JP2004315483A - Orally disintegrating tablet - Google Patents
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- JP2004315483A JP2004315483A JP2003119154A JP2003119154A JP2004315483A JP 2004315483 A JP2004315483 A JP 2004315483A JP 2003119154 A JP2003119154 A JP 2003119154A JP 2003119154 A JP2003119154 A JP 2003119154A JP 2004315483 A JP2004315483 A JP 2004315483A
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Abstract
Description
【０００１】
【技術分野】
本発明は、水の服用なしで口腔内で速やかに崩壊する口腔内崩壊錠剤に関する。
【０００２】
経口投与のための固形製剤の剤形としては錠剤やカプセル剤が一般的である。
これらは投与後そのままの形で食道を通って消化管に達し、消化管内で崩壊して薬物を放出するように設計されている。しかしながら老齢者や小児にとってはその嚥下が困難な場合があり、そのような患者に適した剤形として口腔内崩壊錠剤がある。この剤形は水を同時に飲用しなくても口腔内で嚥液により速やかに崩壊し、老齢者や小児でも容易に嚥下し得るようになっている。しかしながら口腔内崩壊錠剤といえども包装工程を含む生産過程、出荷およびその後の医療現場での取扱い過程において外力によってたやすく崩壊することがないように十分な破壊強度（錠剤の硬度）を持つことが必要である。しかしながら口腔内崩壊速度と錠剤強度とは一般に両立しないから、両者を程よくバランスさせなければならない。
【０００３】
これまで提案された数多くの口腔内崩壊錠剤の中で、ＷＯ９５／２０３８０は乳糖、マンニトール、ブドウ糖、白糖及びキシリットからなる群から選択された成形性の低い糖類を、マルトース、マルチトール、ソルビトール及びオリゴ糖からなる群から選択された成形性の高い糖類で造粒し、得られた造粒物を圧縮成形してなる口腔内崩壊錠剤を開示する。これらの造粒に用いられる成形性の高い糖類はいずれも水溶性であり、その水溶液を低成形性の糖類の粒子に噴霧して造粒物がつくられる。そのため成形性の高い糖類は乾燥後造粒物内に無定形もしくは非晶質の形で存在し、成形性の低い糖類の粒子を強固に結合もしくは少なくとも一部を固溶していると考えられるから、口腔内崩壊速度と錠剤硬度の適度のバランスを得るためにはその低成形性糖類に対する相対的割合、液量、噴霧条件等の造粒条件について厳密なコントロールを必要とする。さらにこの方法は賦形成分が高成形性糖類の場合には適用できない。従って成形性に関係なく錠剤の賦形成分一般に広く適用でき、かつ簡単に口腔内崩壊速度と硬度を最適にバランスさせることができる口腔内崩壊錠剤の開発が望まれる。
【０００４】
【本発明の開示】
本発明は、成形性すなわち単独で実用上満足な硬度を持つ錠剤に圧縮成形できる否かを問わず、広く錠剤の賦形成分に使用される糖または糖アルコールを用いる。先行技術とは対照的に、本発明では水溶性の造粒成分を使用せず、親水性であるがしかし水に溶けない造粒成分を主たる賦形成分の造粒のために用いる。このため造粒成分は乾燥後の造粒物において賦形成分と独立して存在し、親水性のため口腔内の唾液が錠剤の内部まで速やかに浸透し、錠剤の速やかな崩壊を助ける。この水不溶性親水性造粒成分の使用は、圧縮成形した錠剤の口腔内崩壊速度と錠剤硬度の間の適度なバランスを達成するために複雑な条件設定を必要としない。
【０００５】
このため本発明は、錠剤の賦形成分として用いられる糖または糖アルコールを賦形成分とし、水不溶性であるが親水性の造粒成分を用いて造粒した造粒物の圧縮成形物よりなる口腔崩壊錠剤を提供する。
【０００６】
【好ましい実施態様】
本発明において造粒成分に用いることができる好ましい糖の例は、乳糖、トレハロースなどであり、糖アルコールはマンニトールである。先に引用したＷＯ９５／２０３８０によれば、乳糖およびマンニトールは低成形性の糖類に分類される。トレハロースについては記載はないが、単独で実用上十分な硬度を有する錠剤に打錠することができるので、高成形性糖類に分類すべきである。しかしこれらの糖または糖アルコールを水または水溶性高分子結合剤の水溶液を用いて造粒し、造粒物を圧縮成形して錠剤としても、硬度が実用に耐えない程低いか、又は口腔内崩壊に不適となる程高いかのどちらかである。しかしながらこれらの糖または糖アルコールを水不溶性の親水性造粒成分を用いて造粒し、造粒物を圧縮成形することにより、口腔内崩壊速度と硬度が適度にバランスした錠剤を得ることができる。本発明において使用する造粒成分は親水性であるがしかし水には不溶である。一般に打錠用の造粒物には水溶性の高分子物質の水溶液が結合液として使用されるが、水不溶性物質の水分散液が使用されることはない。しかしこれらの水分散液を使用して造粒する時は、乾燥後賦形成分と分離した状態で造粒物中に分布し、もし存在しなければ高過ぎる硬度の錠剤を口腔内崩壊性とし、反対に低過ぎる硬度の錠剤を実用上満足な硬度を持つように働く。
【０００７】
使用し得る水不溶性の親水性造粒成分としては、デンプン、小麦粉のようなデンプンを含む穀粉、微粒子無水ケイ酸、ヒドロキシプロピルスターチ、クロスポビドンおよびそれらの混合物がある。デンプンはトウモロコシデンプンおよびバレイショデンプンが好ましい。微粒子無水ケイ酸としては、疎水化処理を施されていない軽質無水ケイ酸または粒径０．１ミクロン以下の非晶質シリカ微粒子が用いられる。これら微粒子無水ケイ酸は細孔を有し、大きい比表面積を有するのが特色である。賦形成分に対するこれら造粒成分の比は、重量で０．０１〜１．０であることが適切である。任意の造粒方法を採用し得るが、流動層造粒法が好ましい。この場合、糖または糖アルコールの賦形成分の粉末粒子を流動させ、それへ造粒成分の水分散液を噴霧するか、または賦形成分と造粒成分を粉末状態であらかじめ混合し、この混合物へ水を噴霧して造粒することができる。流動層造粒装置内で乾燥した造粒物は、必要により整粒後、ステアリン酸マグネシウムのような滑沢剤と混和した後、打錠機により錠剤に圧縮成形する。その際造粒に用いる造粒成分の一部を粉状状態で造粒物と混和し、打錠しても良い。
【０００８】
このようにして製造された錠剤は、一般に口腔内崩壊時間が１０秒以上６０秒未満の範囲内にあり、硬度は少なくとも１．５ｋｇであることが好ましい。先に述べたように、一般に口腔内崩壊速度と硬度とは両立し難いので、あまり高い硬度例えば５．０ｋｇ以上になると口腔内崩壊速度が許容できないほど延長するであろう。
【０００９】
本発明の口腔内崩壊錠剤は勿論薬物を含まなければならない。その添加方法はいくつか考えられ、１錠あたりの薬物の含量および性格などによって適切な方法を選ぶことができる。最も一般的な方法は少なくとも造粒物の一部分へ薬物を添加する方法である。また打錠前に造粒物と混合して打錠することもできる。薬物の種類によっては錠剤は主薬の安定剤や矯味剤（甘味剤）を含むことがある。これらの補助成分についても上に述べた添加方法を適用し得る。
【００１０】
【実施例】
以下の実施例は例証目的であって本発明をこれらに実施例に限定することを意図しない。また口腔内崩壊錠剤の製剤学的特性が添加した薬物によって有意に影響されるものではないので、多くの実施例においては薬物の添加なしで実験を行なった。
【００１１】
実施例１
トレハロース３５５ｇを流動層造粒装置（マルチプレックスＭＰ−０１）に投入し、トウモロコシデンプン４０ｇを水５００ｍＬに分散した液をスプレーし造粒した。得られた造粒物３９５ｇに、トウモロコシデンプン１００ｇを混合し、さらにステアリン酸マグネシウム５ｇを加え、ロータリー式打錠機を用い、それぞれ打錠圧８ｋＮおよび１０ｋＮにおいて打錠し、直径９．０ｍｍ，重量２５０ｍｇの錠剤を得た。
【００１２】
実施例２
トレハロース３５５ｇを流動層造粒装置に投入し、トウモロコシデンプン１４０ｇを水５００ｍＬに分散した液をスプレーし造粒した。得られた造粒物４９５ｇにステアリン酸マグネシウム５ｇを混合し、ロータリー式打錠機を用い、それぞれ打錠圧８ｋＮおよび１０ｋＮにおいて打錠し、直径９．０ｍｍ、重量２５０ｍｇの錠剤を得た。
【００１３】
実施例３
トレハロース３５５ｇとトウモロコシデンプン１４０ｇの混合物を流動層造粒装置に投入し、精製水３００ｍＬをスプレーして造粒した。得られた造粒物４９５ｇにステアリン酸マグネシウム５ｇを加え、ロータリー式打錠機を用い、それぞれ打錠圧８ｋＮおよび１０ｋＮにおいて打錠し、直径９．０ｍｍ、重量２５０ｍｇの錠剤を得た。
【００１４】
実施例４
乳糖３５５ｇを流動層造粒装置に投入し、トウモロコシデンプン１４０ｇを水５００ｍＬに分散した液をスプレーして造粒した。得られた造粒物４９５ｇに、軽質水ケイ酸４ｇと、ステアリン酸マグネシウム５ｇを混合し、ロータリー式打錠機を用い、それぞれ打錠圧８ｋＮおよび１０ｋＮにおいて打錠し、直径９．０ｍｍ、重量２５２ｍｇの錠剤を得た。
【００１５】
実施例５
Ｄ−マンニトール３５５ｇを流動層造粒装置に投入し、トウモロコシデンプン１４０ｇを水５００ｍＬに分散した液をスプレーして造粒した。得られた造粒物４９５ｇに、軽質無水ケイ酸４ｇと、ステアリン酸マグネシウム５ｇを混合し、ロータリー式打錠機を用い、それぞれ打錠圧１０ｋＮおよび１２ｋＮにおいて打錠し、直径９．０ｍｍ、重量２５２ｍｇの錠剤を得た。
【００１６】
実施例６
Ｄ−マンニトール４７０ｇを流動層造粒装置に投入し、軽質無水ケイ酸２５ｇを水５００ｍＬに分散した液をスプレーして造粒した。得られた造粒物４９５ｇにステアリン酸マグネシウム５ｇを混合し、ロータリー式打錠機を用い、それぞれ打錠圧４ｋＮおよび６ｋＮにおいて打錠し、直径９．０ｍｍ、重量２５０ｍｇの錠剤を得た。
【００１７】
実施例７
テオフィリン１０ｇとトレハロース３４５ｇの混合物を流動層造粒装置に投入し、トウモロコシデンプン１４０ｇを水５００ｍＬに分散した液をスプレーして造粒した。得られた造粒物４９５ｇに、アスパルテーム６ｇと、ステアリン酸マグネシウム５ｇを混合し、ロータリー式打錠機を用いそれぞれ打錠圧８ｋＮおよび１０ｋＮにおいて打錠し、直径９．０ｍｍ、重量２５３ｍｇの錠剤を得た。
【００１８】
実施例８
プラバスタチンナトリウム５０ｇとトレハロース６５０ｇの混合物を流動層造粒装置に投入し、軽質無水ケイ酸１００ｇを水１０００ｍＬに分散した液をスプレーして造粒した。得られた造粒物をＡとする。
【００１９】
別にトレハロース５００ｇを流動層造粒装置に投入し、トウモロコシデンプン１００ｇを水１２５０ｍＬに分散した液をスプレーして造粒した。得られた造粒物をＢとする。
【００２０】
Ａ造粒物８００ｇと、Ｂ造粒物１２００ｇと、トウモロコシデンプン５０ｇと、アスパルテーム５ｇを混合し、さらにステアリン酸マグネシウム２５ｇを加え、ロータリー式打錠機を用い、それぞれ打錠圧６ｋＮおよび８ｋＮにおいて打錠し、直径９．０ｍｍ、重量２５３ｍｇの錠剤を得た。
【００２１】
実施例９
Ｄ−マンニトール２３５ｇおよびトレハロース１２０ｇを流動層造粒装置に投入し、トウモロコシデンプン１４０ｇを水５００ｍＬに分散した液をスプレーして造粒した。得られた造粒物４９５ｇにステアリン酸マグネシウム５ｇを混合し、ロータリー式打錠機を用い、それぞれ打錠圧８ｋＮおよび１０ｋＮにおいて打錠し、直径９．０ｍｍ，重量２５０ｍｇの錠剤を得た。
【００２２】
実施例１０
Ｄ−マンニトール２６７ｇおよびトレハロース８８ｇを流動層造粒装置に投入し、ヒドロキシプロピルスターチ１４０ｇを水５００ｍＬに分散した液をスプレーして造粒した。得られた造粒物４９５ｇにステアリン酸マグネシウム５ｇを混合し、ロータリー式打錠機を用い、それぞれ打錠圧８ｋＮおよび１０ｋＮにおいて打錠し、直径９．０ｍｍ，重量２５０ｍｇの錠剤を得た。
【００２３】
実施例１１
トレハロース３５５ｇを流動層造粒装置に投入し、ヒドロキシプロピルスターチ１４０ｇを水５００ｍＬに分散した液をスプレーして造粒した。得られた造粒物４９５ｇにステアリン酸マグネシウム５ｇを混合し、ロータリー式打錠機を用い、それぞれ打錠圧８ｋＮおよび１０ｋＮにおいて打錠し、直径９．０ｍｍ，重量２５０ｍｇの錠剤を得た。
【００２４】
実施例１２
Ｄ−マンニトール３５５ｇを流動層造粒装置に投入し、ヒドロキシプロピルスターチ１４０ｇを水５００ｍＬに分散した液をスプレーして造粒した。得られた造粒物４９５ｇにステアリン酸マグネシウム５ｇを混合し、ロータリー式打錠機を用い、それぞれ打錠圧１０ｋＮおよび１２ｋＮにおいて打錠し、直径９．０ｍｍ，重量２５０ｍｇの錠剤を得た。
【００２５】
実施例１３
Ｄ−マンニトール４７５ｇを流動層造粒装置に投入し、クロスポピドン２０ｇを水５００ｍＬに分散した液をスプレーして造粒した。得られた造粒物４９５ｇにステアリン酸マグネシウム５ｇを混合し、ロータリー式打錠機を用い、それぞれ打錠圧７ｋＮおよび９ｋＮにおいて打錠し、直径９．０ｍｍ，重量２５０ｍｇの錠剤を得た。
【００２６】
実施例１４
Ｄ−マンニトール４７５ｇを流動層造粒装置に投入し、小麦粉２０ｇを水５００ｍＬに分散した液をスプレーし造粒した。得られた造粒物４７５ｇに軽質無水ケイ酸４ｇを混合し、さらにステアリン酸マグネシウム５ｇを加え、ロータリー式打錠機を用い、それぞれ打錠圧６ｋＮ及び８ｋＮにおいて打錠し、直径９．０ｍｍ，重量２５２ｍｇの錠剤を得た。
【００２７】
実施例１５
Ｄ−マンニトール４７５ｇを流動層造粒装置に投入し、小麦粉２０ｇを水２００ｍＬに分散した液をスプレーし造粒した。得られた造粒物４７５ｇに軽質無水ケイ酸４ｇを混合し、さらにステアリン酸マグネシウム５ｇを加え、ロータリー式打錠機を用い、それぞれ打錠圧６ｋＮ及び８ｋＮにおいて打錠し、直径９．０ｍｍ，重量２５２ｍｍの錠剤を得た。
【００２８】
実施例１６
Ｄ−マンニトール４７５ｇを流動層造粒装置に投入し、小麦粉２０ｇを水１００ｍＬに分散した液をスプレーし造粒した。得られた造粒物４７５ｇに軽質無水ケイ酸４ｇを混合し、さらにステアリン酸マグネシウム５ｇを加え、ロータリー式打錠機を用い、それぞれ打錠圧８ｋＮ及び１０ｋＮにおいて打錠し、直径９．０ｍｍ，重量２５２ｍｇの錠剤を得た。
【００２９】
比較例１
トレハロース５６８ｇを流動層造粒装置に投入し、精製水３００ｍＬをスプレーして造粒した。得られた造粒物４２６ｇにトウモロコシデンプン１６８ｇを混合し、さらにステアリン酸マグネシウム６ｇを加え、ロータリー式打錠機を用いて直径９．０ｍｍ、重量２５０ｍｇの錠剤に打錠した。打錠圧８ｋＮにおいては脆い錠剤（硬度０．２ｋｇ）が得られたが、打錠圧１０ｋＮにおいてはキャッピングが著しく、打錠不可能であった。
【００３０】
比較例２
比較例１において得た造粒物４９５ｇに、ステアリン酸マグネシウム５ｇを混合し、ロータリー打錠機を用い、それぞれ打錠圧３ｋＮおよび５ｋＮにおいて打錠し、直径９．０ｍｍ、重量２５０ｍｇの錠剤を得た。
【００３１】
【硬度および崩壊性試験】
実施例および比較例で得た錠剤について、常法により硬度を測定した。崩壊試験は水を使用して第１４改正薬局方記載の方法に従って水中崩壊時間を測定し、口腔内崩壊時間は健康な成人男子の口腔内に試験錠剤を含ませ、噛まない状態で完全に崩壊するまでの時間を測定した。なお比較例１の錠剤については水中および口腔内崩壊時間を測定しなかった。結果を表１から表６に示す。
【００３２】
表１
表２
表３
表４
表５
表６
表７
【考察】
比較例１および２から理解し得るように、トレハロースを水のみで造粒し、造粒物にデンプンおよび滑沢剤を混合して打錠した場合、許容できる硬度に達しないか又はキャッピングのため打錠できない。トレハロースを水のみで造粒した造粒物へ滑沢剤を加えて打錠すると低い打錠圧で硬い錠剤となり、口腔内崩壊錠剤は得られない。これと対照的に糖又は糖アルコールを水不溶性の親水性造粒成分の水分散液を用いて造粒するか、あるいは両者の混合物を水で造粒した場合は、実施例から理解されるように、口腔内崩壊速度と硬度が適度にバランスした錠剤が得られる。[0001]
【Technical field】
The present invention relates to an orally disintegrating tablet that disintegrates rapidly in the oral cavity without taking water.
[0002]
Tablets and capsules are generally used as dosage forms of solid preparations for oral administration.
They are designed to enter the gastrointestinal tract through the esophagus in an intact form after administration, and disintegrate in the gastrointestinal tract to release the drug. However, swallowing can be difficult for elderly people and children, and orally disintegrating tablets are suitable dosage forms for such patients. This dosage form is rapidly disintegrated by swallowing in the oral cavity without simultaneously drinking water, and can be easily swallowed by elderly people and children. However, even an orally disintegrating tablet must have sufficient breaking strength (tablet hardness) so that it does not easily disintegrate due to external forces during the production process including the packaging process, shipping, and subsequent handling at a medical site. is necessary. However, since the disintegration rate in the oral cavity and the tablet strength are generally incompatible, the two must be properly balanced.
[0003]
Among the many orally disintegrating tablets proposed so far, WO95 / 20380 describes a low formability saccharide selected from the group consisting of lactose, mannitol, glucose, sucrose and xylitol with maltose, maltitol, sorbitol and oligosaccharides. Disclosed is an orally disintegrating tablet obtained by granulating with a highly moldable saccharide selected from the group consisting of sugar and compression-molding the obtained granulated product. All of the saccharides having high moldability used for these granulations are water-soluble, and the aqueous solution is sprayed on the saccharide particles having low moldability to form granules. Therefore, it is considered that the saccharide having high formability exists in the amorphous or amorphous form in the granulated product after drying, and the saccharide particles having low formability are firmly bound or at least partially dissolved. Therefore, in order to obtain an appropriate balance between the disintegration rate in the oral cavity and the tablet hardness, it is necessary to strictly control the granulation conditions such as the relative ratio to the low-forming saccharide, the liquid amount, and the spraying conditions. Furthermore, this method cannot be applied when the excipient is a highly moldable saccharide. Therefore, development of an orally disintegrating tablet that can be widely applied to tablet excipients regardless of moldability and that can easily balance the orally disintegrating rate and hardness easily is desired.
[0004]
[Disclosure of the present invention]
The present invention uses sugars or sugar alcohols widely used as excipients in tablets, regardless of their moldability, ie, whether or not they can be individually compression-molded into tablets having practically satisfactory hardness. In contrast to the prior art, the present invention does not use a water-soluble granulating component, but instead uses a hydrophilic but water-insoluble granulating component for the granulation of the main excipient. For this reason, the granulated component exists independently of the excipient in the dried granulated material, and the saliva in the oral cavity quickly penetrates into the tablet due to its hydrophilicity, which helps the tablet to disintegrate quickly. The use of this water-insoluble hydrophilic granulation component does not require complicated conditions to achieve an adequate balance between the oral disintegration rate of the compressed tablet and the tablet hardness.
[0005]
For this reason, the present invention comprises a compression molded product of a granulated product obtained by granulating using a water-insoluble but hydrophilic granulating component, using a sugar or a sugar alcohol used as an excipient of a tablet as an excipient. An orally disintegrating tablet is provided.
[0006]
[Preferred embodiment]
Examples of preferable sugars that can be used for the granulation component in the present invention include lactose, trehalose, and the like, and the sugar alcohol is mannitol. According to WO 95/20380 cited above, lactose and mannitol are classified as low formable sugars. Although trehalose is not described, it should be classified as a highly moldable saccharide because it can be used alone to form a tablet having practically sufficient hardness. However, even when these sugars or sugar alcohols are granulated using water or an aqueous solution of a water-soluble polymer binder, and the granules are compression-molded into tablets, the hardness is too low to withstand practical use, or in the oral cavity. It is either high enough to be unsuitable for collapse. However, these sugars or sugar alcohols are granulated using a water-insoluble hydrophilic granulation component, and the granules are compression-molded, whereby tablets having an appropriately balanced oral disintegration rate and hardness can be obtained. . The granulation components used in the present invention are hydrophilic but insoluble in water. Generally, an aqueous solution of a water-soluble polymer substance is used as a binding liquid for granules for tableting, but an aqueous dispersion of a water-insoluble substance is not used. However, when granulating using these aqueous dispersions, tablets that are too hard to disperse in the orally disintegrating material, if present, will be distributed in the granulated material separately from excipients after drying. On the other hand, tablets having too low a hardness work to have a practically satisfactory hardness.
[0007]
Water-insoluble hydrophilic granulating ingredients that can be used include starch, flours containing starch, such as flour, particulate silicic anhydride, hydroxypropyl starch, crospovidone and mixtures thereof. The starch is preferably corn starch and potato starch. As the fine silicic acid anhydride, light anhydrous silicic acid which has not been subjected to a hydrophobizing treatment or amorphous silica fine particles having a particle diameter of 0.1 μm or less are used. The feature of these fine particles of silicic anhydride is that they have pores and a large specific surface area. Suitably, the ratio of these granulated components to the excipient is from 0.01 to 1.0 by weight. Although any granulation method can be adopted, a fluidized bed granulation method is preferable. In this case, the powder particles of the excipient of the sugar or sugar alcohol are fluidized, and an aqueous dispersion of the granulated component is sprayed thereon, or the excipient and the granulated component are previously mixed in a powder state, and this mixture is mixed. Water can be sprayed for granulation. The granules dried in the fluidized bed granulator are sized, if necessary, mixed with a lubricant such as magnesium stearate, and then compressed into tablets by a tableting machine. At that time, a part of the granulation component used for granulation may be mixed with the granulated material in a powdery state and tableted.
[0008]
The tablet thus produced generally has a disintegration time in the oral cavity of 10 seconds or more and less than 60 seconds, and preferably has a hardness of at least 1.5 kg. As mentioned above, since the oral disintegration rate and hardness are generally incompatible, if the hardness is too high, for example, 5.0 kg or more, the oral disintegration rate will be unacceptably prolonged.
[0009]
The orally disintegrating tablet of the present invention must of course contain the drug. There are several methods for adding the drug, and an appropriate method can be selected depending on the content and properties of the drug per tablet. The most common method is to add the drug to at least a portion of the granulate. In addition, tableting can be performed by mixing with granules before tableting. Depending on the type of the drug, the tablet may contain a stabilizer for the main drug or a flavoring agent (sweetener). The addition methods described above can be applied to these auxiliary components.
[0010]
【Example】
The following examples are for illustrative purposes and are not intended to limit the invention to these examples. Also, since the pharmaceutical properties of the orally disintegrating tablet were not significantly affected by the added drug, the experiments were performed without the addition of drug in many examples.
[0011]
Example 1
355 g of trehalose was charged into a fluidized bed granulator (multiplex MP-01), and a liquid in which 40 g of corn starch was dispersed in 500 mL of water was sprayed and granulated. To 395 g of the obtained granulated product, 100 g of corn starch was mixed, and 5 g of magnesium stearate was further added. The mixture was tableted using a rotary tableting machine at a tableting pressure of 8 kN and 10 kN, respectively, and was 9.0 mm in diameter and weight. 250 mg tablets were obtained.
[0012]
Example 2
355 g of trehalose was put into a fluidized bed granulator, and a liquid in which 140 g of corn starch was dispersed in 500 mL of water was sprayed and granulated. 5 g of magnesium stearate was mixed with 495 g of the obtained granules, and the mixture was tableted using a rotary tableting machine at a tableting pressure of 8 kN and 10 kN, respectively, to obtain tablets having a diameter of 9.0 mm and a weight of 250 mg.
[0013]
Example 3
A mixture of 355 g of trehalose and 140 g of corn starch was charged into a fluid bed granulator, and 300 mL of purified water was sprayed to granulate. 5 g of magnesium stearate was added to 495 g of the obtained granules, and the mixture was tableted using a rotary tableting machine at a tableting pressure of 8 kN and 10 kN, respectively, to obtain tablets having a diameter of 9.0 mm and a weight of 250 mg.
[0014]
Example 4
Lactose (355 g) was charged into a fluidized bed granulator, and a liquid obtained by dispersing corn starch (140 g) in water (500 mL) was sprayed and granulated. To 495 g of the obtained granules, 4 g of light water silicic acid and 5 g of magnesium stearate were mixed, and the mixture was tableted using a rotary tableting machine at a tableting pressure of 8 kN and 10 kN, respectively, to a diameter of 9.0 mm and a weight of 9.0 g. 252 mg tablets were obtained.
[0015]
Example 5
355 g of D-mannitol was charged into a fluidized bed granulator, and granulated by spraying a liquid in which 140 g of corn starch was dispersed in 500 mL of water. To 495 g of the obtained granules, 4 g of light anhydrous silicic acid and 5 g of magnesium stearate were mixed, and the mixture was compressed using a rotary tableting machine at a compression pressure of 10 kN and 12 kN, respectively, to a diameter of 9.0 mm and a weight of 9.0 g. 252 mg tablets were obtained.
[0016]
Example 6
470 g of D-mannitol was charged into a fluidized bed granulator, and a liquid in which 25 g of light anhydrous silicic acid was dispersed in 500 mL of water was sprayed to perform granulation. 495 g of the obtained granules were mixed with 5 g of magnesium stearate, and the mixture was tableted using a rotary tableting machine at a tableting pressure of 4 kN and 6 kN, respectively, to obtain tablets having a diameter of 9.0 mm and a weight of 250 mg.
[0017]
Example 7
A mixture of 10 g of theophylline and 345 g of trehalose was charged into a fluidized bed granulator, and granulated by spraying a liquid obtained by dispersing 140 g of corn starch in 500 mL of water. 6 g of aspartame and 5 g of magnesium stearate were mixed with 495 g of the obtained granules, and the mixture was tableted at a tableting pressure of 8 kN and 10 kN using a rotary tableting machine to give tablets having a diameter of 9.0 mm and a weight of 253 mg. Obtained.
[0018]
Example 8
A mixture of 50 g of pravastatin sodium and 650 g of trehalose was charged into a fluidized-bed granulator, and a solution in which 100 g of light anhydrous silicic acid was dispersed in 1000 mL of water was sprayed and granulated. The obtained granules are designated as A.
[0019]
Separately, 500 g of trehalose was charged into a fluidized-bed granulator, and a liquid obtained by dispersing 100 g of corn starch in 1250 mL of water was sprayed and granulated. The obtained granules are designated as B.
[0020]
800 g of the granulated product of A, 1200 g of the granulated product of B, 50 g of corn starch and 5 g of aspartame were mixed, 25 g of magnesium stearate was added, and the mixture was compressed at a compression pressure of 6 kN and 8 kN using a rotary tableting machine. The tablets were obtained to obtain tablets having a diameter of 9.0 mm and a weight of 253 mg.
[0021]
Example 9
235 g of D-mannitol and 120 g of trehalose were put into a fluidized bed granulator, and granulated by spraying a liquid in which 140 g of corn starch was dispersed in 500 mL of water. 5 g of magnesium stearate was mixed with 495 g of the obtained granules, and the mixture was tableted using a rotary tableting machine at a tableting pressure of 8 kN and 10 kN, respectively, to obtain tablets having a diameter of 9.0 mm and a weight of 250 mg.
[0022]
Example 10
267 g of D-mannitol and 88 g of trehalose were charged into a fluidized-bed granulator, and granulated by spraying a liquid in which 140 g of hydroxypropyl starch was dispersed in 500 mL of water. 5 g of magnesium stearate was mixed with 495 g of the obtained granules, and the mixture was tableted using a rotary tableting machine at a tableting pressure of 8 kN and 10 kN, respectively, to obtain tablets having a diameter of 9.0 mm and a weight of 250 mg.
[0023]
Example 11
355 g of trehalose was charged into a fluidized bed granulator, and a liquid obtained by dispersing 140 g of hydroxypropyl starch in 500 mL of water was sprayed and granulated. 5 g of magnesium stearate was mixed with 495 g of the obtained granules, and the mixture was tableted using a rotary tableting machine at a tableting pressure of 8 kN and 10 kN, respectively, to obtain tablets having a diameter of 9.0 mm and a weight of 250 mg.
[0024]
Example 12
355 g of D-mannitol was charged into a fluidized bed granulator, and a liquid obtained by dispersing 140 g of hydroxypropyl starch in 500 mL of water was sprayed and granulated. 5 g of magnesium stearate was mixed with 495 g of the obtained granules, and the mixture was tableted using a rotary tableting machine at a tableting pressure of 10 kN and 12 kN, respectively, to obtain tablets having a diameter of 9.0 mm and a weight of 250 mg.
[0025]
Example 13
475 g of D-mannitol was charged into a fluidized bed granulator, and a liquid obtained by dispersing 20 g of crospopidone in 500 mL of water was sprayed and granulated. 5 g of magnesium stearate was mixed with 495 g of the obtained granules, and the mixture was tableted at a tableting pressure of 7 kN and 9 kN using a rotary tableting machine to obtain tablets having a diameter of 9.0 mm and a weight of 250 mg.
[0026]
Example 14
475 g of D-mannitol was charged into a fluidized bed granulator, and a liquid obtained by dispersing 20 g of flour in 500 mL of water was sprayed and granulated. To 475 g of the obtained granules, 4 g of light anhydrous silicic acid was mixed, and 5 g of magnesium stearate was further added. The mixture was tableted using a rotary tableting machine at a tableting pressure of 6 kN and 8 kN, respectively. A tablet weighing 252 mg was obtained.
[0027]
Example 15
475 g of D-mannitol was charged into a fluidized bed granulator, and a liquid in which 20 g of flour was dispersed in 200 mL of water was sprayed and granulated. To 475 g of the obtained granules, 4 g of light anhydrous silicic acid was mixed, and 5 g of magnesium stearate was further added. The mixture was tableted using a rotary tableting machine at a tableting pressure of 6 kN and 8 kN, respectively. A tablet weighing 252 mm was obtained.
[0028]
Example 16
475 g of D-mannitol was charged into a fluidized bed granulator, and a liquid in which 20 g of flour was dispersed in 100 mL of water was sprayed and granulated. 4 g of light anhydrous silicic acid was mixed with 475 g of the obtained granules, and 5 g of magnesium stearate was further added. The mixture was tableted at a tableting pressure of 8 kN and 10 kN using a rotary tableting machine to form a tablet having a diameter of 9.0 mm. A tablet weighing 252 mg was obtained.
[0029]
Comparative Example 1
568 g of trehalose was charged into a fluidized bed granulator, and 300 mL of purified water was sprayed to granulate. To 426 g of the obtained granules, 168 g of corn starch was mixed, and 6 g of magnesium stearate was further added. The mixture was tabletted into tablets having a diameter of 9.0 mm and a weight of 250 mg using a rotary tableting machine. At a tableting pressure of 8 kN, a brittle tablet (hardness 0.2 kg) was obtained, but at a tableting pressure of 10 kN, capping was remarkable and tableting was impossible.
[0030]
Comparative Example 2
To 495 g of the granulated product obtained in Comparative Example 1, 5 g of magnesium stearate was mixed, and the mixture was tableted at a tableting pressure of 3 kN and 5 kN using a rotary tableting machine to obtain a tablet having a diameter of 9.0 mm and a weight of 250 mg. Was.
[0031]
[Hardness and disintegration test]
The hardness of the tablets obtained in Examples and Comparative Examples was measured by a conventional method. The disintegration test measures the disintegration time in water using water according to the method described in the 14th revised pharmacopeia. The disintegration time in the oral cavity is determined by including the test tablet in the mouth of a healthy adult male and completely disintegrating without chewing. The time until it was measured. The disintegration time in water and in the oral cavity was not measured for the tablet of Comparative Example 1. The results are shown in Tables 1 to 6.
[0032]
Table 1
Table 2
Table 3
Table 4
Table 5
Table 6
Table 7
[Discussion]
As can be seen from Comparative Examples 1 and 2, when trehalose was granulated with water only, and the granules were mixed with starch and a lubricant and compressed into tablets, the hardness did not reach acceptable hardness or the capping was not achieved. I cannot tablet. When a lubricant is added to a granulated product of trehalose with water alone and tableted with a lubricant, a hard tablet is formed at a low tableting pressure, and an orally disintegrating tablet cannot be obtained. In contrast, when the sugar or sugar alcohol is granulated using an aqueous dispersion of a water-insoluble hydrophilic granulating component, or when a mixture of both is granulated with water, as will be understood from the examples. In addition, a tablet having an appropriately balanced disintegration rate in the oral cavity and hardness can be obtained.
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