JP4280074B2 - Multiple unit type sustained release tablets - Google Patents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
Description
技術分野
本発明はマルチプルユニット型徐放性錠剤の改良に関する。より詳細には、薬剤の速放性部分と徐放性部分からなるマルチプルユニット型徐放性錠剤において、速放性部分からの成分の溶出速度を向上させたマルチプルユニット型徐放性錠剤に関する。
背景技術
徐放性製剤は、薬剤の放出速度を制御することにより投与回数を減らし、患者の服薬という負担を軽減させることを目的とした剤形である。徐放性製剤の主要な形態として、錠剤全体に徐放性膜を被覆したシングルユニット型徐放性錠剤と、徐放性膜を被覆した多数の薬剤顆粒からなるマルチプルユニット型徐放性錠剤とが知られている。薬物の吸収について個体内及び個体間におけるバラツキを小さくするためにはマルチプルユニット型の製剤が優れていることが知られている。
またマルチプルユニット型の製剤では徐放性部分とともに薬剤を速やかに放出し得る部分（速放性部分）を配合し得るので、薬物の有効血中濃度を迅速に得、かつ持続することができる。例えば、鎮痛成分を速やかに放出しかつ徐放することにより、何らかの原因により痛みを持つ患者において痛みを速やかに抑制するとともに長時間にわたって痛みを抑制することができる。
マルチプルユニット型徐放性製剤に薬剤を速やかに放出する成分を配合する場合、上記のような薬剤の素顆粒に徐放性膜を被覆した徐放性顆粒と、薬剤を速やかに放出する速放性顆粒とを配合することが一般的である。これらの徐放性顆粒と速放性顆粒とは良好な混合を得るためにできるだけ近い粒子寸法を有していることが必要である。徐放性顆粒は上記のように薬剤素顆粒に徐放性膜を被覆して製造するので比較的粒子径が大きくならざるを得ず、速放性顆粒もそれに合わせて比較的大きな粒子を使用する必要がある。また、徐放性顆粒は比較的粒子径が揃っており、徐放性を保持させるため硬い顆粒として設計されるので圧縮成形性に劣ることから、徐放性顆粒と速放性顆粒とを打錠して成形する場合、成形性に優れた速放性顆粒を使用する必要がある。
一般的に流動層造粒法により調製した顆粒は他の造粒法により調製した顆粒と比較して圧縮成形性は優れているが、その顆粒を圧縮して錠剤にすると得られる錠剤の崩壊時間が長くなることが多く、速放性部分を配合した意義が損なわれてしまう。しかし、錠剤の崩壊性を高くするために速放性顆粒に崩壊剤を多量に添加すると造粒物（顆粒）の粒子径を大きくすることが困難になり、比較的粒子径が大きい徐放性顆粒と同程度の粒子径の速放性顆粒を得にくくなる。この場合、結合剤を増量すると造粒物（顆粒）の粒子径は大きくすることができるが、再び錠剤の崩壊性が悪くなる。
このように従来の方法では、徐放性顆粒と速放性顆粒とを配合したマルチプルユニット型徐放性錠剤において、速放性顆粒の結合剤と崩壊剤の配合を調整することのみによっては、徐放性顆粒及び速放性顆粒の粒子径を同程度のものとし、十分に成形が可能で、かつ崩壊性に優れた錠剤とするという目的を同時に達成することは困難であった。
発明の開示
従って本発明は、徐放性顆粒と速放性顆粒とを配合したマルチプルユニット型徐放性錠剤において、徐放性顆粒及び速放性顆粒の粒子径を同程度のものとすることができ、従って両者の良好な混合が得られ、また十分に成形が可能で、かつ崩壊性に優れたマルチプルユニット型徐放性錠剤及びその製造方法を提供することを目的とする。
本発明者は、徐放性顆粒と速放性顆粒とを配合したマルチプルユニット型徐放性錠剤において、その速放性顆粒の造粒方法及び成分を適切に選択し、さらに速放性顆粒に添加される結合剤を粉末として添加することにより、徐放性顆粒と同程度の粒子径を有し、かつ成形性に優れた速放性顆粒を得ることができ、従って徐放性顆粒と速放性顆粒との良好な混合が得られ、また十分に成形が可能で、かつ崩壊性に優れたマルチプルユニット型徐放性錠剤が得られることを見出した。
すなわち本発明は、薬物を持続的に放出する打錠用顆粒（以下、「徐放性顆粒」ともいう）と薬物を速やかに放出する打錠用顆粒（以下、「速放性顆粒」ともいう）からなるマルチプルユニット型徐放性錠剤において、速放性顆粒が崩壊剤及び結合剤を含み、速放性顆粒の製造において結合剤が粉末の状態で混合されることを特徴とする徐放性錠剤を提供する。
上記本発明の徐放性錠剤においては、速放性顆粒の製造において粉末の状態で混合される結合剤は、好ましくは１００μｍ以下、より好ましくは７５μｍ以下の平均粒子径を有する粉末である。
速放性顆粒の製造に使用される崩壊剤は、１００μｍ以下の平均粒子径を有することが好ましく、また低置換度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、クロスカルメロースナトリウム及びクロスポビドンからなる群から選択される一種または二種以上の物質であることが好ましい。
速放性顆粒の製造に使用される結合剤は、ヒドロキシプロピルセルロース及びヒドロキシプロピルメチルセルロースからなる群から選択される一種または二種以上の物質であることが好ましい。
上記速放性顆粒に含まれる崩壊剤の量は、速放性顆粒全体に対して好ましくは５〜５０重量％、より好ましくは１０〜３０重量％程度である。
上記速放性顆粒に含まれる結合剤の量は、速放性顆粒全体に対して好ましくは１〜２０重量％、より好ましくは３〜１５重量％程度である。
本発明の徐放性錠剤においては、徐放性顆粒は、好ましくは１００〜１０００μｍ、より好ましくは２００〜８００μｍの平均粒子径を有し、速放性顆粒は、好ましくは１００〜１０００μｍ、より好ましくは１５０〜８００μｍの平均粒子径を有する。
本発明の徐放性錠剤は、徐放性顆粒及び速放性顆粒に加えて崩壊剤を含んでもよい。この徐放性顆粒及び速放性顆粒以外の部分に含まれる崩壊剤としては、上記速放性顆粒に使用されるものと同様の崩壊剤を使用することができ、その量は徐放性錠剤全体に対して好ましくは１〜２５重量％、より好ましくは７〜１５重量％程度である。
さらに本発明は、薬物を持続的に放出する打錠用顆粒（徐放性顆粒）と薬物を速やかに放出する打錠用顆粒（速放性顆粒）を圧縮打錠することを含むマルチプルユニット型徐放性錠剤の製造方法において、速放性顆粒が崩壊剤及び結合剤を含み、速放性顆粒の製造において結合剤を粉末の状態で混合することを特徴とする徐放性錠剤の製造方法を提供する。
発明を実施するための最良の形態
以下、本発明を詳細に説明する。
本発明のマルチプルユニット型徐放性錠剤は、薬物を持続的に放出する打錠用顆粒（徐放性顆粒）と薬物を速やかに放出する打錠用顆粒（速放性顆粒）からなり、速放性顆粒が崩壊剤及び結合剤を含み、速放性顆粒の製造において結合剤が粉末の状態で混合されることを特徴とする。
すなわち本発明のマルチプルユニット型徐放性錠剤は、その製造において速放性顆粒を流動層造粒法等により製造する際に、結合剤を通常の流動層造粒法のように溶液状態で添加するのではなく、粉末として添加することを特徴とし、それ以外は従来の徐放性顆粒と速放性顆粒とからなるマルチプルユニット型徐放性錠剤と同様に製造することができる。すなわち、薬物等の活性成分、崩壊剤、その他の添加剤に結合剤を粉末で添加し、混合した混合粉末を調製する。そしてその混合粉末に水分を噴霧することにより流動層造粒法により速放性顆粒を得、その速放性顆粒と別途調製した徐放性顆粒及び必要に応じて滑沢剤や崩壊剤等の添加剤を混合し、その顆粒混合物を圧縮することにより、本発明のマルチプルユニット型徐放性錠剤を製造することができる。
上記のようにして製造することにより、速放性顆粒は徐放性顆粒と同程度の比較的大きな粒子寸法に製造することができ、しかも良好な崩壊性と圧縮成形性を維持した速放性顆粒とすることができる。従って、製造されるマルチプルユニット型徐放性錠剤においては、徐放性顆粒と速放性顆粒とが十分に混合されており、マルチプルユニット型徐放性錠剤自体は適切な硬度を保有し、かつ崩壊時間の非常に短い錠剤となる。すなわち、従来のマルチプルユニット型徐放性錠剤において、崩壊剤と結合剤の配合量を調節することのみによっては達成することができなかった、速放性顆粒の十分な粒子寸法、崩壊性及び圧縮成形性を同時に実現し得るものである。
本発明はいかなる理論にも拘束されるものではないが、上記のような本発明の効果は、主として、上記のような特徴を有する流動層造粒法等の造粒法により調製した速放性顆粒における結合剤の分布が従来法により製造した顆粒におけるものとは異なることによると考えられる。すなわち、従来の流動層造粒法のように結合剤を溶剤に溶解して溶液として用いた場合、結合剤は崩壊剤、活性成分等の粒子の内部と表面全体とに均一に分布され、それにより崩壊剤、活性成分等の粒子が接着され顆粒が成長する。このような状態で比較的大きな顆粒を得るためには結合剤の量が相対的に多くなり、また顆粒の表面に結合剤が多く存在して顆粒の溶解や崩壊が阻害され、結果として崩壊性に欠ける顆粒となってしまう。これに対し本発明によれば、粉末状で添加された結合剤は、粉末の粒子として崩壊剤、活性成分等の粒子の表面に分布し、崩壊剤、活性成分等の粒子が接着され顆粒が成長する。これにより結合剤は顆粒の内部に多く存在し、顆粒の表面に存在する結合剤は少なくなり、場合により顆粒がそれ以上成長しない程度まで顆粒の表面に存在する結合剤は少なくなり得る。このように結合剤を溶液として用いて得られる顆粒よりも顆粒表面上に存在する結合剤が少ない顆粒とすることにより、顆粒の溶解や崩壊が阻害されることがなく、崩壊性に優れ、圧縮成形性にも優れた顆粒が得られる。
本発明において、結合剤を粉末の状態で添加するとは、結合剤を溶剤等に溶解することなく原粉末のまま添加することを意味し、粉末であれば特に限定されないが、通常は平均粒子径として好ましくは１００μｍ以下、より好ましくは７５μｍ以下の粒子径を有する粉末を使用する。このような粒子径を有する結合剤を使用することにより、崩壊性に優れ、かつ比較的大きい粒子径の速放性顆粒を製造することができる。
速放性顆粒は、少なくとも崩壊剤、結合剤及び活性成分とからなる。速放性顆粒を構成する崩壊剤及び結合剤は従来から知られているものを使用することができる。
崩壊剤の例としては、コーンスターチ、ヒドロキシプロピルスターチ、部分アルファー化デンプン及びカルボキシメチルスターチナトリウム等のデンプン類、軽質無水ケイ酸、乳糖、カンテン末、微結晶セルロース、カルボシキメチルセルロース、低置換度ヒドロキシプロピルセルロース、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シウム、クロスカルメロースナトリウム、クロスポビドン等が挙げられ、これらの１種以上を使用することができる。これらのうち、低置換度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、クロスカルメロースナトリウム及びクロスポビドンが特に好ましい。
結合剤の例としては、デンプン類、デキストリン、アラビアゴム末、ゼラチン、糖類、ヒドロキシプロピルスターチ、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシプロピルセルロース、低置換度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、ポリビニルピロリドン、マクロゴール等が挙げられ、これらの１種以上を使用することができる。これらのうち、ヒドロキシプロピルセルロース及びヒドロキシプロピルメチルセルロースが特に好ましい。
活性成分としては、本発明のマルチプルユニット型徐放性錠剤の速放部として配合して溶出性の向上が期待できる物質であれば特に限定されず、種々の医薬品化合物等を使用することができる。具体例としては、塩酸ロペラミド、アクリノール、クレオソート、カフェイン、無水カフェイン、塩酸メクリジン、塩酸ジフェンヒドラミン、塩酸フェニルプロパノールアミン、リン酸ジヒドロコデイン、臭化水素酸デキストロメトルファン、ノスカピン、塩酸アンブロキソール、メキタジン、マレイン酸クロルフェニラミン、塩酸ジサイクロミン、臭化水素酸スコポラミン、ベラドンナエキス、ビタミンＢ１、フルスルチアミン、ニコチン酸アミド、イブプロフェン、アセトアミノフェン、プソイドエフェドリン等を挙げることができる。
本発明のマルチプルユニット型徐放性錠剤の速放性顆粒は、上記の成分の他、必要に応じて乳糖、マンニット、トウモロコシデンプン、メタケイ酸アルミン酸マグネシウム、合成もしくは天然ガム等の賦形剤、タルク、ステアリン酸マグネシウム、ステアリン酸カルシウム等の滑沢剤等、アビセル等のような成形助剤、糖類等の添加剤を含んでいてもよい。尚、本発明のマルチプルユニット型徐放性錠剤の速放性顆粒に糖類を使用する場合は、溶解した際に溶液が高い粘性を示すものは結合剤と同様の機能を果たし、崩壊性に悪影響を与えるので好ましくなく、乳糖、マンニット等の溶解速度が速く、溶解した際の溶液の粘性が低い糖類を使用することが好ましい。
速放性顆粒中の崩壊剤及び結合剤の量は、上記のようにして製造される速放性顆粒について十分な顆粒寸法、崩壊性、圧縮成形性が得られ、さらにその速放性顆粒を使用して得られるマルチプルユニット型徐放性錠剤について十分な硬度と崩壊性が得られる限り特に限定されないが、速放性顆粒全体に対して、崩壊剤の量は好ましくは５〜５０重量％、より好ましくは１０〜３０重量％程度であり、結合剤の量は好ましくは１〜２０重量％、より好ましくは３〜１５重量％程度である。
上記のような成分を均一に混合して混合粉末を得、その混合粉末を造粒することにより速放性顆粒を得る。速放性顆粒の造粒方法、造粒条件等は特に限定されず、通常用いられる公知の造粒方法、造粒条件等が適宜使用できるが、流動層造粒法により造粒することが好ましい。流動層造粒法による造粒は、従来の流動層造粒機を用いて行うことができるが、本発明においては上記結合剤を既に含む混合粉末に対し水等の溶媒のみを噴霧することによって行う。水等の溶媒の量は従来の流動層造粒法において結合剤の溶液として添加される場合と同様の量あるいは若干多い量が好ましい。例えば使用される溶媒と混合粉末の重量比は約１：２程度とすることができるが、流動層造粒法においては溶媒が蒸発するため、造粒中における溶媒と混合粉末の重量比は通常約１：９〜２：８程度である。
上記のようにして製造される速放性顆粒は、徐放性顆粒との良好な混合が得られるような粒子径に製造する。速放性顆粒の粒子径は、徐放性顆粒の粒子径と同程度で、徐放性顆粒との良好な混合が得られる限り特に限定されないが、速放性顆粒の平均粒子径が徐放性顆粒の平均粒子径の２０〜２００％であることが好ましく、より好ましくは５０〜１００％である。また速放性顆粒の平均粒子径と徐放性顆粒の平均粒子径の差は、好ましくは約２００μｍ以下、より好ましくは約１５０μｍ以下である。速放性顆粒は、好ましくは１００〜１０００μｍ、より好ましくは１５０〜８００μｍ程度の平均粒子径を有し、かつその平均粒子径が上記の条件を満たすように造粒されることが特に好ましい。尚、徐放性顆粒は通常３００〜１０００μｍ程度の粒子径を有する。
本発明のマルチプルユニット型徐放性錠剤においては、前記速放性顆粒のみを８ｍｍ径、２４０ｍｇ／錠、打錠圧２．４ＭＰａで打錠した場合の錠剤の硬度が１０ｋｐ以上、好ましくは１４ｋｐ以上で、後述の実施例に示した崩壊試験における崩壊時間が２０分以内、好ましくは１０分以内であることが望ましい。このような硬度及び崩壊度とすることにより、速放性顆粒に求められる錠剤圧縮成形性と活性薬剤の速い放出性とが十分に両立される。
本発明のマルチプルユニット型徐放性錠剤に含まれる徐放性顆粒は、従来のマルチプルユニット型徐放性錠剤に使用されるものと同様のものとすることができ、例えば、活性成分及び任意にその他の添加剤からなる顆粒（素顆粒）に徐放性膜をコーティングした徐放性顆粒とすることができる。
素顆粒は活性成分とともに任意に上記速放性顆粒について挙げたものと同様の賦形剤、崩壊剤、滑沢剤等の添加剤を使用して流動層造粒法等の常法により製造することができる。また素顆粒には、結晶セルロース球形顆粒（商品名：セルフィア）、乳糖・結晶セルロース球形顆粒（商品名：ノンパレル）等の添加剤を用いることができる。活性成分の例としては、上記速放性顆粒について挙げたものと同様の薬剤が挙げられる。
徐放性膜を構成する徐放化基剤としては、エチルセルロース、アクリル酸ポリマー等が挙げられる。アクリル酸ポリマーの具体例としては、商品名オイドラギットＮＥ３０Ｄ、同ＲＳ、同ＲＬで販売されているもの等が例示される。本発明においては、エチルセルロースが好ましく使用される。これらの徐放化基剤はそれぞれ単独で用いてもよく、２種以上を併せて用いてもよい。
上記徐放化基剤を素顆粒に被覆するための溶液または分散物を形成するための溶剤としては、水と低級アルコールとの混合物または低級アルコールが好ましい。低級アルコールとしてはエチルアルコールが最も好ましい。溶剤の使用量は所望の被覆に適した使用量とすることができる。徐放化基剤の溶液は上記のような溶媒中に通常の方法により溶解あるいは分散することにより得られるが、徐放化基剤は溶媒中に均一に溶解または分散されていることが好ましく、撹拌機等の装置を用い、十分撹拌して製造することが好ましい。また、徐放化基剤の溶液または分散物には硬化油、ステアリン酸、セタノール等のコーティング助剤、中鎖脂肪酸トリグリセリド、トリアセチン、クエン酸トリエチル、セタノール等の可塑剤等を添加してもよい。
有効成分の種類により徐放性顆粒に望まれる活性成分の溶出速度は異なるが、有効成分と徐放化基剤との配合比、徐放性膜厚、徐放性基剤の種類、分子量等を適当に選択することにより溶出速度を調節することができる。例えば、徐放化基剤がエチルセルロースである場合は、エチルセルロースの分子量を変えることにより溶出速度を制御することができる。
素顆粒上に徐放化基剤の皮膜を形成させる方法としては、複合型コーティング機、転動流動コーティング機及び流動層コーティング機等を利用することができる。また、必要に応じキュアリングを行うことも効果的である。キュアリングは徐放化基剤の軟化点以上で行うことが好ましい。
本発明においては、その後の速放性顆粒との圧縮成形による徐放性顆粒の活性成分の溶出速度の変化をより少なくするために、徐放性顆粒の外層をさらに水溶性高分子の保護皮膜で被覆してもよい。この場合に用いられる水溶性高分子としては、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース等を挙げることができる。水溶性高分子の量は徐放性顆粒に対して１５重量％以下とすることが好ましい。
本発明のマルチプルユニット型徐放性錠剤は、上記のような速放性顆粒と徐放性顆粒とを、通常の混合機、打錠機を用い、通常の方法により圧縮打錠することにより製造することができる。打錠圧は適度な硬度の錠剤が形成される限り特に制限されないが、通常０．５〜４．０ＭＰａ、好ましくは１．４〜３．０ＭＰａ程度である。本発明のマルチプルユニット型徐放性錠剤の硬度は、例えば錠剤の直径が８ｍｍの場合は、通常３ｋｐ以上、好ましくは４ｋｐ以上である。
本発明のマルチプルユニット型徐放性錠剤における速放性顆粒と徐放性顆粒との配合割合は、活性成分の速放及び徐放性能によっても変化し、両者を適度な硬度を有する錠剤として打錠できる限り特に制限されないが、通常は、速放性顆粒と徐放性顆粒との重量比で１：０．５〜１：３、好ましくは１：０．５〜１：１程度である。速放性顆粒の量が少なすぎると錠剤の成形性の悪化などを招き、速放性顆粒の量が多すぎると錠剤が大きくなり服薬しにくくなる、あるいは徐放性顆粒を速やかに放出するための崩壊が妨げられる等の問題が起こり得る。
上記のように、本発明のマルチプルユニット型徐放性錠剤は、その速放性顆粒の製造において結合剤が粉末の状態で混合されることを特徴とする。従って本発明は、薬物を持続的に放出する打錠用顆粒（徐放性顆粒）と薬物を速やかに放出する打錠用顆粒（速放性顆粒）を圧縮打錠することを含むマルチプルユニット型徐放性錠剤の製造方法において、速放性顆粒が崩壊剤及び結合剤を含み、速放性顆粒の製造において結合剤を粉末の状態で混合することを特徴とする徐放性錠剤の製造方法も提供する。
実施例
以下の実施例及び試験例により本発明をさらに詳細に説明するが、本発明は以下の実施例及び試験例により限定されるものではない。
徐放性顆粒の調製
塩酸フェニルプロパノールアミン８１０ｇ、エチルセルロース６０８ｇをエタノール８５８６ｇ、水２１４７ｇの混合液に溶解し造粒液とした。セルフィア８００ｇを内筒付きボトムスプレー型流動層造粒コーティング機に投入し、先に調製した造粒液を給気温度５０℃、スプレー速度を２０〜３０ｇ／ｍｉｎの範囲でスプレーし、造粒液１２０００ｇをスプレーした後、給気温度８０℃で約３０分乾燥しコーティング前の素顆粒を得た。
次に、エチルセルロース４９７ｇ及びクエン酸トリエチル２４．９ｇをエタノール７９３５ｇ、水１９８３ｇの混合液に溶解し、徐放性膜塗布液とした。前記コーティング前の素顆粒８１０ｇを内筒付きボトムスプレー型流動層造粒コーティング機に投入し、給気温度３５℃、スプレー速度を２０〜３０ｇ／ｍｉｎの範囲で調整して徐放性膜塗布液１０１２８ｇをスプレーした後、給気温度８０℃で約２０分乾燥した。凝集物を篩過により除去して徐放性顆粒を得た。得られた徐放性顆粒は３７８μｍの平均粒子径を有していた。
この徐放性顆粒を以下の実施例及び比較例に用いた。
（実施例１）
表１に示す処方で、無水カフェイン１００ｇ、塩酸フェニルプロパノールアミン３２ｇ、マレイン酸カルビノキサミン１２ｇ、グリチルリチン３０ｇ、乳糖１８０ｇ、軽質無水ケイ酸１４ｇ、クロスカルメロースナトリウム１３０ｇ、ヒドロキシプロピルセルロース４０ｇを混合し、フロイント産業社製流動層造粒機に投入した。給気温度７０℃、スプレー速度５〜８ｇ／ｍｉｎの範囲で２７８ｇの水をスプレーし、速放性顆粒を得た。得られた速放性顆粒は２０５μｍの平均粒子径を有していた。
この速放性顆粒４３０ｇ、前記徐放性顆粒１６０ｇ、ステアリン酸マグネシウム２．７ｇをビニール袋に入れて混合し、打錠用顆粒混合物とした。この混合物を菊水製作所製打錠機コレクト１２ＨＵを用いて打錠し（圧縮圧２．９６ＭＰａ）、直径８ｍｍ、１錠重量約１８５．５ｍｇの錠剤を得た。得られた錠剤の硬度は約４ｋｐであった。
（比較例１）
表１に比較例１として示す処方を使用し、実施例１と同様の手順で速放性顆粒を調製した。但し結合剤のヒドロキシプロピルセルロースは、７％水溶液として実施例１でスプレーした水に代えてスプレーすることにより添加した。得られた速放性顆粒は２５６μｍの平均粒子径を有していた。
この速放性顆粒３２６ｇ、前記徐放性顆粒１２５．５ｇ、ステアリン酸マグネシウム２．２５ｇをビニール袋に入れて混合し、打錠用顆粒混合物とした。この混合物を菊水製作所製打錠機コレクト１２ＨＵを用いて打錠し（圧縮圧２．９６ＭＰａ）、直径８ｍｍ、１錠重量約１８５．５ｍｇの錠剤を得た。得られた錠剤の硬度は約４ｋｐであった。
（比較例２）
表１に比較例２として示す処方を使用し、実施例１と同様の手順で速放性顆粒を調製した。但し結合剤のヒドロキシプロピルセルロースは、７％水溶液として実施例１でスプレーした水に代えてスプレーすることにより添加した。得られた速放性顆粒は２１３μｍの平均粒子径を有していた。
この速放性顆粒３２６ｇ、前記徐放性顆粒１２５．５ｇ、ステアリン酸マグネシウム２．２５ｇをビニール袋に入れて混合し、打錠用顆粒混合物とした。この混合物を菊水製作所製打錠機コレクト１２ＨＵを用いて打錠し（圧縮圧２．９６ＭＰａ）、直径８ｍｍ、１錠重量約１８５．５ｍｇの錠剤を得た。得られた錠剤の硬度は約４ｋｐであった。
（比較例３）
表１に比較例３として示す処方の各成分の粉末を各々秤量し、混合してパウレック社製バーチカルグラニュレーターに投入し、適量の水を添加して造粒した。すなわち、混合造粒法により結合剤を含む粉末から造粒した。得られた湿粒をフロイント産社製流動層乾燥機を用いて乾燥し、２４号篩を通過させて速放性顆粒を得た。得られた速放性顆粒は２１２μｍの平均粒子径を有していた。
この速放性顆粒４２４ｇ、前記徐放性顆粒１４０ｇ、ステアリン酸マグネシウム２．８ｇをビニール袋に入れて混合し、打錠用顆粒混合物とした。この混合物を菊水製作所製打錠機コレクト１２ＨＵを用いて打錠し（圧縮圧２．９６ＭＰａ）、直径８ｍｍ、１錠重量約２０２．５ｍｇの錠剤を得た。得られた錠剤の硬度は約４ｋｐであった。
実施例１と同じ処方及び手順を使用して速放性顆粒を調製した。得られた速放性顆粒は２１１μｍの平均粒子径を有していた。
この速放性顆粒４３０．６ｇ、前記徐放性顆粒１６０．６ｇ、ステアリン酸マグネシウム２．６９ｇ、クロスポビドン９６ｇをビニール袋に入れて混合し、打錠用顆粒混合物とした。この混合物を菊水製作所製打錠機コレクト１２ＨＵを用いて打錠し（圧縮圧２．９６ＭＰａ）、直径８ｍｍ、１錠重量約２１５．５ｍｇの錠剤を得た。得られた錠剤の硬度は約４ｋｐであった。
（実施例３）
実施例１と同じ処方及び手順を使用して速放性顆粒を調製した。得られた速放性顆粒は２１８μｍの平均粒子径を有していた。
この速放性顆粒４３０ｇ、前記徐放性顆粒１６０ｇ、ステアリン酸マグネシウム２．７ｇ、クロスポビドン６４ｇをビニール袋に入れて混合し、打錠用顆粒混合物とした。この混合物を菊水製作所製打錠機コレクト１２ＨＵを用いて打錠し（圧縮圧２．９６ＭＰａ）、直径８ｍｍ、１錠重量約２０５．５ｍｇの錠剤を得た。得られた錠剤の硬度は約４ｋｐであった。
（試験例１）
実施例及び比較例で得られた錠剤について第十三改正日本薬局方に記載の方法により崩壊試験を行った。
すなわち、第十三改正日本薬局方に記載の装置及び方法で、３６．５℃の水を試験液として用い、各錠剤が崩壊するまでの時間（崩壊した錠剤片の全てが試験装置底面の２ｍｍの網を通過するまでの時間）を測定した。結果を表２に示す。
産業上の利用可能性
本発明によれば、崩壊時間の短いマルチプルユニット型徐放性錠剤が調製でき、より迅速な即効性と持効性とを期待できる錠剤が得られる。Technical field
The present invention relates to an improvement of multiple unit type sustained release tablets. More specifically, the present invention relates to a multiple unit type sustained release tablet in which the dissolution rate of components from the immediate release part is improved in a multiple unit type sustained release tablet comprising a drug immediate release part and a sustained release part.
Background art
The sustained-release preparation is a dosage form for the purpose of reducing the number of administrations by controlling the drug release rate and reducing the burden of patient administration. As main forms of sustained-release preparations, a single unit-type sustained-release tablet in which the entire tablet is coated with a sustained-release film, a multiple-unit-type sustained-release tablet composed of a large number of drug granules coated with a sustained-release film, and It has been known. It is known that multiple unit type preparations are excellent for reducing the variation in drug absorption within and between individuals.
In addition, since multiple unit type preparations can contain a sustained release part and a part capable of promptly releasing the drug (fast release part), the effective blood concentration of the drug can be obtained quickly and sustained. For example, by quickly and slowly releasing the analgesic component, it is possible to quickly suppress pain in a patient who has pain for some reason and to suppress pain for a long time.
When a component that releases a drug quickly is added to a multiple unit type sustained-release preparation, a sustained-release granule having a sustained-release membrane coated on the elementary granules of the drug as described above, and an immediate release that releases the drug quickly. It is common to blend with sexual granules. These sustained-release granules and immediate-release granules need to have particle sizes as close as possible to obtain good mixing. Sustained-release granules are manufactured by coating the drug substance granules with a sustained-release membrane as described above, so the particle size must be relatively large, and the rapid-release granules use relatively large particles accordingly. There is a need to. In addition, sustained-release granules have a relatively uniform particle size and are designed as hard granules to maintain sustained-release properties, so they are inferior in compression moldability. When forming by locking, it is necessary to use immediate-release granules having excellent moldability.
In general, granules prepared by fluidized bed granulation have superior compression moldability compared to granules prepared by other granulation methods, but the tablet disintegration time obtained when the granules are compressed into tablets Often becomes long, and the significance of blending the quick-release part is lost. However, if a large amount of a disintegrant is added to the immediate release granules to increase the disintegration of the tablet, it becomes difficult to increase the particle size of the granulated product (granule), and the sustained release has a relatively large particle size. It becomes difficult to obtain an immediate-release granule having the same particle size as the granule. In this case, when the amount of the binder is increased, the particle size of the granulated product (granule) can be increased, but the disintegration property of the tablet is deteriorated again.
As described above, in the conventional method, in the multiple unit type sustained release tablet containing the sustained release granules and the immediate release granules, only by adjusting the combination of the binder and the disintegrant of the immediate release granules, It has been difficult to simultaneously achieve the purpose of making the sustained-release granule and the rapid-release granule of the same size so that the tablet can be sufficiently molded and has excellent disintegration properties.
Disclosure of the invention
Therefore, in the present invention, in the multiple unit type sustained release tablet containing the sustained release granules and the immediate release granules, the sustained release granules and the immediate release granules can have the same particle size. Accordingly, it is an object of the present invention to provide a multiple unit type sustained-release tablet which can be well mixed and can be sufficiently molded and is excellent in disintegration and a method for producing the same.
The present inventor appropriately selects the granulation method and ingredients of the rapid release granule in a multiple unit type sustained release tablet containing the sustained release granule and the immediate release granule. By adding the added binder as a powder, it is possible to obtain a fast-release granule having a particle size comparable to that of the sustained-release granule and excellent in moldability. It has been found that a good mixing with the releasable granules can be obtained, and a multiple unit type sustained-release tablet that can be sufficiently molded and is excellent in disintegration is obtained.
That is, the present invention is also referred to as a tableting granule for sustained release of a drug (hereinafter also referred to as “sustained release granule”) and a tableting granule for immediate release of a drug (hereinafter referred to as “rapid release granule”). A multiple unit type sustained-release tablet comprising a rapid-release granule containing a disintegrant and a binder, and the binder is mixed in the form of powder in the production of the rapid-release granule Provide tablets.
In the sustained-release tablet of the present invention, the binder mixed in the powder state in the production of immediate-release granules is preferably a powder having an average particle size of 100 μm or less, more preferably 75 μm or less.
The disintegrant used for the production of immediate release granules preferably has an average particle size of 100 μm or less, and is selected from the group consisting of low-substituted hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium and crospovidone. One kind or two or more kinds of substances are preferable.
It is preferable that the binder used for production of the immediate release granule is one or two or more substances selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose.
The amount of the disintegrant contained in the immediate release granules is preferably about 5 to 50% by weight, more preferably about 10 to 30% by weight with respect to the entire immediate release granules.
The amount of the binder contained in the immediate release granule is preferably about 1 to 20% by weight, more preferably about 3 to 15% by weight with respect to the entire immediate release granule.
In the sustained-release tablet of the present invention, the sustained-release granules preferably have an average particle size of 100 to 1000 μm, more preferably 200 to 800 μm, and the quick-release granules are preferably 100 to 1000 μm, more preferably Has an average particle size of 150-800 μm.
The sustained-release tablet of the present invention may contain a disintegrating agent in addition to the sustained-release granule and the immediate-release granule. As the disintegrant contained in parts other than the sustained-release granules and immediate-release granules, the same disintegrants as those used in the above-mentioned immediate-release granules can be used, and the amount thereof is a sustained-release tablet. Preferably it is 1-25 weight% with respect to the whole, More preferably, it is about 7-15 weight%.
Furthermore, the present invention relates to a multiple unit type comprising compressing and compressing granules for tablet release (sustained release granules) for sustained release of drug and granules for tablet release (rapid release granules) for rapid release of drug. A method for producing a sustained-release tablet, characterized in that the immediate-release granules contain a disintegrant and a binder, and the binder is mixed in the form of powder in the production of the rapid-release granules. I will provide a.
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in detail.
The multiple unit type sustained release tablet of the present invention comprises a tableting granule (sustained release granule) that releases the drug continuously and a tableting tablet (fast release granule) that releases the drug quickly. The release granules include a disintegrant and a binder, and the binder is mixed in a powder state in the production of the immediate release granules.
That is, the multiple unit type sustained-release tablet of the present invention is prepared by adding a binder in a solution state as in a normal fluidized bed granulation method when producing an immediate release granule by the fluidized bed granulation method or the like. Instead, it is added as a powder, and other than that, it can be produced in the same manner as a conventional multiple unit type sustained release tablet comprising a sustained release granule and an immediate release granule. That is, a powder mixture is added to an active ingredient such as a drug, a disintegrant, and other additives, and a mixed powder is prepared. And by spraying water on the mixed powder, a quick-release granule is obtained by fluidized bed granulation method, and the immediate-release granule and a separately-released sustained-release granule and, if necessary, a lubricant, a disintegrant, etc. The multiple unit type sustained-release tablet of the present invention can be produced by mixing the additive and compressing the granule mixture.
By producing as described above, the immediate-release granules can be produced in relatively large particle sizes comparable to the sustained-release granules, while maintaining rapid disintegration and compression moldability. It can be a granule. Therefore, in the produced multiple unit type sustained release tablet, the sustained release granule and the immediate release granule are sufficiently mixed, and the multiple unit type sustained release tablet itself has an appropriate hardness, and It becomes a tablet with a very short disintegration time. That is, in the conventional multiple unit type sustained-release tablet, sufficient particle size, disintegration and compression of the immediate-release granule, which could not be achieved only by adjusting the blending amount of the disintegrant and the binder. Formability can be realized at the same time.
The present invention is not bound by any theory, but the effects of the present invention as described above are mainly immediate release prepared by a granulation method such as a fluidized bed granulation method having the above characteristics. It is considered that the distribution of the binder in the granule is different from that in the granule produced by the conventional method. That is, when the binder is dissolved in a solvent and used as a solution as in the conventional fluidized bed granulation method, the binder is uniformly distributed inside and over the entire surface of the disintegrant, active ingredient, etc. As a result, particles such as a disintegrant and an active ingredient are adhered to grow granules. In order to obtain relatively large granules in such a state, the amount of the binder is relatively large, and the presence of a large amount of binder on the surface of the granules inhibits dissolution and disintegration of the granules, resulting in disintegration. It becomes a granule that lacks. On the other hand, according to the present invention, the binder added in powder form is distributed as powder particles on the surface of the particles such as the disintegrant and active ingredient, and the particles such as the disintegrant and active ingredient are adhered to form granules. grow up. As a result, a large amount of the binder is present inside the granule, the binder present on the surface of the granule is reduced, and in some cases, the binder present on the surface of the granule is reduced to the extent that the granule does not grow any more. Thus, by using a binder as a granule with less binder present on the surface of the granule than a granule obtained by dissolution, the dissolution and disintegration of the granule is not hindered, the disintegration is excellent, and the compression Granules excellent in moldability can be obtained.
In the present invention, adding the binder in the state of powder means adding the binder as a raw powder without dissolving it in a solvent or the like. Preferably, a powder having a particle size of 100 μm or less, more preferably 75 μm or less is used. By using a binder having such a particle size, it is possible to produce quick-release granules having excellent disintegration and a relatively large particle size.
The immediate release granule comprises at least a disintegrant, a binder and an active ingredient. Conventionally known disintegrants and binders constituting the immediate release granules can be used.
Examples of disintegrants include starches such as corn starch, hydroxypropyl starch, partially pregelatinized starch and sodium carboxymethyl starch, light anhydrous silicic acid, lactose, agar powder, microcrystalline cellulose, carboxymethyl cellulose, low substituted hydroxypropyl Examples thereof include cellulose, hydroxypropylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, and one or more of these can be used. Of these, low-substituted hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium and crospovidone are particularly preferred.
Examples of binders include starches, dextrin, gum arabic powder, gelatin, saccharides, hydroxypropyl starch, sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, Macrogols and the like can be mentioned, and one or more of these can be used. Of these, hydroxypropylcellulose and hydroxypropylmethylcellulose are particularly preferred.
The active ingredient is not particularly limited as long as it is a substance that can be blended as an immediate release part of the multiple unit type sustained release tablet of the present invention and expected to improve dissolution, and various pharmaceutical compounds and the like can be used. . Specific examples include loperamide hydrochloride, acrinol, creosote, caffeine, anhydrous caffeine, meclizine hydrochloride, diphenhydramine hydrochloride, phenylpropanolamine hydrochloride, dihydrocodeine phosphate, dextromethorphan hydrobromide, noscapine, ambroxol hydrochloride, Examples include mequitazine, chlorpheniramine maleate, dicyclomine hydrochloride, scopolamine hydrobromide, belladonna extract, vitamin B1, fursultiamine, nicotinamide, ibuprofen, acetaminophen, pseudoephedrine and the like.
The immediate-release granules of the multiple unit type sustained-release tablet of the present invention include excipients such as lactose, mannitol, corn starch, magnesium aluminate metasilicate, synthetic or natural gum as necessary in addition to the above components In addition, lubricants such as talc, magnesium stearate, calcium stearate, and the like, molding aids such as Avicel, and additives such as sugars may be included. In addition, when saccharides are used in the immediate-release granules of the multiple unit type sustained-release tablet of the present invention, those having a high viscosity when dissolved serve the same function as a binder and adversely affect disintegration. It is not preferable to use saccharides such as lactose and mannitol, which have a high dissolution rate and have a low viscosity when dissolved.
The amount of disintegrant and binder in the immediate release granule is sufficient to obtain sufficient granule size, disintegration and compression moldability for the immediate release granule produced as described above. The multiple unit type sustained-release tablet obtained by use is not particularly limited as long as sufficient hardness and disintegration are obtained, but the amount of disintegrant is preferably 5 to 50% by weight based on the entire rapid-release granules. More preferably, it is about 10-30 weight%, The amount of a binder becomes like this. Preferably it is 1-20 weight%, More preferably, it is about 3-15 weight%.
The above components are uniformly mixed to obtain a mixed powder, and the mixed powder is granulated to obtain immediate release granules. The granulation method, granulation conditions, etc. of the immediate release granule are not particularly limited, and known granulation methods, granulation conditions, etc. that are usually used can be used as appropriate, but granulation by a fluidized bed granulation method is preferred. . Granulation by the fluidized bed granulation method can be performed using a conventional fluidized bed granulator, but in the present invention, only the solvent such as water is sprayed on the mixed powder that already contains the binder. Do. The amount of the solvent such as water is preferably the same as or slightly larger than the amount added as a binder solution in the conventional fluidized bed granulation method. For example, the weight ratio of the solvent used and the mixed powder can be about 1: 2, but in the fluidized bed granulation method, the solvent evaporates, so the weight ratio of the solvent and the mixed powder during granulation is usually About 1: 9 to 2: 8.
The immediate-release granules produced as described above are produced to have a particle size that allows good mixing with the sustained-release granules. The particle size of the immediate release granule is about the same as the particle size of the sustained release granule and is not particularly limited as long as good mixing with the sustained release granule is obtained, but the average particle size of the immediate release granule is not limited. It is preferably 20 to 200%, more preferably 50 to 100%, of the average particle size of the sexual granules. The difference between the average particle size of the immediate release granules and the average particle size of the sustained release granules is preferably about 200 μm or less, more preferably about 150 μm or less. The immediate-release granules preferably have an average particle diameter of preferably about 100 to 1000 μm, more preferably about 150 to 800 μm, and are particularly preferably granulated so that the average particle diameter satisfies the above conditions. The sustained-release granules usually have a particle size of about 300 to 1000 μm.
In the multiple unit type sustained-release tablet of the present invention, the tablet hardness is 10 kp or more, preferably 14 kp or more when only the immediate-release granules are tableted at 8 mm diameter, 240 mg / tablet, and tableting pressure 2.4 MPa. Therefore, it is desirable that the disintegration time in the disintegration test shown in the examples described later is within 20 minutes, preferably within 10 minutes. By setting it as such hardness and disintegration degree, tablet compression moldability calculated | required by the immediate release granule and the quick release of an active agent are fully compatible.
The sustained release granules contained in the multiple unit type sustained release tablet of the present invention can be the same as those used in conventional multiple unit type sustained release tablets. For example, the active ingredient and optionally It can be set as the sustained release granule which coated the sustained release film | membrane with the granule (elementary granule) which consists of another additive.
Elementary granules are produced by conventional methods such as fluidized bed granulation using additives such as the same excipients, disintegrants, lubricants, etc. as those mentioned for the immediate release granules together with the active ingredient. be able to. For the elementary granules, additives such as crystalline cellulose spherical granules (trade name: SELPHYR), lactose / crystalline cellulose spherical granules (trade name: non-parrel) can be used. Examples of the active ingredient include the same drugs as those mentioned for the immediate release granules.
Examples of the sustained release base constituting the sustained release membrane include ethyl cellulose and acrylic acid polymer. Specific examples of the acrylic acid polymer include those sold under the trade names Eudragit NE30D, RS, and RL. In the present invention, ethyl cellulose is preferably used. These sustained release bases may be used alone or in combination of two or more.
As a solvent for forming a solution or dispersion for coating the above-mentioned sustained release base on elementary granules, a mixture of water and a lower alcohol or a lower alcohol is preferred. As the lower alcohol, ethyl alcohol is most preferred. The amount of the solvent used can be an amount suitable for the desired coating. The sustained-release base solution can be obtained by dissolving or dispersing in the above-mentioned solvent by a usual method, but the sustained-release base is preferably dissolved or dispersed uniformly in the solvent, It is preferable to produce by sufficiently stirring using a device such as a stirrer. Further, a hardened oil, stearic acid, cetanol and other coating aids, medium chain fatty acid triglycerides, triacetin, triethyl citrate, cetanol and other plasticizers may be added to the sustained release base solution or dispersion. .
The elution rate of the active ingredient desired for the sustained-release granules varies depending on the type of active ingredient, but the compounding ratio of active ingredient and sustained-release base, sustained-release film thickness, type of sustained-release base, molecular weight, etc. The elution rate can be adjusted by appropriately selecting. For example, when the sustained release base is ethyl cellulose, the elution rate can be controlled by changing the molecular weight of ethyl cellulose.
As a method for forming a sustained release base film on the elementary granules, a composite coating machine, a rolling fluid coating machine, a fluidized bed coating machine, or the like can be used. It is also effective to perform curing as necessary. It is preferable to perform the curing at or above the softening point of the sustained release base.
In the present invention, the outer layer of the sustained-release granules is further coated with a water-soluble polymer protective film in order to reduce the change in the dissolution rate of the active ingredient of the sustained-release granules by compression molding with the subsequent immediate-release granules. You may coat with. Examples of the water-soluble polymer used in this case include hydroxypropyl methylcellulose and hydroxypropylcellulose. The amount of the water-soluble polymer is preferably 15% by weight or less based on the sustained-release granules.
The multiple unit type sustained-release tablet of the present invention is produced by compressing and compressing the above-mentioned immediate-release granule and sustained-release granule by the usual method using an ordinary mixer and tablet press. can do. The tableting pressure is not particularly limited as long as a tablet having an appropriate hardness is formed, but is usually about 0.5 to 4.0 MPa, preferably about 1.4 to 3.0 MPa. The hardness of the multiple unit type sustained release tablet of the present invention is usually 3 kp or more, preferably 4 kp or more, for example, when the tablet diameter is 8 mm.
In the multiple unit type sustained-release tablet of the present invention, the blending ratio of the immediate-release granules and the sustained-release granules varies depending on the immediate release and sustained-release performance of the active ingredient, and both are formed as tablets having appropriate hardness. Although it is not particularly limited as long as the tablet can be used, it is usually in the range of 1: 0.5 to 1: 3, preferably about 1: 0.5 to 1: 1 in terms of the weight ratio of immediate release granules to sustained release granules. If the amount of the immediate release granule is too small, the moldability of the tablet will be deteriorated. If the amount of the immediate release granule is too large, the tablet will become large and difficult to take, or the sustained release granule will be released quickly. Problems such as hindering the collapse of can occur.
As described above, the multiple unit type sustained release tablet of the present invention is characterized in that the binder is mixed in the state of powder in the production of the immediate release granule. Accordingly, the present invention provides a multiple unit type comprising compression-compressing a tableting granule (sustained release granule) that releases drug continuously and a tableting granule (fast release granule) that releases drug quickly. A method for producing a sustained-release tablet, characterized in that the immediate-release granules contain a disintegrant and a binder, and the binder is mixed in the form of powder in the production of the rapid-release granules. Also provide.
Example
The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited to the following examples and test examples.
Preparation of sustained release granules
810 g of phenylpropanolamine hydrochloride and 608 g of ethyl cellulose were dissolved in a mixed solution of 8586 g of ethanol and 2147 g of water to obtain a granulated liquid. 800 g of SELPHYA is put into a bottom spray type fluidized bed granulation coating machine with an inner cylinder, and the previously prepared granulation liquid is sprayed at an air supply temperature of 50 ° C. and a spray speed of 20-30 g / min. After spraying 12000 g, it was dried at an air supply temperature of 80 ° C. for about 30 minutes to obtain an elementary granule before coating.
Next, 497 g of ethyl cellulose and 24.9 g of triethyl citrate were dissolved in a mixed solution of 7935 g of ethanol and 1983 g of water to obtain a sustained-release film coating solution. 810 g of the elementary granules before coating are put into a bottom spray type fluidized bed granulation coating machine with an inner cylinder, and the sustained-release film coating solution is adjusted by adjusting the air supply temperature at 35 ° C. and the spray speed in the range of 20-30 g / min After spraying 10128 g, it was dried at an air supply temperature of 80 ° C. for about 20 minutes. Aggregates were removed by sieving to obtain sustained-release granules. The obtained sustained-release granules had an average particle size of 378 μm.
This sustained release granule was used in the following Examples and Comparative Examples.
(Example 1)
In the formulation shown in Table 1, 100 g of anhydrous caffeine, 32 g of phenylpropanolamine hydrochloride, 12 g of carbinoxamine maleate, 30 g of glycyrrhizin, 180 g of lactose, 14 g of light anhydrous silicic acid, 130 g of croscarmellose sodium and 40 g of hydroxypropylcellulose are mixed. The fluidized bed granulator manufactured by Sangyo Co., Ltd. was used. 278 g of water was sprayed at an air supply temperature of 70 ° C. and a spray rate of 5 to 8 g / min to obtain immediate release granules. The obtained immediate release granules had an average particle size of 205 μm.
430 g of the immediate release granules, 160 g of the sustained release granules, and 2.7 g of magnesium stearate were placed in a plastic bag and mixed to obtain a granule mixture for tableting. This mixture was tableted using a tableting machine collect 12HU manufactured by Kikusui Seisakusho (compression pressure: 2.96 MPa) to obtain a tablet having a diameter of 8 mm and a tablet weight of about 185.5 mg. The resulting tablet had a hardness of about 4 kp.
(Comparative Example 1)
Using the formulation shown in Table 1 as Comparative Example 1, immediate release granules were prepared in the same procedure as in Example 1. However, the binder hydroxypropyl cellulose was added as a 7% aqueous solution by spraying instead of the water sprayed in Example 1. The obtained immediate release granules had an average particle size of 256 μm.
326 g of the immediate release granules, 125.5 g of the sustained release granules, and 2.25 g of magnesium stearate were placed in a plastic bag and mixed to obtain a granule mixture for tableting. This mixture was tableted using a tableting machine collect 12HU manufactured by Kikusui Seisakusho (compression pressure: 2.96 MPa) to obtain a tablet having a diameter of 8 mm and a tablet weight of about 185.5 mg. The resulting tablet had a hardness of about 4 kp.
(Comparative Example 2)
Using the formulation shown in Table 1 as Comparative Example 2, immediate release granules were prepared by the same procedure as Example 1. However, the binder hydroxypropyl cellulose was added as a 7% aqueous solution by spraying instead of the water sprayed in Example 1. The obtained immediate release granules had an average particle size of 213 μm.
326 g of the immediate release granules, 125.5 g of the sustained release granules, and 2.25 g of magnesium stearate were placed in a plastic bag and mixed to obtain a granule mixture for tableting. This mixture was tableted using a tableting machine collect 12HU manufactured by Kikusui Seisakusho (compression pressure: 2.96 MPa) to obtain a tablet having a diameter of 8 mm and a tablet weight of about 185.5 mg. The resulting tablet had a hardness of about 4 kp.
(Comparative Example 3)
The powders of each component of the formulation shown in Table 1 as Comparative Example 3 were weighed, mixed, put into a vertical granulator manufactured by POWREC, and granulated by adding an appropriate amount of water. That is, it was granulated from powder containing a binder by a mixed granulation method. The obtained wet granules were dried using a fluidized bed dryer manufactured by Freund Corporation, and passed through a No. 24 sieve to obtain immediate-release granules. The obtained immediate release granules had an average particle size of 212 μm.
424 g of the immediate release granules, 140 g of the sustained release granules, and 2.8 g of magnesium stearate were placed in a plastic bag and mixed to obtain a granule mixture for tableting. This mixture was tableted using a tableting machine collect 12HU (manufactured by Kikusui Seisakusho) (compression pressure 2.96 MPa) to obtain a tablet having a diameter of 8 mm and a tablet weight of about 202.5 mg. The resulting tablet had a hardness of about 4 kp.
Immediate release granules were prepared using the same formulation and procedure as Example 1. The obtained immediate release granules had an average particle size of 211 μm.
430.6 g of the immediate release granules, 160.6 g of the sustained release granules, 2.69 g of magnesium stearate, and 96 g of crospovidone were mixed in a plastic bag to obtain a granule mixture for tableting. This mixture was tableted using a tableting machine collect 12HU manufactured by Kikusui Seisakusho (compression pressure: 2.96 MPa) to obtain a tablet having a diameter of 8 mm and a tablet weight of about 215.5 mg. The resulting tablet had a hardness of about 4 kp.
(Example 3)
Immediate release granules were prepared using the same formulation and procedure as Example 1. The obtained immediate release granules had an average particle size of 218 μm.
430 g of the immediate release granules, 160 g of the sustained release granules, 2.7 g of magnesium stearate, and 64 g of crospovidone were mixed in a plastic bag to obtain a granule mixture for tableting. This mixture was tableted using a tableting machine collect 12HU manufactured by Kikusui Seisakusho (compression pressure: 2.96 MPa) to obtain a tablet having a diameter of 8 mm and a tablet weight of about 205.5 mg. The resulting tablet had a hardness of about 4 kp.
(Test Example 1)
The tablets obtained in Examples and Comparative Examples were subjected to a disintegration test by the method described in the 13th revised Japanese Pharmacopoeia.
That is, in the apparatus and method described in the 13th revised Japanese Pharmacopoeia, using 36.5 ° C. water as a test solution, the time until each tablet disintegrates (all disintegrated tablet pieces are 2 mm on the bottom of the test apparatus). Time to pass through the net). The results are shown in Table 2.
Industrial applicability
ADVANTAGE OF THE INVENTION According to this invention, the multiple unit type sustained release tablet with a short disintegration time can be prepared, and the tablet which can anticipate quicker immediate effect and sustained-release property is obtained.
Claims (11)
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| JP2001126891 | 2001-04-25 | ||
| JP2001126891 | 2001-04-25 | ||
| PCT/JP2002/004023 WO2002087549A1 (en) | 2001-04-25 | 2002-04-23 | Multiple unit type sustained-release tablets |
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| KR100891887B1 (en) | 2001-01-29 | 2009-04-03 | 시오노기세이야쿠가부시키가이샤 | Medicinal preparation containing 5-methyl-1-phenyl-2-(1h)-pyridone as active ingredient |
| CA2581282A1 (en) * | 2004-10-01 | 2006-04-13 | Nippon Zoki Pharmaceutical Co., Ltd. | Solid pharmaceutical preparation |
| NZ591443A (en) * | 2005-09-22 | 2013-04-26 | Intermune Inc | Granule formation of pirfenidone and pharmaceutically acceptable excipients |
| KR100762847B1 (en) * | 2006-01-27 | 2007-10-04 | 씨제이 주식회사 | Multiple unit type sustained release oral formulation and process for the preparation thereof |
| AU2007232836B2 (en) * | 2006-03-30 | 2012-12-06 | Nippon Zoki Pharmaceutical Co., Ltd. | Solid pharmaceutical preparation |
| JP2009161495A (en) * | 2008-01-09 | 2009-07-23 | Everest Pharm Industrial Co Ltd | Kind of quickly disintegrable oral tablet containing slow-dissolving microparticle ascorbic acid |
| JP5827952B2 (en) * | 2009-10-09 | 2015-12-02 | ユンジン・ファーム・カンパニー・リミテッドＹｕｎｇｊｉｎ Ｐｈａｒｍ． Ｃｏ． Ｌｔｄ． | Pharmaceutical composition having both rapid action and durability |
| US9358204B2 (en) * | 2012-02-08 | 2016-06-07 | Supernus Pharmaceuticals, Inc. | Formulations of viloxazine |
| CA2937365C (en) | 2016-03-29 | 2018-09-18 | F. Hoffmann-La Roche Ag | Granulate formulation of 5-methyl-1-phenyl-2-(1h)-pyridone and method of making the same |
| JP7330948B2 (en) * | 2017-08-29 | 2023-08-22 | コンリグ ファーマ エーピーエス | Compositions containing suplatast tosylate |
| CN113634195A (en) * | 2021-09-16 | 2021-11-12 | 上海泰坦科技股份有限公司 | Novel instant particle buffer solution and preparation method thereof |
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| JP3929522B2 (en) * | 1996-03-14 | 2007-06-13 | 塩野義製薬株式会社 | Sustained release formulation of poorly water-soluble drugs |
| JP3870470B2 (en) * | 1997-02-07 | 2007-01-17 | 大正製薬株式会社 | Multiple unit type sustained release tablets |
| JP4189044B2 (en) * | 1997-07-01 | 2008-12-03 | 大正製薬株式会社 | Multiple unit type sustained release tablets |
| JP3677156B2 (en) * | 1997-09-05 | 2005-07-27 | 武田薬品工業株式会社 | Medicine |
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