し、イミダフェナシン２ｍｇ素錠を６６４．９５ｇ（１３４．９０ｍｇ／錠）得た。
(Step 2) Preparation of imidafenacin 2 mg plain tablet 202.2 g of 10% imidafenacin powder obtained in step 1, 1077.8 g of crystalline cellulose (Avicel PH-301) and 66.0 g of partially pregelatinized starch (starch 1500) It mixed using the V-type mixer (small V mixing 15) the conditions of several 31 min < -1 > and mixing time 20 minutes. To this, 4.00 g of magnesium stearate was added, and the mixture was adjusted and mixed by a V-type mixer (small V mixture 15) under the conditions of a rotation number of 31 min -1 and a mixing time of 20 minutes to obtain 1349.0 g of adjusted mixed powder ( Content uniformity test result: Average content 100.3%, judgment value 1.0%).
The prepared mixed powder of 1045.0 g was compression molded using a small-sized high-speed tableting machine (HT-AP18-SS-II) under conditions of lower pressure of 538-569 kg to give 664.95 g of imidafenacin 2 mg plain tablet. (134.90 mg / tablet) was obtained.
（実施例６）
イミダフェナシン２ｍｇＦＣ錠の製造
(Example 6)
Manufacture of imidafenacin 2 mg FC tablets
実施例５で得られたイミダフェナシン２ｍｇ素錠３０００錠（４０４．７０ｇ）に、ハイコーター試験機（ＨＣＴ−ＭＩＮＩ）を用いて実施例２の工程１で得られたコーティング液１８７．５０ｇをコーティングし、イミダフェナシン２ｍｇコーティング錠を４１６．０５ｇ（１３８．７５ｍｇ／錠）得た。
得られたイミダフェナシン２ｍｇコーティング錠２９９８錠に、カルナウバロウ（ポリシングワックス−１０３）６．０２ｍｇを添加、混合し、イミダフェナシン２ｍｇＦＣ錠を４１６．００ｇ（１３８．７５ｍｇ／錠）得た。
The imidafenacin 2 mg plain tablet 3000 tablets (404.70 g) obtained in Example 5 were coated with 187.50 g of the coating solution obtained in step 1 of Example 2 using a high coater tester (HCT-MINI). And imidafenacin 2 mg coated tablets were obtained at 406.05 g (138.75 mg / tablet).
To the obtained imidafenacin 2 mg coated tablet 2998 tablets, 6.02 mg of carnauba wax (Policing Wax-103) was added and mixed to obtain 416.00 g (138.75 mg / tablet) imidafenacin 2 mg FC tablet.
実施例５で得られた素錠および実施例６で得られたＦＣ錠の処方（各成分の量の単位：ｍｇ／錠）と物性を表３に示す。なお、表中、ＨＰＭＣはヒドロキシプロピルメチルセルロースを表す。 Table 3 shows the formulations (unit of amount of each component: mg / tablet) and physical properties of the core tablet obtained in Example 5 and the FC tablet obtained in Example 6. In the table, HPMC represents hydroxypropyl methylcellulose.
得られた錠剤は、含量均一性、硬度、摩損度のいずれも良好な物性を示した。 The obtained tablets exhibited good physical properties in all of content uniformity, hardness and friability.
本発明によれば、イミダフェナシンの倍散粉末を直打法の製造工程に用いることで、イミダフェナシンの含量均一性が優れた錠剤を製造することができる。 According to the present invention, a tablet having excellent imidafenacin content uniformity can be produced by using imidafenacin powdered powder in the production process of the direct hitting method.
Claims (1)
（ｉ−２）必要により、上記１０〜２０％イミダフェナシン散と薬学的に許容される１または２以上の賦形剤とを混合し、イミダフェナシン１０〜１６００倍散を製造する工程、
（ｉｉ）上記イミダフェナシン倍散と薬学的に許容される１または２以上の添加剤とを混合し、調整混合粉末を製造する工程、および
（ｉｉｉ）上記調整混合粉末を圧縮成型する工程を含む、
イミダフェナシンを含有する錠剤の製造方法。 (I-1) mixing imidafenacin with one or more pharmaceutically acceptable excipients using a grinder to produce 10-20% imidafenacin powder ;
(I-2) optionally mixing the above 10-20% imidafenacin powder with one or more pharmaceutically acceptable excipients to produce imidafenacin 10 to 1600 times powder ;
(Ii) mixing the above imidafenacin powder with pharmaceutically acceptable one or more additives to produce a modified mixed powder;
(Iii) including the step of compacting the above prepared mixed powder,
Process for the preparation of tablets containing imidafenacin .
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