JP5630902B2 - Method for producing orally disintegrating tablets containing zolpidem tartrate - Google Patents
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本発明は、不眠症等の治療剤として有用なゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法に関する。 The present invention relates to a method for producing an orally disintegrating tablet containing zolpidem tartrate useful as a therapeutic agent for insomnia and the like.
口腔内崩壊錠は、水なしで服用することができ、高齢者、小児、嚥下困難な患者等に、飲みやすい剤形であり、高齢化社会の到来や患者のコンプライアンス向上のため、その意義が重要視されるようになって来た。 Orally disintegrating tablets can be taken without water and are easy to drink for elderly people, children, patients with difficulty swallowing, etc., and their significance is due to the arrival of an aging society and improved patient compliance. It has come to be regarded as important.
ゾルピデム酒石酸塩は、苦味等の不快な味を有するため、口腔内で速やかに溶ける口腔内崩壊錠への適用は困難であるという問題があった。 Since zolpidem tartrate has an unpleasant taste such as a bitter taste, there is a problem that application to an orally disintegrating tablet that dissolves rapidly in the oral cavity is difficult.
上記問題を解消して、苦味等の不快な味が低減されたゾルピデム酒石酸塩含有口腔内崩壊錠を製造できる製造方法として、ゾルピデム酒石酸塩、塩基性物質、着色剤、マンニトール等を粉体混合する第一の混合工程；この混合物に、ポリビニルピロリドンを溶解した水溶液を加えて、練合する練合工程；乾燥工程；整粒工程；崩壊剤や滑沢剤等を混合する第二の混合工程；及びこの混合物を錠剤に成型する成型工程を含む方法が公知である（特許文献１特に段落〔００３６〕〜〔００３７〕、図１等参照）。 Zolpidem tartrate, basic substance, colorant, mannitol, etc. are powder mixed as a manufacturing method that can solve the above problems and can produce a zolpidem tartrate-containing orally disintegrating tablet with reduced unpleasant taste such as bitterness A first mixing step; a kneading step in which an aqueous solution in which polyvinylpyrrolidone is dissolved is added to the mixture and kneading; a drying step; a sizing step; a second mixing step in which a disintegrant, a lubricant, and the like are mixed; And a method including a molding step of molding this mixture into a tablet is known (see Patent Document 1, especially paragraphs [0036] to [0037], FIG. 1 and the like).
しかしながら、上記従来公知のゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法においては、第一の混合工程〜成型工程の一連の工程が開放下で行われるので、各工程で使用する機器の開閉の際、次工程に移る際等にゾルピデム酒石酸塩を含む粉体が飛散することを避けるのはほぼ不可能である。そのため、作業員に対して睡眠導入作用を有するゾルピデム酒石酸塩が暴露される機会が非常に多くなり、作業員が眠気を催し、また時にはその眠気が原因で大事故を引き起こすおそれもあるなど、上記従来公知の方法には作業環境が悪いという問題がある。 However, in the above-described conventional method for producing a zolpidem tartrate-containing orally disintegrating tablet, a series of steps from the first mixing step to the molding step is performed under open conditions. It is almost impossible to avoid the scattering of the powder containing zolpidem tartrate when moving to the next step. For this reason, there are numerous opportunities for workers to be exposed to zolpidem tartrate, which has a sleep-inducing action, causing workers to be sleepy and sometimes causing serious accidents due to their sleepiness, etc. The known method has a problem that the working environment is bad.
本発明の目的は、作業環境の問題が無く、苦味等の不快な味が低減され、しかも口腔内崩壊性にも優れた、ゾルピデム酒石酸塩含有口腔内崩壊錠を得ることができる製造方法、及び該製造方法により得られたゾルピデム酒石酸塩含有口腔内崩壊錠を提供することにある。 The object of the present invention is a production method capable of obtaining an orally disintegrating tablet containing zolpidem tartrate, which has no problem in the working environment, has an unpleasant taste such as bitterness, and is excellent in disintegration in the oral cavity, and It is to provide a zolpidem tartrate-containing orally disintegrating tablet obtained by the production method.
本発明者は、上記目的を達成すべく鋭意研究した。その結果、ゾルピデム酒石酸塩含有口腔内崩壊錠を製造するに当たって、ゾルピデム酒石酸塩及び無機塩基性物質を含む混合物に、水をスプレーしつつ流動層造粒して水分含有量が５重量％以上である造粒物を得、次いでこの造粒物を更に流動層造粒する場合には、上記目的を悉く達成し得ることを見出した。即ち、上記の場合には、流動層造粒では原料の混合、造粒及び乾燥が同一の機器中にて閉鎖下で行われることにより、ゾルピデム酒石酸塩を含む粉体が飛散することが実質的に無いこと、１段目の造粒物の水分含有量が特定範囲であることによって、苦味等の不快な味が著しく低減され、かつ口腔内崩壊性にも優れた、ゾルピデム酒石酸塩含有口腔内崩壊錠を得ることができることを見出した。本発明者は、かかる知見に基づいて、更に検討を重ねた結果、本発明を完成するに至った。 The inventor has intensively studied to achieve the above object. As a result, in producing a zolpidem tartrate-containing orally disintegrating tablet, a mixture containing zolpidem tartrate and an inorganic basic substance is granulated in a fluidized bed while spraying water and has a water content of 5% by weight or more. It has been found that when the granulated product is obtained and then this granulated product is further subjected to fluidized bed granulation, the above object can be achieved. That is, in the above case, in the fluidized bed granulation, the mixing of the raw materials, granulation and drying are performed in the same apparatus under closure, so that the powder containing zolpidem tartrate is substantially scattered. In the oral cavity containing zolpidem tartrate, the unpleasant taste such as bitter taste is remarkably reduced and the oral disintegration is excellent because the moisture content of the first-stage granulated product is in a specific range. It was found that a disintegrating tablet can be obtained. As a result of further studies based on this knowledge, the present inventor has completed the present invention.
本発明は、以下に示す、ゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法及び該製造方法により得られたゾルピデム酒石酸塩含有口腔内崩壊錠を提供するものである。 The present invention provides the following method for producing a zolpidem tartrate-containing orally disintegrating tablet and a zolpidem tartrate-containing orally disintegrating tablet obtained by the method.
１．ゾルピデム酒石酸塩含有口腔内崩壊錠を製造する方法であって、ゾルピデム酒石酸塩及び無機塩基性物質を含む混合物に、水をスプレーしつつ流動層造粒して、水分含有量が５重量％以上である１段目の造粒物を得ること、次いでこの１段目の造粒物を更に流動層造粒することを特徴とするゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法。 1. A method for producing an orally disintegrating tablet containing zolpidem tartrate, wherein fluid mixture granulation is performed while spraying water on a mixture containing zolpidem tartrate and an inorganic basic substance, and the water content is 5% by weight or more. A method for producing an orally disintegrating tablet containing zolpidem tartrate, characterized in that a certain first-stage granulated product is obtained, and then the first-stage granulated product is further fluidized-bed granulated.
２．無機塩基性物質が、酸化マグネシウム、炭酸マグネシウム、水酸化マグネシウム、水酸化ナトリウム、ケイ酸カルシウム及び炭酸カルシウムからなる群より選ばれる少なくとも1種である上記項１に記載の製造方法。 2. Item 2. The method according to Item 1, wherein the inorganic basic substance is at least one selected from the group consisting of magnesium oxide, magnesium carbonate, magnesium hydroxide, sodium hydroxide, calcium silicate, and calcium carbonate.
３．無機塩基性物質の使用量が、ゾルピデム酒石酸塩１００重量部に対して、１〜１００重量部である上記項１又は２に記載の製造方法。 3. The manufacturing method of said claim | item 1 or 2 whose usage-amount of an inorganic basic substance is 1-100 weight part with respect to 100 weight part of zolpidem tartrate.
４．１段目の造粒物の水分含有量が、８〜３０重量％である上記項１〜３のいずれかに記載の製造方法。 4. The production method according to any one of Items 1 to 3, wherein the water content of the first-stage granulated product is 8 to 30% by weight.
５．１段目の造粒物の水分含有量が、１０〜２０重量％である上記項４に記載の製造方法。 5. The production method according to item 4, wherein the water content of the first-stage granulated product is 10 to 20% by weight.
６．２段目の流動層造粒工程を、溶媒に結合剤を溶解した溶液をスプレーして行う上記項１〜５のいずれかに記載の製造方法。 6. The production method according to any one of Items 1 to 5, wherein the fluidized bed granulation step in the second stage is performed by spraying a solution in which a binder is dissolved in a solvent.
７．上記項１〜６のいずれかに記載の製造方法によって得られたゾルピデム酒石酸塩含有口腔内崩壊錠。 7). The zolpidem tartrate-containing orally disintegrating tablet obtained by the production method according to any one of Items 1 to 6.
本発明のゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法によれば、ゾルピデム酒石酸塩及び無機塩基性物質を含む混合物に、水をスプレーしつつ流動層造粒（１段目の造粒工程）して水分含有量が５重量％以上である１段目の造粒物を得ること、及び１段目の造粒物を更に流動層造粒（２段目の造粒工程）することによって、以下の如き格別顕著な効果を得ることができる。 According to the method for producing an orally disintegrating tablet containing zolpidem tartrate of the present invention, fluidized-bed granulation (first-stage granulation step) is performed while spraying water on a mixture containing zolpidem tartrate and an inorganic basic substance. By obtaining a first-stage granulated product having a water content of 5% by weight or more and further subjecting the first-stage granulated product to fluidized bed granulation (second-stage granulation step), It is possible to obtain a particularly remarkable effect as follows.
（１）流動層造粒では、原料の混合、造粒及び乾燥が閉鎖下で行われることにより、ゾルピデム酒石酸塩を含む粉体の飛散が実質的に無いので、作業環境が悪化するという問題が生じない。 (1) In fluidized bed granulation, the mixing of the raw materials, granulation, and drying are performed in a closed state, so that there is substantially no scattering of the powder containing zolpidem tartrate, so that the working environment is deteriorated. Does not occur.
（２）上記１段目の流動層造粒の造粒物の水分含有量が特定範囲であることによって、苦味、酸味等の不快な味が著しく低減されたゾルピデム酒石酸塩含有口腔内崩壊錠を得ることができる。 (2) A zolpidem tartrate-containing orally disintegrating tablet in which the unpleasant taste such as bitterness and sourness is remarkably reduced by the water content of the granulated product of the first-stage fluidized bed granulation in a specific range. Can be obtained.
（３）また、得られたゾルピデム酒石酸塩含有口腔内崩壊錠は、口腔内崩壊時間が通常約３０秒以内程度であり、口腔内崩壊性にも優れている。また、優れた口腔内崩壊性を有していながら、自動分包機にも適用可能な錠剤硬度を有している。 (3) Moreover, the obtained zolpidem tartrate-containing orally disintegrating tablet usually has an oral disintegration time of about 30 seconds or less, and is excellent in oral disintegration. Moreover, it has a tablet hardness applicable to an automatic packaging machine while having excellent oral disintegration properties.
（４）従って、本発明の製造方法によれば、作業環境が悪化する等の問題を起こすことなく、苦味等の不快な味が著しく低減され、しかも口腔内崩壊性にも優れたゾルピデム酒石酸塩含有口腔内崩壊錠を得ることができる。 (4) Therefore, according to the production method of the present invention, the uncomfortable taste such as bitter taste is remarkably reduced without causing problems such as deterioration of the working environment, and the oral disintegration property is also excellent. A containing orally disintegrating tablet can be obtained.
ゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法
本発明のゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法は、ゾルピデム酒石酸塩及び無機塩基性物質を含む混合物に、水をスプレーしつつ流動層造粒して水分含有量が５重量％以上である１段目の造粒物を得、次いで得られた１段目の造粒物を更に流動層造粒することを特徴とするものである。即ち、本発明では、かかる少なくとも２段階の流動層造粒工程を行うことを必須とし、１段階の流動層造粒のみでは、苦味等の不快な味が著しく低減され、口腔内崩壊性にも優れ、しかも錠剤強度にも優れたゾルピデム酒石酸塩含有口腔内崩壊錠を得ることは困難である。
Method for Producing Zolpidem Tartrate-Containing Orally Disintegrating Tablet The method for producing the zolpidem tartrate-containing orally disintegrating tablet of the present invention comprises fluidized-bed granulation while spraying water onto a mixture containing zolpidem tartrate and an inorganic basic substance. Thus, a first-stage granulated product having a water content of 5% by weight or more is obtained, and then the obtained first-stage granulated product is further subjected to fluidized bed granulation. That is, in the present invention, it is essential to carry out such a fluidized bed granulation process of at least two stages, and unpleasant taste such as bitterness is remarkably reduced by only one stage of fluidized bed granulation, and the oral disintegration property is also improved. It is difficult to obtain a zolpidem tartrate-containing orally disintegrating tablet that is excellent in tablet strength.
本発明のゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法においては、通常、ゾルピデム酒石酸塩及び無機塩基性物質を含む混合物に、水をスプレーしつつ流動層造粒して、１段目の流動層造粒工程を行って水分含有量が５重量％以上である１段目の造粒物を得、更に、１段目の流動層造粒工程で得られた造粒物を用いて２段目の流動層造粒工程を行った後、成型工程を行うことによって、ゾルピデム酒石酸塩含有口腔内崩壊錠を調製する。ここで、ゾルピデム酒石酸塩及び無機塩基性物質以外の製剤原料として、賦形剤、結合剤、崩壊剤、着色剤、滑沢剤、甘味剤、香料等の添加剤を、適宜使用することができる。これらの添加剤の添加時期は、特に限定されず、任意の工程で添加することができ、又これらのいずれかの添加剤を１の工程または複数の工程において複数回添加することもできる。 In the method for producing an orally disintegrating tablet containing zolpidem tartrate according to the present invention, fluidized bed granulation is usually performed while spraying water onto a mixture containing zolpidem tartrate and an inorganic basic substance, and then the first fluidized bed. A granulation step is performed to obtain a first-stage granulated product having a water content of 5% by weight or more, and a second-stage granule obtained using the first-stage fluidized bed granulation step is used. After performing the fluidized bed granulation step, a zolpidem tartrate-containing orally disintegrating tablet is prepared by performing a molding step. Here, additives such as excipients, binders, disintegrants, colorants, lubricants, sweeteners, and fragrances can be appropriately used as raw materials for preparations other than zolpidem tartrate and inorganic basic substances. . The addition timing of these additives is not particularly limited, and can be added in any step, and any of these additives can be added multiple times in one step or in a plurality of steps.
ゾルピデム酒石酸塩
ゾルピデム酒石酸塩は、本発明の口腔内崩壊錠の活性成分であり、化学名が（＋）−Ｎ，Ｎ，６−トリメチル−２−ｐ−トリルイミダゾ[１，２−ａ]ピリジン−３−アセタミド ヘミ Ｌ−タルトレート（Ｃ１９Ｈ２１Ｎ３Ｏ・1/2Ｃ４Ｈ６Ｏ６）である。ゾルピデム酒石酸塩は、ω１（ＢＺＤ１）受容体に対して選択的な親和性を示し、不眠症等の治療剤として有用である。
Zolpidem tartrate Zolpidem tartrate is an active ingredient of the orally disintegrating tablet of the present invention, and its chemical name is (+)-N, N, 6-trimethyl-2-p-tolyrimidazo [1,2-a] pyridine. -3-acetamido hemi L- tartrate (C 19 H 21 N 3 O · 1 / 2C 4 H 6 O 6). Zolpidem tartrate shows selective affinity for the ω 1 (BZD 1 ) receptor and is useful as a therapeutic agent for insomnia and the like.
無機塩基性物質
本発明のゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法においては、ゾルピデム酒石酸塩及び無機塩基性物質を含む混合物に、水をスプレーしつつ流動層造粒して、１段目の流動層造粒工程を行って水分含有量が５重量％以上である１段目の造粒物を得ることによって、水の存在下で、無機塩基性物質によりゾルピデム酒石酸塩が解離して、ゾルピデムのフリー体が生成して、ゾルピデム酒石酸塩の苦味等の不快な味が低減されるものと推定される。１段目の流動層造粒工程において用いる無機塩基性物質としては、例えば、酸化マグネシウム、炭酸マグネシウム、水酸化マグネシウム、水酸化ナトリウム、ケイ酸カルシウム、炭酸カルシウム等を挙げることができる。これらの無機塩基性物質は、いずれか1種を単独で、又は二種以上を適宜組み合わせて用いることができる。無機塩基性物質の使用量は、ゾルピデム酒石酸塩１００重量部に対して、１〜１００重量部程度であるのが好ましく、１０〜５０重量部程度であるのが、より好ましい。
Inorganic basic substance In the method for producing a zolpidem tartrate-containing orally disintegrating tablet of the present invention, fluidized bed granulation is carried out while spraying water onto a mixture containing zolpidem tartrate and an inorganic basic substance. By performing a fluidized bed granulation step to obtain a first-stage granulated product having a water content of 5% by weight or more, zolpidem tartrate is dissociated by an inorganic basic substance in the presence of water, and zolpidem It is estimated that an unpleasant taste such as the bitter taste of zolpidem tartrate is reduced. Examples of the inorganic basic substance used in the first-stage fluidized bed granulation step include magnesium oxide, magnesium carbonate, magnesium hydroxide, sodium hydroxide, calcium silicate, and calcium carbonate. Any one of these inorganic basic substances can be used alone, or two or more thereof can be used in appropriate combination. The amount of the inorganic basic substance used is preferably about 1 to 100 parts by weight and more preferably about 10 to 50 parts by weight with respect to 100 parts by weight of zolpidem tartrate.
添加剤
本発明のゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法においては、ゾルピデム酒石酸塩及び無機塩基性物質以外の製剤原料として、製薬分野において通常使用される薬理学的に許容される各種添加剤、例えば、賦形剤、崩壊剤、結合剤、着色剤、滑沢剤、甘味剤、香料等の添加剤を、適宜組み合わせて、用いることができる。
Additives In the method for producing the orally disintegrating tablet containing zolpidem tartrate of the present invention, various pharmacologically acceptable additives usually used in the pharmaceutical field as pharmaceutical raw materials other than zolpidem tartrate and inorganic basic substances. For example, additives such as excipients, disintegrants, binders, colorants, lubricants, sweeteners, and fragrances can be used in appropriate combinations.
賦形剤としては、例えば、デキストリン、白糖、果糖、乳糖、トウモロコシデンプン、デンプン、カルボキシメチルスターチナトリウム、部分アルファー化デンプン、ヒドロキシプロピルスターチ、マンニトール、エリスリトール、ソルビトール、キシリトール、トレハロース、マルチトール、ラクチトール、低置換度ヒドロキシプロピルセルロース、結晶セルロース、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポピドン、軽質無水ケイ酸、酸化マグネシウム、炭酸マグネシウム、炭酸カルシウム、クエン酸カルシウム、合成ケイ酸アルミニウムなどが挙げられる。これらの賦形剤は、単独でまたは二種以上組み合わせて使用できる。 Examples of the excipient include dextrin, sucrose, fructose, lactose, corn starch, starch, sodium carboxymethyl starch, partially pregelatinized starch, hydroxypropyl starch, mannitol, erythritol, sorbitol, xylitol, trehalose, maltitol, lactitol, Low substituted hydroxypropyl cellulose, crystalline cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, light anhydrous silicic acid, magnesium oxide, magnesium carbonate, calcium carbonate, calcium citrate, synthetic aluminum silicate, etc. . These excipients can be used alone or in combination of two or more.
崩壊剤としては、例えば、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、架橋化ポリビニルピロリドン、低置換度ヒドロキシプロピルセルロース、各種デンプン類などが挙げられる。これらの崩壊剤は、単独でまたは二種以上組み合わせて使用できる。 Examples of the disintegrant include carmellose calcium, carmellose sodium, croscarmellose sodium, cross-linked polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, and various starches. These disintegrants can be used alone or in combination of two or more.
結合剤としては、例えば、ショ糖等の糖類、ゼラチン、アラビアゴム末、メチルセルロース、エチルセルロース、ヒプロメロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、カルボキシメチルセルロース（カルメロース）、結晶セルロース・カルボキシメチルセルロースナトリウム、ポリビニルピロリドン、ポリビニルアルコール、マクロゴール、プルラン、デキストリン、トラガント、アルギン酸ナトリウム、キサンタンガム、部分α化デンプン、寒天などが挙げられる。これらの結合剤は、単独でまたは二種以上組み合わせて使用できる。 Examples of the binder include saccharides such as sucrose, gelatin, gum arabic powder, methyl cellulose, ethyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose (carmellose), crystalline cellulose / sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol , Macrogol, pullulan, dextrin, tragacanth, sodium alginate, xanthan gum, partially pregelatinized starch, agar and the like. These binders can be used alone or in combination of two or more.
着色剤としては、例えば、黄色三二酸化鉄、三二酸化鉄、黒酸化鉄、食用黄色５号、食用黄色５号アルミニウムレーキ、リボフラビン等が挙げられる。これらの着色剤は、単独でまたは二種以上組み合わせて使用できる。 Examples of the colorant include yellow iron sesquioxide, iron sesquioxide, black iron oxide, edible yellow No. 5, edible yellow No. 5 aluminum lake, riboflavin and the like. These colorants can be used alone or in combination of two or more.
滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、軽質無水ケイ酸、フマル酸ステアリルナトリウム、タルク、水素添加植物油、マイクロクリスタリンワックス、ショ糖脂肪酸エステル、ポリエチレングリコールなどを挙げることができる。 Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, light anhydrous silicic acid, sodium stearyl fumarate, talc, hydrogenated vegetable oil, microcrystalline wax, sucrose fatty acid ester, polyethylene glycol and the like. it can.
甘味剤としては、例えば、スクラロース、サッカリン、サッカリンナトリウム、アスパルテーム、ステビオシドなどを挙げることができる。 Examples of the sweetening agent include sucralose, saccharin, saccharin sodium, aspartame, stevioside and the like.
香料としては、例えば、ストロベリーフレーバー、レモンフレーバー、レモンライムフレーバー、オレンジフレーバー、ｌ−メントール、ハッカ油などが挙げられる。 Examples of the fragrances include strawberry flavor, lemon flavor, lemon lime flavor, orange flavor, l-menthol and peppermint oil.
本発明においては、更に、その他の添加剤として、例えば、甘味剤以外の矯味剤、流動化剤、帯電防止剤、界面活性剤、湿潤剤、充填剤、増量剤、吸着剤、防湿剤、抗酸化剤、保存剤（例えば防腐剤など）、緩衝剤などを用いることもできる。 In the present invention, other additives include, for example, taste-masking agents other than sweeteners, fluidizing agents, antistatic agents, surfactants, wetting agents, fillers, extenders, adsorbents, moisture-proofing agents, Oxidizing agents, preservatives (such as preservatives), buffering agents, and the like can also be used.
本発明において、ゾルピデム酒石酸塩及び無機塩基性物質以外の製剤原料として用いられる、上記各種添加剤の使用量としては、特に制限はない。 In the present invention, there are no particular limitations on the amount of the above-mentioned various additives used as pharmaceutical raw materials other than zolpidem tartrate and inorganic basic substances.
第１流動層造粒工程
本発明のゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法においては、先ず、ゾルピデム酒石酸塩及び無機塩基性物質を含み、更に、必要に応じて、上記各種添加剤などを含む混合物に、水をスプレーしつつ流動層造粒して、１段目の流動層造粒工程を行う。ここで、この流動層造粒は、水をスプレーしつつ行うことが必要である。水をスプレーすることによって、無機塩基性物質がゾルピデム酒石酸塩を解離して、ゾルピデムのフリー体が生成して、ゾルピデム酒石酸塩の苦味等の不快な味を低減するものと考えられるからである。
First fluidized bed granulation step In the method for producing a zolpidem tartrate-containing orally disintegrating tablet of the present invention, first, it contains zolpidem tartrate and an inorganic basic substance, and further contains the above-mentioned various additives as necessary. A fluidized bed granulation step is performed by spraying water on the mixture to be included and performing a first fluidized bed granulation step. Here, it is necessary to perform this fluidized bed granulation while spraying water. This is because it is considered that by spraying water, the inorganic basic substance dissociates zolpidem tartrate to produce a free form of zolpidem, thereby reducing unpleasant tastes such as the bitter taste of zolpidem tartrate.
第１流動層造粒工程は、例えば、流動層造粒装置を用いて、ゾルピデム酒石酸塩を含む粉末状の上記混合物に、水をスプレーしながら、混合し、造粒することが好ましい。水の使用量としては、特に限定されないが、〔（水重量／固形分全重量）×１００〕で表される固液比（重量％）として、通常、２５〜１００重量％程度とするのが、好ましい。また、流動層造粒装置の吸気温度は、特に限定されないが、通常、４０〜８０℃程度とするのが、好ましい。 In the first fluidized bed granulation step, for example, using a fluidized bed granulator, the powdery mixture containing zolpidem tartrate is mixed and granulated while spraying water. The amount of water used is not particularly limited, but the solid-liquid ratio (% by weight) represented by [(water weight / total solid content) × 100] is usually about 25 to 100% by weight. ,preferable. In addition, the intake air temperature of the fluidized bed granulator is not particularly limited, but it is usually preferably about 40 to 80 ° C.
また、第１流動層造粒工程で得られる１段目の造粒物は、その水分含有量が、５重量％以上程度であることが、ゾルピデム酒石酸塩の苦味等の不快な味を低減する観点から、必要である。造粒物の水分含有量が５重量％未満では、苦味等の不快な味の低減が不十分な傾向にあるので、好ましくない。１段目の造粒物の水分含有量は、８〜３０重量％程度であるのが好ましく、１０〜２０重量％程度であるのがより好ましい。造粒物の水分含有量は、流動層造粒装置の吸気温度と液速度を適宜調節することによって、調整することができる。例えば、液速度をほぼ一定にして、所望の水分含有量を達成するために、吸気温度で調整してもよいし、逆に、吸気温度をほぼ一定にして、所望の水分含有量を達成するために、液速度で調整してもよい。 Further, the first-stage granulated product obtained in the first fluidized bed granulation step has a water content of about 5% by weight or more, which reduces unpleasant taste such as zolpidem tartrate bitterness. Necessary from a viewpoint. If the water content of the granulated product is less than 5% by weight, it is not preferable because the reduction of unpleasant taste such as bitterness tends to be insufficient. The water content of the first-stage granulated product is preferably about 8 to 30% by weight, and more preferably about 10 to 20% by weight. The moisture content of the granulated product can be adjusted by appropriately adjusting the intake air temperature and the liquid velocity of the fluidized bed granulator. For example, in order to achieve a desired water content by making the liquid speed substantially constant, the intake air temperature may be adjusted, or conversely, the desired water content may be achieved by making the intake air temperature substantially constant. Therefore, the liquid speed may be adjusted.
第１流動層造粒工程で得られた造粒物は、通常、乾燥後、２段目の流動層造粒工程に供される。 The granulated product obtained in the first fluidized bed granulation step is usually subjected to a second-stage fluidized bed granulation step after drying.
本発明の製造方法において、流動層造粒装置としては、「ＭＰ−１」（パウレック社製）、「ＦＬＯ−５」（フロイント社製）等の市販品を用いることができる。 In the production method of the present invention, commercially available products such as “MP-1” (manufactured by POWREC) and “FLO-5” (manufactured by Freund Corporation) can be used as the fluidized bed granulator.
第２流動層造粒工程
次に、第２流動層造粒工程において、第１流動層造粒工程において得られた１段目の造粒物に、溶媒に結合剤を溶解した溶液をスプレーしつつ、更に造粒する。第２流動層造粒工程においては、溶媒に結合剤を溶解した溶液をスプレーして造粒することが、錠剤の硬度を向上させる観点から、好ましい。溶媒としては、水；エタノール、イソプロパノール等の水性有機溶媒等を１種単独で又は２種以上組み合わせて使用することができる。結合剤の使用量は、結合剤の種類によって変動するが、通常、１錠中に、１〜３重量％程度とするのが好ましい。また、必要に応じて、結合剤に加えて、甘味剤等の添加剤を溶媒に溶解させた溶液をスプレーしてもよい。第２流動層造粒工程において、水等の溶媒の使用量としては、特に限定されないが、固液比として、通常、２５〜１００重量％程度とするのが、好ましい。また、流動層造粒装置の吸気温度は、特に限定されないが、通常、４０〜８０℃程度とするのが、好ましい。
Second fluidized bed granulation step Next, in the second fluidized bed granulation step, a solution in which a binder is dissolved in a solvent is sprayed on the first-stage granulated product obtained in the first fluidized bed granulation step. While further granulating. In the second fluidized bed granulation step, it is preferable to perform granulation by spraying a solution in which a binder is dissolved in a solvent from the viewpoint of improving the hardness of the tablet. As a solvent, water; aqueous organic solvents, such as ethanol and isopropanol, etc. can be used individually by 1 type or in combination of 2 or more types. The amount of the binder used varies depending on the type of the binder, but it is usually preferred to be about 1 to 3% by weight per tablet. Moreover, you may spray the solution which dissolved additives, such as a sweetener, in the solvent in addition to the binder as needed. In the second fluidized bed granulation step, the amount of a solvent such as water is not particularly limited, but the solid-liquid ratio is usually preferably about 25 to 100% by weight. In addition, the intake air temperature of the fluidized bed granulator is not particularly limited, but it is usually preferably about 40 to 80 ° C.
また、第２流動層造粒工程で得られる２段目の造粒物の水分含有量は、特に限定されない。２段目の造粒物は、乾燥後、必要に応じて、整粒後、成型工程に供される。 Moreover, the water content of the second-stage granulated product obtained in the second fluidized bed granulating step is not particularly limited. The second-stage granulated product is subjected to a molding step after drying and, if necessary, after drying.
第２流動層造粒工程で得られた２段目の造粒物は、乾燥後、整粒機を用いて整粒するのが好ましい。整粒に使用する装置としては、特に制限はないが、例えば、「パワーミル」（（株）ダルトン製）、「コーミル」（パウレック社製）、「ロールグラニュレーター」（日本グラニュレーター（株）製）等の整粒機が挙げられる。また、篩などを使用して整粒してもよい。 The second-stage granulated product obtained in the second fluidized bed granulation step is preferably sized using a sizing machine after drying. There are no particular restrictions on the apparatus used for sizing, but for example, “Power Mill” (manufactured by Dalton Co., Ltd.), “Komil” (manufactured by Paulek), “Roll Granulator” (manufactured by Nippon Granulator Co., Ltd.) ) And the like. Moreover, you may size-size using a sieve etc.
本発明のゾルピデム酒石酸塩含有口腔内崩壊錠の製造方法においては、第１流動層造粒工程及び第２流動層造粒工程の２段階の流動層造粒工程を行うことを必須とするが、更に必要に応じて、３段階目以上の造粒工程を行ってもよい。 In the production method of the zolpidem tartrate-containing orally disintegrating tablet of the present invention, it is essential to perform the two-stage fluidized bed granulation step of the first fluidized bed granulation step and the second fluidized bed granulation step, Furthermore, you may perform the granulation process of the 3rd step or more as needed.
成型工程
次いで、成型工程においては、打錠に先立って、必要に応じて、第２流動層造粒工程で得られた２段目の造粒物に、通常、滑沢剤、崩壊剤等の添加剤の少なくとも１種を混合する混合工程を行った後、常法により、打錠を行う。打錠機としては、医薬品の製造に使用しうるものであれば特に制限はなく、例えばロータリー式打錠機や単発打錠機などが使用される。
Molding step Next, in the molding step, prior to tableting, if necessary, the second-stage granulated product obtained in the second fluidized bed granulation step is usually mixed with a lubricant, a disintegrant, etc. After performing the mixing process which mixes at least 1 type of an additive, tableting is performed by a conventional method. The tableting machine is not particularly limited as long as it can be used for the production of pharmaceuticals. For example, a rotary tableting machine or a single-shot tableting machine is used.
かくして得られる本発明のゾルピデム酒石酸塩含有口腔内崩壊錠を使用する場合には、不眠症等の疾患に対する治療有効量を投与すればよい。患者の年令、体重、症状、性別などにより投与量は変わりうるが、１日当たり、就寝前に、ゾルピデム酒石酸塩として、通常、５〜１０ｍｇ程度を、水無しで、唾液のみで経口的に投与することができる。この場合において、本発明のゾルピデム酒石酸塩含有口腔内崩壊錠は、口腔内崩壊性が、通常約３０秒以内程度と良好であり、また優れた口腔内崩壊性を有していながら、ＰＴＰ（プレススルーパッケージ）包装からの押し出しに耐える硬度を有している。 When the thus obtained zolpidem tartrate-containing orally disintegrating tablet of the present invention is used, a therapeutically effective amount for diseases such as insomnia may be administered. The dose may vary depending on the patient's age, weight, symptoms, sex, etc., but per day, before going to bed, usually about 5-10 mg of zolpidem tartrate is given orally in the absence of water and in saliva alone can do. In this case, the zolpidem tartrate-containing orally disintegrating tablet of the present invention has a good orally disintegrating property, usually within about 30 seconds, and has an excellent orally disintegrating property. Through package) Hardness to withstand extrusion from packaging.
本発明のゾルピデム酒石酸塩含有口腔内崩壊錠は、通常、ＰＴＰ包装またはボトル包装（例：ポリ瓶、ガラス瓶、アルミ缶）されているのが好ましい。また、包装中には脱臭剤、乾燥剤、脱酸素剤等を同封しても良い。 The zolpidem tartrate-containing orally disintegrating tablet of the present invention is preferably preferably PTP-packaged or bottle-packaged (eg, a plastic bottle, a glass bottle, an aluminum can). Further, a deodorant, a desiccant, an oxygen scavenger, etc. may be enclosed during packaging.
以下、実施例及び比較例を挙げて、本発明を更に具体的に説明するが、本発明はこれらの実施例によって何ら制限されるものではない。 EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated further more concretely, this invention is not restrict | limited at all by these Examples.
各実施例及び比較例において、造粒物の水分含有量は、赤外線式水分計（ＳＨＩＭＡＤＺＵ社製、機種「ＥＢ−３４０ＭＯＣ」）を用い、乾燥減量を測定して求めた。即ち、造粒物粉末２ｇを９０℃で１５分間乾燥後、重量変化分を水分含有量とした。 In each Example and Comparative Example, the moisture content of the granulated product was determined by measuring the loss on drying using an infrared moisture meter (manufactured by SHIMADZU, model “EB-340MOC”). That is, 2 g of the granulated powder was dried at 90 ° C. for 15 minutes, and the weight change was taken as the water content.
また、各実施例及び比較例において、錠剤の硬度は、錠剤硬度計（ＳＣＨＬＥＵＮＩＧＥＲ社製、機種「ＭＯＤＥＬ ６Ｄ」）を用いて測定し、５錠の測定値の平均値を示した。 Moreover, in each Example and the comparative example, the hardness of the tablet was measured using a tablet hardness meter (manufactured by SCHLEUNIGER, model “MODEL 6D”), and the average value of the measured values of 5 tablets was shown.
実施例１
ゾルピデム酒石酸塩（活性成分、３０．０ｇ）、D−マンニトール（４２１．５ｇ）、低置換度ヒドロキシプロピルセルロース（６０．０ｇ）及び酸化マグネシウム（６．０ｇ）を、流動層造粒装置（パウレック(株)製、機種「ＭＰ−０１」）を用いて混合し、得られた混合物に精製水（４０５ｇ、固液比：７５重量％）を、液速度８．５ｇ／minで噴霧し、吸気温度８０℃、排気温度２５．６℃で、流動層造粒した。１段目の造粒物を該流動層造粒装置で乾燥し、該乾燥物に、ヒドロキシプロピルセルロース（１．５ｇ）及びスクラロース（３．０ｇ）の水溶液（１６２ｇ）を、液速度６．７ｇ／minで噴霧し、吸気温度５５℃、排気温度２５．３℃で、流動層造粒した。２段目の造粒物を乾燥した乾燥物を、「パワーミル」（（株）ダルトン製、機種「Ｐ−０４Ｓ」）にて、φ１．２ｍｍのスクリーンを用いて整粒した。得られた整粒物、軽質無水ケイ酸（６．０ｇ）及びステアリン酸マグネシウム（１２．０ｇ）をV型混合機（不二パルダル(株)製、機種「VM−５」）に投入し、粉末を７分間混合した（固形分量合計５４０．０ｇ）。得られた混合物を、単発打錠機（菊水製作所(株)製）にて、φ８．５ｍｍＲ面（割線入り）杵を用い、打錠圧力約７５０ｋｇで打錠し、１錠あたり活性成分を１０．０ｍｇ含有する重量１８０ｍｇ、厚み３．４０ｍｍの口腔内崩壊錠を製造した。得られた口腔内崩壊錠の硬度は４．３ｋｇであった。
Example 1
Zolpidem tartrate (active ingredient, 30.0 g), D-mannitol (421.5 g), low-substituted hydroxypropylcellulose (60.0 g) and magnesium oxide (6.0 g) were mixed in a fluidized bed granulator (Paurek ( Co., Ltd., model “MP-01”), and purified water (405 g, solid-liquid ratio: 75% by weight) is sprayed on the resulting mixture at a liquid speed of 8.5 g / min. Fluidized bed granulation was performed at 80 ° C. and an exhaust temperature of 25.6 ° C. The granulated product in the first stage is dried with the fluidized bed granulator, and an aqueous solution (162 g) of hydroxypropylcellulose (1.5 g) and sucralose (3.0 g) is added to the dried product at a liquid speed of 6.7 g. Spraying was performed at / min, and fluidized bed granulation was performed at an intake temperature of 55 ° C and an exhaust temperature of 25.3 ° C. The dried product obtained by drying the second-stage granulated product was sized using a screen of φ1.2 mm with “Power Mill” (Dalton Co., Ltd., model “P-04S”). The obtained sized product, light anhydrous silicic acid (6.0 g) and magnesium stearate (12.0 g) were put into a V-type mixer (manufactured by Fuji Pardal Co., Ltd., model “VM-5”), The powder was mixed for 7 minutes (total solid content 540.0 g). The obtained mixture was tableted with a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) using a φ8.5 mmR face (with secant) at a tableting pressure of about 750 kg, and 10 active ingredients per tablet. An orally disintegrating tablet having a weight of 180 mg and a thickness of 3.40 mm was prepared. The hardness of the obtained orally disintegrating tablet was 4.3 kg.
実施例２
ゾルピデム酒石酸塩（活性成分、３０．０ｇ）、D−マンニトール（４２１．５ｇ）、低置換度ヒドロキシプロピルセルロース（６０．０ｇ）及び炭酸マグネシウム（６．０ｇ）を、流動層造粒装置（パウレック(株)製、機種「ＭＰ−０１」）を用いて混合し、得られた混合物に精製水（４０５ｇ、固液比：７５重量％）を、液速度６．５ｇ／minで噴霧し、吸気温度６０℃、排気温度２４．１℃で、流動層造粒した。１段目の造粒物を該流動層造粒装置で乾燥し、該乾燥物に、ヒドロキシプロピルセルロース（１．５ｇ）及びスクラロース（３．０ｇ）の水溶液（１６２ｇ）を、液速度６．７ｇ／minで噴霧し、吸気温度６０℃、排気温度２４．６℃で、流動層造粒した。２段目の造粒物を乾燥した乾燥物を用いて、実施例１と同様にして、整粒し、軽質無水ケイ酸（６．０ｇ）及びステアリン酸マグネシウム（１２．０ｇ）を混合し、打錠して、１錠あたり活性成分を１０．０ｍｇ含有する重量１８０ｍｇ、厚み３．４７ｍｍの口腔内崩壊錠を製造した。得られた口腔内崩壊錠の硬度は４．６ｋｇであった。
Example 2
Zolpidem tartrate (active ingredient, 30.0 g), D-mannitol (421.5 g), low-substituted hydroxypropylcellulose (60.0 g) and magnesium carbonate (6.0 g) were mixed in a fluidized bed granulator (Paurek ( Co., Ltd., model “MP-01”), and purified water (405 g, solid-liquid ratio: 75 wt%) is sprayed on the resulting mixture at a liquid speed of 6.5 g / min. Fluidized bed granulation was performed at 60 ° C. and an exhaust temperature of 24.1 ° C. The granulated product in the first stage is dried with the fluidized bed granulator, and an aqueous solution (162 g) of hydroxypropylcellulose (1.5 g) and sucralose (3.0 g) is added to the dried product at a liquid speed of 6.7 g. Spraying was performed at a rate of / min, and fluidized bed granulation was performed at an intake temperature of 60 ° C and an exhaust temperature of 24.6 ° C. Using the dried product obtained by drying the second-stage granulated product, the size is adjusted in the same manner as in Example 1, and light anhydrous silicic acid (6.0 g) and magnesium stearate (12.0 g) are mixed. Tableting was carried out to produce an orally disintegrating tablet having a weight of 180 mg and a thickness of 3.47 mm containing 10.0 mg of the active ingredient per tablet. The hardness of the obtained orally disintegrating tablet was 4.6 kg.
実施例３
ゾルピデム酒石酸塩（活性成分、３０．０ｇ）、D−マンニトール（４２１．５ｇ）、低置換度ヒドロキシプロピルセルロース（６０．０ｇ）及び水酸化マグネシウム（６．０ｇ）を、流動層造粒装置（パウレック(株)製、機種「ＭＰ−０１」）を用いて混合し、得られた混合物に精製水（４０５ｇ、固液比：７５重量％）を、液速度６．５ｇ／minで噴霧し、吸気温度６０℃、排気温度２４．７℃で、流動層造粒した。１段目の造粒物を該流動層造粒装置で乾燥し、該乾燥物に、ヒドロキシプロピルセルロース（１．５ｇ）及びスクラロース（３．０ｇ）の水溶液（１６２ｇ）を、液速度６．８ｇ／minで噴霧し、吸気温度６０℃、排気温度２４．６℃で、流動層造粒した。２段目の造粒物を乾燥した乾燥物を用いて、実施例１と同様にして、整粒し、軽質無水ケイ酸（６．０ｇ）及びステアリン酸マグネシウム（１２．０ｇ）を混合し、打錠して、１錠あたり活性成分を１０．０ｍｇ含有する重量１８０ｍｇ、厚み３．４７ｍｍの口腔内崩壊錠を製造した。得られた口腔内崩壊錠の硬度は４．０ｋｇであった。
Example 3
Zolpidem tartrate (active ingredient, 30.0 g), D-mannitol (421.5 g), low-substituted hydroxypropylcellulose (60.0 g) and magnesium hydroxide (6.0 g) were mixed in a fluidized bed granulator (Paurec). (Made by Co., Ltd., model “MP-01”), and the resulting mixture was sprayed with purified water (405 g, solid-liquid ratio: 75 wt%) at a liquid speed of 6.5 g / min. Fluidized bed granulation was performed at a temperature of 60 ° C and an exhaust temperature of 24.7 ° C. The granulated product in the first stage is dried with the fluidized bed granulator, and an aqueous solution (162 g) of hydroxypropylcellulose (1.5 g) and sucralose (3.0 g) is added to the dried product at a liquid speed of 6.8 g. Spraying was performed at a rate of / min, and fluidized bed granulation was performed at an intake temperature of 60 ° C and an exhaust temperature of 24.6 ° C. Using the dried product obtained by drying the second-stage granulated product, the size is adjusted in the same manner as in Example 1, and light anhydrous silicic acid (6.0 g) and magnesium stearate (12.0 g) are mixed. Tableting was carried out to produce an orally disintegrating tablet having a weight of 180 mg and a thickness of 3.47 mm containing 10.0 mg of the active ingredient per tablet. The hardness of the obtained orally disintegrating tablet was 4.0 kg.
比較例１
ゾルピデム酒石酸塩（活性成分、３０．０ｇ）、D−マンニトール（４２１．５ｇ）、低置換度ヒドロキシプロピルセルロース（６０．０ｇ）、酸化マグネシウム（６．０ｇ）を、流動層造粒装置（パウレック(株)製、機種「ＭＰ−０１」）を用いて混合し、得られた混合物に、ヒドロキシプロピルセルロース（１．５ｇ）及びスクラロース（３．０ｇ）の水溶液（１６２ｇ）を、液速度６．８ｇ／minで噴霧し、吸気温度５５℃、排気温度２３．７℃で、流動層造粒した。この造粒物を乾燥した乾燥物を、「パワーミル」（（株）ダルトン製、機種「Ｐ−０４Ｓ」）にて、φ１．２ｍｍのスクリーンを用いて整粒した。得られた整粒物、軽質無水ケイ酸（６．０ｇ）及びステアリン酸マグネシウム（１２．０ｇ）をV型混合機（不二パルダル(株)製、機種「VM−５」）に投入し、粉末を７分間混合した（固形分量合計５４０．０ｇ）。得られた混合物を、単発打錠機（菊水製作所(株)製）にて、φ８．５ｍｍＲ面（割線入り）杵を用い、打錠圧力約７５０ｋｇで打錠し、１錠あたり活性成分を１０．０ｍｇ含有する重量１８０ｍｇ、厚み３．４８ｍの口腔内崩壊錠を製造した。得られた口腔内崩壊錠の硬度は３．２ｋｇであった。
Comparative Example 1
Zolpidem tartrate (active ingredient, 30.0 g), D-mannitol (421.5 g), low-substituted hydroxypropylcellulose (60.0 g), magnesium oxide (6.0 g) were added to a fluidized bed granulator (Paurek ( Co., Ltd., model “MP-01”), and an aqueous solution (162 g) of hydroxypropylcellulose (1.5 g) and sucralose (3.0 g) was added to the resulting mixture at a liquid speed of 6.8 g. The mixture was sprayed at / min, and fluidized bed granulation was performed at an intake air temperature of 55 ° C and an exhaust gas temperature of 23.7 ° C. The dried product obtained by drying the granulated product was sized using a screen of φ1.2 mm with “Power Mill” (Dalton Co., Ltd., model “P-04S”). The obtained sized product, light anhydrous silicic acid (6.0 g) and magnesium stearate (12.0 g) were put into a V-type mixer (manufactured by Fuji Pardal Co., Ltd., model “VM-5”), The powder was mixed for 7 minutes (total solid content 540.0 g). The obtained mixture was tableted with a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) using a φ8.5 mmR face (with secant) at a tableting pressure of about 750 kg, and 10 active ingredients per tablet. An orally disintegrating tablet having a weight of 180 mg and a thickness of 3.48 m was prepared. The hardness of the obtained orally disintegrating tablet was 3.2 kg.
実施例１〜３及び比較例１で得られた各ゾルピデム酒石酸塩含有口腔内崩壊錠の苦味を、下記方法によって、評価した。
苦味評価方法：ゾルピデム酒石酸塩含有口腔内崩壊錠を、水無しで、服用したときの苦味を、下記基準により、評価した。
○：苦味を感じることなく、容易に服用できた。
△：やや苦味を感じたが、十分に服用可能であった。
×：苦くて、服用できなかった。
The bitterness of each zolpidem tartrate-containing orally disintegrating tablet obtained in Examples 1 to 3 and Comparative Example 1 was evaluated by the following method.
Bitter taste evaluation method: The bitter taste when taking orally disintegrating tablets containing zolpidem tartrate without water was evaluated according to the following criteria.
○: Can be easily taken without feeling bitter.
Δ: Slight bitterness was felt, but it could be taken sufficiently.
X: It was bitter and could not be taken.
表１に、実施例１〜３及び比較例１における造粒方法及び回数、実施例１〜３及び比較例１で得られた各ゾルピデム酒石酸塩含有口腔内崩壊錠の口腔内崩壊時間、並びに苦味評価結果を示した。 In Table 1, the granulation method and frequency in Examples 1 to 3 and Comparative Example 1, the oral disintegration time of each zolpidem tartrate-containing orally disintegrating tablet obtained in Examples 1 to 3 and Comparative Example 1, and bitterness The evaluation results are shown.
表１から、ゾルピデム酒石酸塩と、酸化マグネシウム、炭酸マグネシウム、水酸化マグネシウム等の無機塩基性物質とを含む混合物に、水をスプレーしつつ流動層造粒して１段目の造粒物を得、次いで得られた１段目の造粒物を更に流動層造粒するという２段階の流動層造粒工程を行うことによって、口腔内崩壊性に優れ、しかも苦味等の不快な味が低減された口腔内崩壊錠が得られることが明らかである。 From Table 1, fluidized-bed granulation is performed while spraying water on a mixture containing zolpidem tartrate and an inorganic basic substance such as magnesium oxide, magnesium carbonate, magnesium hydroxide, etc. to obtain a first-stage granulated product. Then, by carrying out a two-stage fluidized bed granulation process of further fluidized bed granulation of the obtained first stage granulated product, the oral disintegration is excellent and unpleasant taste such as bitterness is reduced. It is clear that an orally disintegrating tablet is obtained.
実施例４
ゾルピデム酒石酸塩（活性成分、３００ｇ）、D−マンニトール（３９００ｇ）、低置換度ヒドロキシプロピルセルロース（６００ｇ）、結晶セルロース（３００ｇ）、酸化マグネシウム（６０ｇ）、黄色三二酸化鉄（微量）及び三二酸化鉄（微量）を、流動層造粒装置（フロイント社製、機種「ＦＬＯ−５」）を用いて混合し、得られた混合物に精製水（２７００ｇ、固液比：５０重量％）を、液速度３４ｇ／minで噴霧し、吸気温度４０℃、排気温度２０．９℃で、流動層造粒した。得られた１段目の造粒物の水分含有量は、１４．２重量％であった。１段目の造粒物を該流動層造粒装置で乾燥し、該乾燥物に、ヒドロキシプロピルセルロース（３０ｇ）及びスクラロース（３０ｇ）の水溶液（１０００ｇ）を、液速度３３ｇ／minで噴霧し、吸気温度６０℃、排気温度２６．９℃で、流動層造粒した。得られた２段目の造粒物の水分含有量は、３．５重量％であった。２段目の造粒物を乾燥した乾燥物を、「パワーミル」（（株）ダルトン製、機種「Ｐ−０４Ｓ」）にて、φ１．２ｍｍのスクリーンを用いて整粒した。得られた整粒物、軽質無水ケイ酸（６０ｇ）及びステアリン酸マグネシウム（１２０ｇ）をV型混合機（不二パルダル(株)製、機種「VM−５」）に投入し、粉末を７分間混合した（固形分量合計５４００ｇ）。得られた混合物を、ロータリー式打錠機（菊水製作所(株)製、機種「ＶＩＲＧＯ−５１２」）にて、φ８．５ｍｍＲ面（割線入り）杵を用い、打錠圧力約７５０ｋｇで打錠し、１錠あたり活性成分を１０．０ｍｇ含有する重量１８０ｍｇ、厚み３．３９ｍｍの口腔内崩壊錠を製造した。得られた口腔内崩壊錠の硬度は５．０ｋｇであった。
Example 4
Zolpidem tartrate (active ingredient, 300 g), D-mannitol (3900 g), low-substituted hydroxypropylcellulose (600 g), crystalline cellulose (300 g), magnesium oxide (60 g), yellow ferric oxide (trace amount) and ferric oxide (Trace amount) was mixed using a fluidized bed granulator (Freund Corporation, model “FLO-5”), and purified water (2700 g, solid-liquid ratio: 50% by weight) was added to the resulting mixture at a liquid speed. Spraying was performed at 34 g / min, and fluidized bed granulation was performed at an intake temperature of 40 ° C. and an exhaust temperature of 20.9 ° C. The water content of the obtained first-stage granulated product was 14.2% by weight. The first-stage granulated product is dried with the fluidized bed granulator, and an aqueous solution (1000 g) of hydroxypropylcellulose (30 g) and sucralose (30 g) is sprayed on the dried product at a liquid speed of 33 g / min. Fluidized bed granulation was performed at an intake temperature of 60 ° C and an exhaust temperature of 26.9 ° C. The water content of the obtained second-stage granulated product was 3.5% by weight. The dried product obtained by drying the second-stage granulated product was sized using a screen of φ1.2 mm with “Power Mill” (Dalton Co., Ltd., model “P-04S”). The obtained sized product, light anhydrous silicic acid (60 g) and magnesium stearate (120 g) are put into a V-type mixer (model “VM-5” manufactured by Fuji Pardal Co., Ltd.), and the powder is added for 7 minutes. Mixed (total amount of solids 5400 g). The obtained mixture was tableted with a rotary tabletting machine (manufactured by Kikusui Seisakusho Co., Ltd., model “VIRGO-512”) using a φ8.5 mmR face (with secant) and a tableting pressure of about 750 kg. An orally disintegrating tablet having a weight of 180 mg and a thickness of 3.39 mm containing 10.0 mg of the active ingredient per tablet was produced. The hardness of the obtained orally disintegrating tablet was 5.0 kg.
実施例５
ゾルピデム酒石酸塩（活性成分、３００ｇ）、D−マンニトール（３９００ｇ）、低置換度ヒドロキシプロピルセルロース（６００ｇ）、結晶セルロース（３００ｇ）、酸化マグネシウム（６０ｇ）、黄色三二酸化鉄（微量）及び三二酸化鉄（微量）を、流動層造粒装置（フロイント社製、機種「ＦＬＯ−５」）を用いて混合し、得られた混合物に精製水（２７００ｇ、固液比：５０重量％）を、液速度３８ｇ／minで噴霧し、吸気温度５０℃、排気温度２３．１℃で、流動層造粒した。得られた１段目の造粒物の水分含有量は、１０．５重量％であった。１段目の造粒物を該流動層造粒装置で乾燥し、該乾燥物に、ヒドロキシプロピルセルロース（３０ｇ）及びスクラロース（３０ｇ）の水溶液（１０００ｇ）を、液速度３７ｇ／minで噴霧し、吸気温度５０℃、排気温度２３．２℃で、流動層造粒した。得られた２段目の造粒物の水分含有量は、１４．６重量％であった。２段目の造粒物を乾燥した乾燥物を、「パワーミル」（（株）ダルトン製、機種「Ｐ−０４Ｓ」）にて、φ１．２ｍｍのスクリーンを用いて整粒した。得られた整粒物、軽質無水ケイ酸（６０ｇ）及びステアリン酸マグネシウム（１２０ｇ）をV型混合機（不二パルダル(株)製、機種「VM−５」）に投入し、粉末を７分間混合した（固形分量合計５４００ｇ）。得られた混合物を、ロータリー式打錠機（菊水製作所(株)製、機種「ＶＩＲＧＯ−５１２」）にて、φ８．５ｍｍＲ面（割線入り）杵を用い、打錠圧力約７５０ｋｇで打錠し、１錠あたり活性成分を１０．０ｍｇ含有する重量１８０ｍｇ、厚み３．４１ｍｍの口腔内崩壊錠を製造した。得られた口腔内崩壊錠の硬度は４．２ｋｇであった。
Example 5
Zolpidem tartrate (active ingredient, 300 g), D-mannitol (3900 g), low-substituted hydroxypropylcellulose (600 g), crystalline cellulose (300 g), magnesium oxide (60 g), yellow ferric oxide (trace amount) and ferric oxide (Trace amount) was mixed using a fluidized bed granulator (Freund Corporation, model “FLO-5”), and purified water (2700 g, solid-liquid ratio: 50% by weight) was added to the resulting mixture at a liquid speed. Spraying was performed at 38 g / min, and fluidized bed granulation was performed at an intake temperature of 50 ° C and an exhaust temperature of 23.1 ° C. The water content of the obtained first-stage granulated product was 10.5% by weight. The granulated product in the first stage is dried with the fluidized bed granulator, and an aqueous solution (1000 g) of hydroxypropylcellulose (30 g) and sucralose (30 g) is sprayed on the dried product at a liquid speed of 37 g / min. Fluidized bed granulation was performed at an intake temperature of 50 ° C and an exhaust temperature of 23.2 ° C. The water content of the obtained second-stage granulated product was 14.6% by weight. The dried product obtained by drying the second-stage granulated product was sized using a screen of φ1.2 mm with “Power Mill” (Dalton Co., Ltd., model “P-04S”). The obtained sized product, light anhydrous silicic acid (60 g) and magnesium stearate (120 g) are put into a V-type mixer (model “VM-5” manufactured by Fuji Pardal Co., Ltd.), and the powder is added for 7 minutes. Mixed (total amount of solids 5400 g). The obtained mixture was tableted with a rotary tabletting machine (manufactured by Kikusui Seisakusho Co., Ltd., model “VIRGO-512”) using a φ8.5 mmR face (with secant) and a tableting pressure of about 750 kg. An orally disintegrating tablet having a weight of 180 mg and a thickness of 3.41 mm containing 10.0 mg of the active ingredient per tablet was produced. The hardness of the obtained orally disintegrating tablet was 4.2 kg.
実施例６
ゾルピデム酒石酸塩（活性成分、３００ｇ）、D−マンニトール（３９１５ｇ）、低置換度ヒドロキシプロピルセルロース（６００ｇ）、結晶セルロース（３００ｇ）、酸化マグネシウム（６０ｇ）、黄色三二酸化鉄（微量）及び三二酸化鉄（微量）を、流動層造粒装置（フロイント社製、機種「ＦＬＯ−５」）を用いて混合し、得られた混合物に精製水（２７００ｇ、固液比：５０重量％）を、液速度３４ｇ／minで噴霧し、吸気温度４０℃、排気温度２０．９℃で、流動層造粒した。得られた１段目の造粒物の水分含有量は、１４．２重量％であった。１段目の造粒物を該流動層造粒装置で乾燥し、該乾燥物に、ヒドロキシプロピルセルロース（１５ｇ）及びスクラロース（３０ｇ）の水溶液（１０００ｇ）を、液速度３３ｇ／minで噴霧し、吸気温度６０℃、排気温度２８．３℃で、流動層造粒した。得られた２段目の造粒物の水分含有量は、３．２重量％であった。２段目の造粒物を乾燥した乾燥物を、「パワーミル」（（株）ダルトン製、機種「Ｐ−０４Ｓ」）にて、φ１．２ｍｍのスクリーンを用いて整粒した。得られた整粒物、軽質無水ケイ酸（６０ｇ）及びステアリン酸マグネシウム（１２０ｇ）をV型混合機（不二パルダル(株)製、機種「VM−５」）に投入し、粉末を７分間混合した（固形分量合計５４００ｇ）。得られた混合物を、ロータリー式打錠機（菊水製作所(株)製、機種「ＶＩＲＧＯ−５１２」）にて、φ８．５ｍｍＲ面（割線入り）杵を用い、打錠圧力約７５０ｋｇで打錠し、１錠あたり活性成分を１０．０ｍｇ含有する重量１８０ｍｇ、厚み３．４２ｍｍの口腔内崩壊錠を製造した。得られた口腔内崩壊錠の硬度は４．１ｋｇであった。
Example 6
Zolpidem tartrate (active ingredient, 300 g), D-mannitol (3915 g), low-substituted hydroxypropylcellulose (600 g), crystalline cellulose (300 g), magnesium oxide (60 g), yellow iron sesquioxide (trace amount) and iron sesquioxide (Trace amount) was mixed using a fluidized bed granulator (Freund Corporation, model “FLO-5”), and purified water (2700 g, solid-liquid ratio: 50% by weight) was added to the resulting mixture at a liquid speed. Spraying was performed at 34 g / min, and fluidized bed granulation was performed at an intake temperature of 40 ° C. and an exhaust temperature of 20.9 ° C. The water content of the obtained first-stage granulated product was 14.2% by weight. The granulated product in the first stage is dried with the fluidized bed granulator, and an aqueous solution (1000 g) of hydroxypropylcellulose (15 g) and sucralose (30 g) is sprayed onto the dried product at a liquid speed of 33 g / min. Fluidized bed granulation was performed at an intake temperature of 60 ° C and an exhaust temperature of 28.3 ° C. The water content of the obtained second-stage granulated product was 3.2% by weight. The dried product obtained by drying the second-stage granulated product was sized using a screen of φ1.2 mm with “Power Mill” (Dalton Co., Ltd., model “P-04S”). The obtained sized product, light anhydrous silicic acid (60 g) and magnesium stearate (120 g) are put into a V-type mixer (model “VM-5” manufactured by Fuji Pardal Co., Ltd.), and the powder is added for 7 minutes. Mixed (total amount of solids 5400 g). The obtained mixture was tableted with a rotary tabletting machine (manufactured by Kikusui Seisakusho Co., Ltd., model “VIRGO-512”) using a φ8.5 mmR face (with secant) and a tableting pressure of about 750 kg. An orally disintegrating tablet having a weight of 180 mg and a thickness of 3.42 mm containing 10.0 mg of the active ingredient per tablet was produced. The hardness of the obtained orally disintegrating tablet was 4.1 kg.
実施例７
ゾルピデム酒石酸塩（活性成分、３００ｇ）、D−マンニトール（３９１５ｇ）、低置換度ヒドロキシプロピルセルロース（６００ｇ）、結晶セルロース（３００ｇ）、酸化マグネシウム（６０ｇ）、黄色三二酸化鉄（微量）及び三二酸化鉄（微量）を、流動層造粒装置（フロイント社製、機種「ＦＬＯ−５」）を用いて混合し、得られた混合物に精製水（２７００ｇ、固液比：５０重量％）を、液速度３８ｇ／minで噴霧し、吸気温度５０℃、排気温度２３．１℃で、流動層造粒した。得られた１段目の造粒物の水分含有量は、１０．５重量％であった。１段目の造粒物を該流動層造粒装置で乾燥し、該乾燥物に、ヒドロキシプロピルセルロース（１５ｇ）及びスクラロース（３０ｇ）の水溶液（１０００ｇ）を、液速度３７ｇ／minで噴霧し、吸気温度５０℃、排気温度２３．８℃で、流動層造粒した。得られた２段目の造粒物の水分含有量は、９．５重量％であった。２段目の造粒物を乾燥した乾燥物を、「パワーミル」（（株）ダルトン製、機種「Ｐ−０４Ｓ」）にて、φ１．２ｍｍのスクリーンを用いて整粒した。得られた整粒物、軽質無水ケイ酸（６０ｇ）及びステアリン酸マグネシウム（１２０ｇ）をV型混合機（不二パルダル(株)製、機種「VM−５」）に投入し、粉末を７分間混合した（固形分量合計５４００ｇ）。得られた混合物を、ロータリー式打錠機（菊水製作所(株)製、機種「ＶＩＲＧＯ−５１２」）にて、φ８．５ｍｍＲ面（割線入り）杵を用い、打錠圧力約７５０ｋｇで打錠し、１錠あたり活性成分を１０．０ｍｇ含有する重量１８０ｍｇ、厚み３．３７ｍｍの口腔内崩壊錠を製造した。得られた口腔内崩壊錠の硬度は４．６ｋｇであった。
Example 7
Zolpidem tartrate (active ingredient, 300 g), D-mannitol (3915 g), low-substituted hydroxypropylcellulose (600 g), crystalline cellulose (300 g), magnesium oxide (60 g), yellow iron sesquioxide (trace amount) and iron sesquioxide (Trace amount) was mixed using a fluidized bed granulator (Freund Corporation, model “FLO-5”), and purified water (2700 g, solid-liquid ratio: 50% by weight) was added to the resulting mixture at a liquid speed. Spraying was performed at 38 g / min, and fluidized bed granulation was performed at an intake temperature of 50 ° C and an exhaust temperature of 23.1 ° C. The water content of the obtained first-stage granulated product was 10.5% by weight. The granulated product in the first stage is dried with the fluidized bed granulator, and an aqueous solution (1000 g) of hydroxypropylcellulose (15 g) and sucralose (30 g) is sprayed on the dried product at a liquid speed of 37 g / min. Fluidized bed granulation was performed at an intake temperature of 50 ° C and an exhaust temperature of 23.8 ° C. The water content of the obtained second-stage granulated product was 9.5% by weight. The dried product obtained by drying the second-stage granulated product was sized using a screen of φ1.2 mm with “Power Mill” (Dalton Co., Ltd., model “P-04S”). The obtained sized product, light anhydrous silicic acid (60 g) and magnesium stearate (120 g) are put into a V-type mixer (model “VM-5” manufactured by Fuji Pardal Co., Ltd.), and the powder is added for 7 minutes. Mixed (total amount of solids 5400 g). The obtained mixture was tableted with a rotary tabletting machine (manufactured by Kikusui Seisakusho Co., Ltd., model “VIRGO-512”) using a φ8.5 mmR face (with secant) and a tableting pressure of about 750 kg. An orally disintegrating tablet with a weight of 180 mg and a thickness of 3.37 mm containing 10.0 mg of the active ingredient per tablet was produced. The hardness of the obtained orally disintegrating tablet was 4.6 kg.
実施例８
ゾルピデム酒石酸塩（活性成分、３００ｇ）、D−マンニトール（３９１２ｇ）、低置換度ヒドロキシプロピルセルロース（６００ｇ）、結晶セルロース（３００ｇ）及び酸化マグネシウム（６０ｇ）を、流動層造粒装置（フロイント社製、機種「ＦＬＯ−５」）を用いて混合し、得られた混合物に精製水（２７００ｇ、固液比：５０重量％）を、液速度３７ｇ／minで噴霧し、吸気温度５０℃、排気温度２３．２℃で、流動層造粒した。得られた１段目の造粒物の水分含有量は、１３．１重量％であった。１段目の造粒物を該流動層造粒装置で乾燥し、該乾燥物に、ヒドロキシプロピルセルロース（１８ｇ）及びスクラロース（３０ｇ）の水溶液（１０００ｇ）を、液速度３７ｇ／minで噴霧し、吸気温度５０℃、排気温度２３．６℃で、流動層造粒した。得られた２段目の造粒物の水分含有量は、８．９重量％であった。２段目の造粒物を乾燥した乾燥物を、「パワーミル」（（株）ダルトン製、機種「Ｐ−０４Ｓ」）にて、φ１．２ｍｍのスクリーンを用いて整粒した。得られた整粒物、軽質無水ケイ酸（６０ｇ）及びステアリン酸マグネシウム（１２０ｇ）をV型混合機（不二パルダル(株)製、機種「VM−５」）に投入し、粉末を７分間混合した（固形分量合計５４００ｇ）。得られた混合物を、ロータリー式打錠機（菊水製作所(株)製、機種「ＶＩＲＧＯ−５１２」）にて、φ８．５ｍｍＲ面（割線入り）杵を用い、打錠圧力約７５０ｋｇで打錠し、１錠あたり活性成分を１０．０ｍｇ含有する重量１８０ｍｇ、厚み３．３９ｍｍの口腔内崩壊錠を製造した。得られた口腔内崩壊錠の硬度は４．６ｋｇであった。
Example 8
Zolpidem tartrate (active ingredient, 300 g), D-mannitol (3912 g), low-substituted hydroxypropyl cellulose (600 g), crystalline cellulose (300 g) and magnesium oxide (60 g) were mixed in a fluidized bed granulator (Freund Corporation, Using model “FLO-5”), purified water (2700 g, solid-liquid ratio: 50% by weight) was sprayed at a liquid speed of 37 g / min to the resulting mixture, intake temperature 50 ° C., exhaust temperature 23 Fluidized bed granulation at 2 ° C. The water content of the obtained first-stage granulated product was 13.1% by weight. The first-stage granulated product is dried with the fluidized bed granulator, and an aqueous solution (1000 g) of hydroxypropylcellulose (18 g) and sucralose (30 g) is sprayed on the dried product at a liquid speed of 37 g / min. Fluidized bed granulation was performed at an intake temperature of 50 ° C and an exhaust temperature of 23.6 ° C. The water content of the obtained second-stage granulated product was 8.9% by weight. The dried product obtained by drying the second-stage granulated product was sized using a screen of φ1.2 mm with “Power Mill” (Dalton Co., Ltd., model “P-04S”). The obtained sized product, light anhydrous silicic acid (60 g) and magnesium stearate (120 g) are put into a V-type mixer (model “VM-5” manufactured by Fuji Pardal Co., Ltd.), and the powder is added for 7 minutes. Mixed (total amount of solids 5400 g). The obtained mixture was tableted with a rotary tabletting machine (manufactured by Kikusui Seisakusho Co., Ltd., model “VIRGO-512”) using a φ8.5 mmR face (with secant) and a tableting pressure of about 750 kg. An orally disintegrating tablet having a weight of 180 mg and a thickness of 3.39 mm containing 10.0 mg of the active ingredient per tablet was produced. The hardness of the obtained orally disintegrating tablet was 4.6 kg.
比較例２
ゾルピデム酒石酸塩（活性成分、３００ｇ）、D−マンニトール（３９００ｇ）、低置換度ヒドロキシプロピルセルロース（６００ｇ）、結晶セルロース（３００ｇ）、酸化マグネシウム（６０ｇ）、黄色三二酸化鉄（微量）及び三二酸化鉄（微量）を、流動層造粒装置（フロイント社製、機種「ＦＬＯ−５」）を用いて混合し、得られた混合物に精製水（２７００ｇ、固液比：５０重量％）を、液速度３３ｇ／minで噴霧し、吸気温度６０℃、排気温度２６．３℃で、流動層造粒した。得られた１段目の造粒物の水分含有量は、３．０重量％であった。１段目の造粒物を該流動層造粒装置で乾燥し、該乾燥物に、ヒドロキシプロピルセルロース（３０ｇ）及びスクラロース（３０ｇ）の水溶液（１０００ｇ）を、液速度３３ｇ／minで噴霧し、吸気温度６０℃、排気温度２６．７℃で、流動層造粒した。得られた２段目の造粒物の水分含有量は、２．７重量％であった。２段目の造粒物を乾燥した乾燥物を、「パワーミル」（（株）ダルトン製、機種「Ｐ−０４Ｓ」）にて、φ１．２ｍｍのスクリーンを用いて整粒した。得られた整粒物、軽質無水ケイ酸（６０ｇ）及びステアリン酸マグネシウム（１２０ｇ）をV型混合機（不二パルダル(株)製、機種「VM−５」）に投入し、粉末を７分間混合した（固形分量合計５４００ｇ）。得られた混合物を、ロータリー式打錠機（菊水製作所(株)製、機種「ＶＩＲＧＯ−５１２」）にて、φ８．５ｍｍＲ面（割線入り）杵を用い、打錠圧力約７５０ｋｇで打錠し、１錠あたり活性成分を１０．０ｍｇ含有する重量１８０ｍｇ、厚み３．４３ｍｍの口腔内崩壊錠を製造した。得られた口腔内崩壊錠の硬度は４．６ｋｇであった。
Comparative Example 2
Zolpidem tartrate (active ingredient, 300 g), D-mannitol (3900 g), low-substituted hydroxypropylcellulose (600 g), crystalline cellulose (300 g), magnesium oxide (60 g), yellow ferric oxide (trace amount) and ferric oxide (Trace amount) was mixed using a fluidized bed granulator (Freund Corporation, model “FLO-5”), and purified water (2700 g, solid-liquid ratio: 50% by weight) was added to the resulting mixture at a liquid speed. Spraying was performed at 33 g / min, and fluidized bed granulation was performed at an intake temperature of 60 ° C. and an exhaust temperature of 26.3 ° C. The water content of the obtained first-stage granulated product was 3.0% by weight. The first-stage granulated product is dried with the fluidized bed granulator, and an aqueous solution (1000 g) of hydroxypropylcellulose (30 g) and sucralose (30 g) is sprayed on the dried product at a liquid speed of 33 g / min. Fluidized bed granulation was performed at an intake temperature of 60 ° C and an exhaust temperature of 26.7 ° C. The water content of the obtained second-stage granulated product was 2.7% by weight. The dried product obtained by drying the second-stage granulated product was sized using a screen of φ1.2 mm with “Power Mill” (Dalton Co., Ltd., model “P-04S”). The obtained sized product, light anhydrous silicic acid (60 g) and magnesium stearate (120 g) are put into a V-type mixer (model “VM-5” manufactured by Fuji Pardal Co., Ltd.), and the powder is added for 7 minutes. Mixed (total amount of solids 5400 g). The obtained mixture was tableted with a rotary tabletting machine (manufactured by Kikusui Seisakusho Co., Ltd., model “VIRGO-512”) using a φ8.5 mmR face (with secant) and a tableting pressure of about 750 kg. An orally disintegrating tablet having a weight of 180 mg and a thickness of 3.43 mm containing 10.0 mg of the active ingredient per tablet was produced. The hardness of the obtained orally disintegrating tablet was 4.6 kg.
実施例４〜８及び比較例２で得られた各ゾルピデム酒石酸塩含有口腔内崩壊錠の苦味を、前記と同じ苦味評価方法によって、評価した。 The bitterness of each zolpidem tartrate-containing orally disintegrating tablet obtained in Examples 4 to 8 and Comparative Example 2 was evaluated by the same bitterness evaluation method as described above.
表２に、実施例４〜８及び比較例２における1段目の造粒物の水分含有量、２段目の造粒物の水分含有量、造粒方法及び回数、実施例４〜８及び比較例２で得られた各ゾルピデム酒石酸塩含有口腔内崩壊錠の口腔内崩壊時間、及び苦味評価結果を示した。 Table 2 shows the moisture content of the first-stage granulated product in Examples 4 to 8 and Comparative Example 2, the moisture content of the second-stage granulated product, the granulation method and frequency, Examples 4 to 8 and The oral disintegration time of each zolpidem tartrate-containing orally disintegrating tablet obtained in Comparative Example 2 and the bitter taste evaluation results are shown.
表２から明らかなように、実施例４〜８の錠剤は、１段目の造粒物の水分含有量がいずれも１０重量％以上であり、いずれも、苦味を感じることがなく、又口腔内崩壊時間も約３０秒以内で、水無しで十分に服用でき、口腔内崩壊錠として優れた製剤である。これに対して、比較例２の錠剤は、１段目の造粒物の水分含有量が５重量％未満であり、苦味が強く、水無しでは服用は困難であり、口腔内崩壊錠時間も約１分以上で、口腔内崩壊錠としてのメリットはない。また、実施例４〜８の結果から、２段目の造粒物の水分含有量は、苦味との関連性が殆ど認められないことが明らかである。 As is apparent from Table 2, the tablets of Examples 4 to 8 each have a water content of 10% by weight or more in the first-stage granulated product, and none of them feels a bitter taste. The disintegration time is about 30 seconds or less, and it can be sufficiently taken without water, and is an excellent preparation as an orally disintegrating tablet. On the other hand, the tablet of Comparative Example 2 has a water content of less than 5% by weight in the first-stage granulated product, has a strong bitter taste, is difficult to take without water, and has an orally disintegrating tablet time. About 1 minute or more, there is no merit as an orally disintegrating tablet. Moreover, it is clear from the results of Examples 4 to 8 that the water content of the second-stage granulated product is hardly associated with bitterness.
本発明の製造方法により得られるゾルピデム酒石酸塩含有口腔内崩壊錠は、口腔内崩壊性に優れ、しかも苦味等の不快な味が低減されており、不眠症治療剤として有用であり、本発明は製薬業分野において有効に利用される。
The zolpidem tartrate-containing orally disintegrating tablet obtained by the production method of the present invention is excellent in oral disintegration and has an unpleasant taste such as bitterness reduced, and is useful as a therapeutic agent for insomnia. Effectively used in the pharmaceutical industry.
Claims (7)
A zolpidem tartrate-containing orally disintegrating tablet obtained by the production method according to claim 1.
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| JP6009199B2 (en) * | 2012-04-09 | 2016-10-19 | あゆみ製薬株式会社 | Preparation method of the preparation |
| JP6030130B2 (en) * | 2012-06-25 | 2016-11-24 | 興和株式会社 | Pharmaceutical composition containing crude drugs |
| US20160136097A1 (en) * | 2013-07-06 | 2016-05-19 | Daicel Corporation | Ultrafast-disintegrating tablet and method for manufacturing same |
| JP2017014119A (en) * | 2015-06-26 | 2017-01-19 | 東和薬品株式会社 | Oral pharmaceutical composition |
| JP2018108950A (en) * | 2016-12-28 | 2018-07-12 | 沢井製薬株式会社 | Levocetirizine hydrochloride-containing orally disintegrating tablet |
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| JP2006022039A (en) * | 2004-07-08 | 2006-01-26 | Towa Yakuhin Kk | Simvastatin solid preparation having high stability |
| JP4963846B2 (en) * | 2006-03-03 | 2012-06-27 | エルメッド エーザイ株式会社 | Orally disintegrating tablet and method for producing the same |
| PE20080180A1 (en) * | 2006-05-23 | 2008-04-22 | Takeda Pharmaceutical | ORAL PREPARATION OF PIOGLITAZONE |
| CA2662938A1 (en) * | 2006-09-15 | 2008-03-20 | Astellas Pharma Inc. | Light-stable solid pharmaceutical composition of ramosetron |
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