JP3751287B2 - Miniaturized nifedipine nucleated tablets - Google Patents

Description

【００１９】
上記アミノアルキルメタクリレート共重合体としては、上記式（Ｉ）、（ＩＩ）及び（ＩＩＩ）の繰返し単位の重量比（Ｉ）／（ＩＩ）／（ＩＩＩ）が１／２／０.１〜０.２であるものが好ましく、また、粘度が約１〜約４センチストークスの範囲内にあるものが好ましい。そのようなアミノアルキルメタクリレート共重合体は市販されており、オイドラギット（Eudragit）ＲＳ又はＲＬなる商品名［ドイツ、レーム・ファーマ社（Roehm Pharma GmbH）製］で入手することができる。
【００２０】
芯部に配合される崩壊抑制作用物質は、芯部の重量を基準にして、２〜３０重量％、好ましくは５〜２５重量％、さらに好ましくは８〜２０重量％の範囲内とすることができる。
【００２１】
また、ニフェジピン結晶の濡れを改善したり、芯部内への水や胃腸管液の浸透を促して、芯部からのニフェジピンの溶出を促進するために、芯部には界面活性剤を配合するのが好ましい。配合しうる界面活性剤としては、例えば、ポリソルベート８０、ポリソルベート６０、ポリソルベート２０、ラウリル硫酸ナトリウム、各種のショ糖脂肪酸エステルなどが挙げられ、これらはそれぞれ単独で又は２種以上を適宜選択、組み合わせて使用してもよい。これらの界面活性剤の配合量は、芯部の重量を基準として、通常、０.０３〜３重量％、好ましくは０.０５〜２重量％、より好ましくは０.１〜０.５重量％の範囲内とすることができる。
【００２２】
また、芯部には必要に応じて流動化剤を配合することができ、配合しうる流動化剤としては、例えば、軽質無水ケイ酸、重質無水ケイ酸、含水二酸化ケイ素、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウムなどが挙げられる。これらの流動化剤の配合量は、芯部の重量を基準にして、通常、０.０２〜２重量％、好ましくは０.０５〜１重量％、より好ましくは０.１〜０.５重量％の範囲内とすることができる。
【００２３】
芯部にはまた必要に応じて滑沢剤を配合することができ、配合しうる滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸、フマル酸ステアリルナトリウム、ショ糖脂肪酸エステルなどが挙げられる。これらの滑沢剤の配合量は、芯部の重量を基準にして、通常、０.０２〜２重量％、好ましくは０.０５〜１重量％、より好ましくは０.１〜０.５重量％の範囲内とすることができる。
【００２４】
さらに、芯部には、場合により、トウモロコシデンプン、バレイショデンプン、アルファデンプン、デキストリン、カルボキシメチルデンプン等のデンプン類、乳糖、白糖、ぶどう糖、マンニトール、ソルビトール等の糖類、軽質無水ケイ酸、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム、リン酸カルシウム、炭酸カルシウム等の無機塩類、パラフィン、ワックス、高級脂肪酸等の油脂類、セルロース類等の賦形剤；デンプン類、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロース、結晶セルロース、架橋ポリビニルピロリドン等の崩壊剤；各種の食用色素等や三二酸化鉄等の着色剤（顔料）；などの医薬品添加物を配合することができる。
【００２５】
しかしながら、芯部の小型のためには、これら医薬品添加物の配合量は必要最小限にとどめることが望ましいことは言うまでもない。
【００２６】
芯部の最終的組成は、該芯部と同一組成の錠剤からのニフェジピンの溶出率が、日本薬局方の溶出試験第２法によるシンカーを使用しない溶出試験（以下、「局方第２法溶出試験（シンカー不使用）」という）において、一般に、４５分後２０〜７０％、好ましくは２５〜６５％、より好ましくは３０〜６０％、２時間後６５％以上、好ましくは７０％以上、より好ましくは７５％以上となるように調節することが望ましい。
【００２７】
ここで、局方第２法溶出試験（シンカー不使用）は、下記の条件下で実施されたものである。
【００２８】
・試験液：ラウリル硫酸ナトリウムを１％含有するｐＨ６.８のリン酸緩衝液９００ｍｌ
・温 度：３７℃
・回転数：毎分７５回転。
なお、上記溶出試験に用いる芯部と同一組成の錠剤としては、有核錠剤の芯部の打錠条件と同じ条件下で打錠することによって調製されたものを使用する。
【００２９】
一方、上記芯部の表面に圧縮被覆により形成される外殻部は、芯部と同様に、ニフェジピン及び親水性ゲル形成性高分子物質、さらにニフェジピン及び該親水性ゲル形成性高分子物質とともにｐＨ非依存性のマトリックスを形成する水不溶性高分子よりなる崩壊抑制作用物質を必須成分として含有し、さらに必要に応じて、界面活性剤、流動化剤、滑沢剤及びその他の医薬品添加物を含有するものである。
【００３０】
外殻部におけるこれらニフェジピン、親水性ゲル形成性高分子物質、崩壊抑制作用物質、界面活性剤、流動化剤、滑沢剤及びその他の医薬品添加物としては、いずれも、芯部に用いるものとして前記したものの中から同一又は異なるものを適宜選択して使用することができる。
【００３１】
外殻部におけるニフェジピンの含有率は、外殻部の重量を基準にして、５〜５０重量％、好ましくは５〜４０重量％、さらに好ましくは５〜３０重量％の範囲内とすることができ、親水性ゲル形成性高分子物質の配合量は、外殻部の重量を基準にして、３０〜９０重量％、好ましくは４５〜８５重量％、さらに好ましくは５５〜７５重量％の範囲内とすることができ、そして崩壊抑制作用物質の配合量は、外殻部の重量を基準にして、５〜５０重量％、好ましくは７.５〜４０重量％、さらに好ましくは１０〜３０重量％の範囲内とすることができる。
【００３２】
また、ニフェジピン結晶の濡れを改善したり、錠剤内部への水や胃腸管液の浸透を促してニフェジピンの溶出を促進するために、外殻部には界面活性剤を配合することが好ましい。その配合量は、外殻部の重量を基準にして、通常、０.０２〜２重量％、好ましくは０.０５〜１重量％、より好ましくは０.１〜０.５重量％の範囲内とすることができる。
【００３３】
外殻部に流動化剤を配合する場合、その配合量は、外殻部の重量を基準にして、通常、０.０２〜２重量％、好ましくは０.０５〜１重量％、より好ましくは０.１〜０.５重量％の範囲内とすることができる。
【００３４】
外殻部に滑沢剤を配合する場合、その配合量は、外殻部の重量を基準にして、通常、０.０２〜２重量％、好ましくは０.０５〜１重量％、より好ましくは０.１〜０.５重量％の範囲内とすることができる。
【００３５】
さらに、外殻部には、上記成分のほか、必要に応じて、芯部と同様の種々の医薬品添加物を配合することができる。
【００３６】
外殻部の最終的な組成は、該外殻部と同一組成の錠剤からのニフェジピンの溶出率が、
（ａ）日本薬局方の溶出試験第２法によるシンカーを使用する溶出試験（以下、「局方第２法溶出試験（シンカー使用）」という）において、
２時間後 ２０〜５０％、好ましくは２５〜４５％、より好ましくは３０〜４０％、
４時間後 ４０〜９０％、好ましくは４５〜８５％、より好ましくは５０〜８０％、
６時間後 ７５％以上、好ましくは８０％以上、より好ましくは８５％以上であり、そして
（ｂ）日本薬局方の崩壊試験法による溶出試験（以下、「局方崩壊試験装置法」という）において、
３時間後 ３０〜６０％、好ましくは３５〜５５％、より好ましくは４０〜５０％、
４時間後 ４０〜９０％、好ましくは４５〜８５％、より好ましくは５０〜８０％
となるように調節することが望ましい。
【００３７】
本明細書において、局方第２法溶出試験（シンカー使用）は下記の条件下で実施されたものである。
【００３８】
・試験液：ラウリル硫酸ナトリウムを１％含有するｐＨ６.８のリン酸緩衝液９００ｍｌ
・温 度：３７℃
・回転数：毎分１００回転
・シンカーの固定位置：試験液の液面と撹拌翼の上端との中間で且つ容器壁から１０ｍｍ離れた位置に、線径１.０ｍｍ以下の耐酸性針金で固定。
【００３９】
また、局方崩壊試験装置法は、下記の条件下で実施されたものである。
【００４０】
・試験液：ラウリル硫酸ナトリウムを１％含有するｐＨ６.８のリン酸緩衝液９００ｍｌ
・温 度：３７℃
・補助盤使用。
【００４１】
なお、上記溶出試験に用いる外殻部と同一組成の錠剤は、有核錠剤の打錠条件と同じ条件下で、ただし、芯部を用いることなく、打錠することによって調製されたものを使用する。
【００４２】
以上に述べた芯部と外殻部とからなる有核錠剤は、例えば、それ自体既知の方法で芯部となる内核錠をつくり、次いで、有核打錠機（プレスコーター）を用いて該内核錠を前述した組成の外殻部で被覆することにより製造することができる。その際の打錠条件は厳密に制限されるものではなく、最終錠剤に望まれる溶出特性等に応じて変えることができるが、通常、芯部内核錠の打錠圧は１００〜１０００ｋｇｆ程度が適当であり、また有核錠の打錠圧は５００〜２０００ｋｇｆ程度が適当である。
【００４３】
かくして、本発明によれば、特許文献１に記載の有核錠剤よりも芯部を小型化することができ、芯部の直径は２.５〜４.８ｍｍ、好ましくは３〜４.７ｍｍ、より好ましくは３.５〜４.５ｍｍの範囲内に、また、芯部の厚さは１.０〜２.５ｍｍ、好ましくは１.３〜２.２ｍｍ、より好ましくは１.５〜２.０ｍｍの範囲内にすることができる。そしてこれに外殻部を圧縮被覆（打錠）して製した有核錠剤（裸錠）は、一般に、直径を４.５〜８.５ｍｍ、好ましくは５.０〜８ｍｍ以下、より好ましくは５.５〜７.５ｍｍの範囲内にすることができ、また、厚さは３.５〜５.５ｍｍ、好ましくは３.８〜５.２ｍｍ、より好ましくは４.０〜５.０ｍｍの範囲内にすることができる。
【００４４】
上記芯部には外殻部で被覆するに先立ち、薄いフィルムコーティングを施してもよい。該フィルムコーティング基剤としては、例えば、ＨＰＣ、ＨＰＭＣ、ヒドロキシエチルセルロース、メチルヒドロキシエチルセルロース等のセルロース系水溶性コーティング基剤；ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース等のセルロース系腸溶性コーティング基剤；メタアクリル酸コポリマー、セラック等その他の腸溶性フィルムコーティング基剤などが挙げられる。
【００４５】
上記のようにして製造される有核錠剤は、有核錠剤に成形した後にさらに外側に少なくとも１層の遮光性のフィルムコーティングを設けてもよい。そのような遮光性のフィルムコーティングとしては、例えば、三二酸化鉄及び／又は酸化チタン等の遮光剤を適量配合したセルロース系水溶性コーティングが挙げられる。該セルロース系水溶性コーティングとしては、中でも、造膜性の点でＨＰＭＣを用いるのが好適であり、２０℃における２％水溶液の粘度が１００ｃｐ以下、特に１５ｃｐ以下のＨＰＭＣが特に好適である。これらのフィルムコーティング基剤には、必要に応じてポリエチレングリコール等の可塑剤を添加することができる。
【００４６】
このようにして調製される本発明のニフェジピン有核錠剤は、小型化されているにもかかわらず、特許文献１に開示されている１日１回投与型のニフェジピン有核錠剤と同等のニフェジピンの溶出特性を発揮する。すなわち、本発明の小型化されたニフェジピン有核錠剤からのニフェジピンの溶出率は、
（ａ） 局方第２法（シンカー使用）溶出試験において、
２時間後 １０〜４０％、好ましくは１５〜３５％、より好ましくは２０〜２９％、
４時間後 ３０〜６５％、好ましくは３５〜６０％、より好ましくは３９〜５６％、
６時間後 ５５％以上、好ましくは６０％以上、より好ましくは６５％以上であり、そして
（ｂ） 局方崩壊試験装置法において、
３時間後 ２０〜４５％、好ましくは２５〜４０％、より好ましくは２８〜３５％、
４時間後 ３０〜６５％、好ましくは３５〜６０％、より好ましくは４０〜５５％
である。
【００４７】
本発明のニフェジピン含有有核錠剤は、ニフェジピンの有効血中濃度を長時間（少なくとも２４時間）にわたって持続させることができるだけでなく、小型化されているので、従来の市販品に比べて患者の嚥下・服用が極めて容易である。
【００４８】
また、本発明により提供されるニフェジピン含有有核錠剤は、前記のとおり小型化することができるので、該ニフェジピン含有有核錠剤上に第２医薬成分を含有する速放部を設けて、ニフェジピンと第２医薬成分との合剤とすることができる。かくして、本発明によれば、以上に述べたニフェジピン含有有核錠剤に、その少なくとも一部表面が露出するようにして、第２医薬成分を含有する速放部が部分的に圧縮被覆されてなることを特徴とする錠剤（以下、合剤という）が提供される。
【００４９】
本発明の合剤は、本発明の小型化されたニフェジピン含有有核錠剤と第２医薬成分を含有する速放部とからなる錠剤であって、該ニフェジピン含有有核錠剤の上面、底面及び側面の３面のうちの少なくとも一面を外部に露出させて該速放部が配置された構成からなる。
【００５０】
このような錠剤としては、具体的には、上記小型化されたニフェジピン含有有核錠剤をベースとして、その上、下面いずれか片面もしくは両面に速放部を圧縮被覆した単純な平行二層もしくは三層錠、又は上記小型化されたニフェジピン含有有核錠剤を芯とし、その底面及び側面が第２医薬成分含有の速放部で包囲され且つ該有核錠剤の上面が該速放部の上面に実質的に同心状に露出するよう圧縮した錠剤（別名“ｂｕｌｌ’ｓ ｅｙｅ ｔａｂｌｅｔ”）を挙げることができる。なお、上記小型化されたニフェジピン含有有核錠剤を芯として、この全面を第２医薬成分含有の速放部で圧縮被覆して有核３重錠とすることもできるが、そうするとサイズが大きくなりすぎて患者の利便を害する可能性がある。
【００５１】
本発明の合剤に使用しうる第２医薬成分としては、ニフェジピンとの間で有害な相互作用のない薬物であって、速溶性が求められ、かつ１日１回経口投与型のものであれば特に制限されないが、ニフェジピンと併用されたときに互いに相乗的に作用する薬剤が望ましい。
そのような第２医薬成分としては、例えば、カンデサルタン・シレキセチル、ロサルタン・カリウム、バルサルタン、オルメサルタン・メドキソミル、テルミサルタン及びイルベサルタンよりなる群から選ばれるアンジオテンシンII受容体拮抗薬；マレイン酸エナラプリル、リシノプリル、シラザプリル及び塩酸デラプリルよりなる群から選ばれるアンジオテンシン変換酵素阻害薬が挙げられる。なかでも、カンデサルタン・シレキセチル及びマレイン酸エナラプリルは、その用量が少なく速放部の体積を小さくすることができるので、本発明の小型化されたニフェジピン有核錠剤との組合わせに特に好適である。
また、緩除な降圧効果を有するために降圧薬として古くから使用されている利尿薬も第2医薬成分として用いることができる。この目的のために使用される利尿薬としては、例えば、エチアジド、シクロペンチアジド、トリクロルメチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、ベンチルヒドロクロロチアジド、ポリチアジド、メチクロチアジド、ペンフルチジド、クロロチアジド、シクロチアジド、フルメチアジド、ベンズチアジド、ベンドロフルメチアジドなどのサイアザイド系利尿薬；アセタゾラミド、アゾセミド、エタクリン酸、エタクリン酸ナトリウム、キネサゾン、クロフェナミド、クロルタリドン、スピロノラクトン、トリアムテレン、ピレタニド、ブメタニド、フロセミド、メトラゾン、メフルシド、アミロライド、インダパミド、チクリナフェン、トリパミド、トルセミド、メチクラン、アミノフィリンなどの非サイアザイド系利尿薬が挙げられる。
【００５２】
本発明の合剤に使用される第２医薬成分の配合量は、該第２医薬成分の用法用量、成形性、嵩密度などに依存するが、通常、１５０ｍｇ以下、好ましくは１２０ｍｇ以下、より好ましくは１００ｍｇ以下、さらにより好ましくは８０ｍｇ以下である。
【００５３】
第２医薬成分を含有する速放部には、崩壊剤、結合剤、界面活性剤、滑沢剤などの必要な医薬品添加物が配合される。これら医薬品添加物としては、上記小型化されたニフェジピン含有有核錠剤について前記したものと同様のものを使用することができる。速放部の特徴は、服用後、胃内で短い時間内に崩壊して第２医薬成分を放出することである。このため、崩壊剤、結合剤、界面活性剤、滑沢剤などの必要な医薬品添加物を適宜選択し又はこれらを組み合わせて速放部の組成を決定する。速放部での第２医薬成分の含有率は、第２医薬成分の用量、物理化学的性質、特に溶解性やぬれ性などを勘案して決定することができる。
【００５４】
速放部からの第２医薬成分の溶出率は、日本薬局方の溶出試験第２法による溶出試験（５０ｒｐｍ）において、１時間後８０％以上になるよう製剤設計することが望ましい。ここで、局方第２法による溶出試験（５０ｒｐｍ）とは、下記の条件下で実施されたものである。
【００５５】
・試験液：ポルソルベート８０を０.３％含有する精製水９００ｍｌ
・温 度：３７℃
・回転数：毎分５０回転。
【００５６】
本発明の小型化されたニフェジピン含有有核錠剤と第２医薬成分含有の速放部との接合には、上記小型化されたニフェジピン含有有核錠剤の製造に用いた有核打錠機（プレスコーター）と同一又は類似の打錠機を使用することができる。市販の機械をそのまま用いてもよいし、改造して用いてもよい。打錠は、具体的には、例えば、以下に述べる３つの方法のいずれかによって行なうことができ、使用する有核打錠機（プレスコーター）の性能に合わせて適宜選択すればよい。
（１） 本発明のニフェジピン含有有核錠剤の直径と同じか、あるいはわずかに大きめ（＋０.０５〜０.２ｍｍ程度）の直径を有する臼と杵をセットした有核打錠機（プレスコーター）を準備し、速放部用打錠末を臼の中に充填し、その上にニフェジピン含有有核錠剤を載せ、第２充填のないまま臼の中で圧縮成形する方法。
【００５７】
この方法では、ニフェジピン含有有核錠剤の底面のみに第２医薬成分を含有した速放部が層状に接合され、ニフェジピン含有有核錠剤の上面と側面が外部に露出した状態の錠剤が得られる。この方法は、第２医薬成分の用量が十分に少量の場合（例えば１０ｍｇ以下）で、速放部を小型に設計できる場合に、特に有用である。
（２） 本発明のニフェジピン含有有核錠剤の直径と同じか、あるいはわずかに大きめ（＋０.０５〜０.２ｍｍ程度）の直径を有する臼と杵をセットした有核打錠機（プレスコーター）を準備し、速放部用打錠末を臼の中に充填し、その上にニフェジピン含有有核錠剤を載せ、さらに速放部用打錠末を充填して、臼の中で圧縮成形する方法。
【００５８】
この方法では、ニフェジピン含有有核錠剤の上面と底面に第２医薬成分含有速放部が層状に接合され、ニフェジピン含有有核錠剤の側面のみが外部に露出した状態の錠剤が得られる。この方法は、第２医薬成分の用量が十分に少量の場合（例えば１０ｍｇ以下）で、速放部を小型に設計できる場合に、特に有用である。
（３） 本発明のニフェジピン含有有核錠剤よりも大きいサイズ（通常、直径が＋２.４ｍｍ以上のもの；円形でも楕円でも可）の臼と杵をセットした有核打錠機（プレスコーター）を準備し、速放部用打錠末を臼の中に充填し、その上にニフェジピン含有有核錠剤を載せ、第２充填のないまま臼の中で圧縮成形する方法。
【００５９】
この方法では、ニフェジピン含有有核錠剤の底面と側面に第２医薬成分含有速放部が凹状に接合され、実質的にニフェジピン含有有核錠剤の上面のみが速放部の上面に同心状に露出した状態の錠剤が得られる。この方法は、第２医薬成分の用量による制約を受けにく、柔軟に合剤を製剤設計できるという利点を有するので、より多くの種類の第２医薬成分を対象にすることができ、最も広範囲に利用可能な方法である。
【００６０】
上記（１）〜（３）いずれの場合も、ニフェジピン含有有核錠剤と第２医薬成分含有速放部との良好な接合を得るために、ニフェジピン含有有核錠剤にあらかじめフィルムコーティングすることを避けるのが望ましい。
【００６１】
圧縮被覆（プレスコーティング）のための打錠圧は、ニフェジピン含有有核錠剤を実質的に破壊しない限度の圧力範囲で、速放部が適切な硬度や崩壊性を示すように調節すればよい。通常、プレスコーティングに要する打錠圧は５００〜２０００ｋｇｆ程度とすることができる。
【００６２】
また、最終合剤のサイズは、大きいと、特に高齢の患者にとっては嚥下が困難になる場合があるので、患者が無理なく嚥下できるようなサイズに設計することが望まれる。円形錠の場合、最終錠剤の直径は、通常、１２ｍｍ以下、好ましくは１０ｍｍ以下、より好ましくは９.５ｍｍ以下とし、錠剤の厚さは、通常、６ｍｍ以下、好ましくは５.８ｍｍ以下、より好ましくは５.６ｍｍ以下の範囲内にする。速放部を大きくせざるを得ない場合には、オブロング型、オーバル（楕円）型にし且つ短径を９ｍｍ程度に設計することが望ましい。
【００６３】
本発明の小型化されたニフェジピン含有有核錠剤と第２医薬成分含有速放部からなる合剤は、必要に応じて、通常のフィルムコーティングを施すことができる。フィルムコーティングの組成は、前述の小型化されたニフェジピン含有有核錠剤に用いるものと同様のものが挙げられる。
【００６４】
上記のように製造される、ニフェジピン含有有核錠剤と第２医薬成分を含有する速放部とからなる合剤は、ヒトに経口投与されると、まず速放部が速やかに崩壊し、第２医薬成分が溶出される。続いて、ニフェジピン含有有核錠剤からは（特許文献１記載のとおり）ニフェジピンが安定に溶出し、２４時間にわたって有効血中濃度を維持する。
【００６５】
【実施例】
以下、本発明の好ましい態様を実施例及び比較例によって更に詳細に説明する。しかしながら、本発明はこれらの実施例のみに限定されるものではない。なお、実施例及び比較例に使用したＨＰＣッＬ及びＨＰＣッＭは、それぞれ日本曹達（株）製のヒドロキシプロピルセルロース、粘度６.０〜１０.０ｃｐ（２％水溶液、２０℃）及び日本曹達（株）製のヒドロキシプロピルセルロース、粘度１５０〜４００ｃｐ（２％水溶液、２０℃）である。また、ＨＰＭＣとしては、信越化学工業（株）製の各種粘度グレードのヒドロキシプロピルメチルセルロースを用いた。「オイドラギット ＲＬ ＰＯ」はアクリル酸エチル・メタアクリル酸メチル・メタアクリル酸塩化トリメチルアンモニウムエチル共重合体に対するドイツ、レーム・ファーマ社の商品名である。
【００６６】
実施例１
１錠中にニフェジピンを１５重量％含有する芯部の組成：
ニフェジピン（微粉砕結晶） １５０.０ｇ （１５.００％）
ＨＰＭＣ ２９１０、３ｃＰ ２６４.４ｇ （２６.４４％）
ＨＰＣ−Ｌ ３４０.０ｇ （３４.００％）
オイドラギットＲＬＰＯ ２４０.０ｇ （２４.００％）
ポリソルベート８０ １.２ｇ （ ０.１２％）
三二酸化鉄（赤色） ０.４ｇ （ ０.０４％）
軽質無水ケイ酸 ２.０ｇ （ ０.２０％）
ステアリン酸マグネシウム ２.０ｇ （ ０.２０％）
ステアリン酸マグネシウムを除く上記原料を均一に混合し造粒後、乾燥し、整粒した。これにステアリン酸マグネシウムを加えて混合した後、ロータリープレス（打錠機）を用いて打錠圧４００ｋｇｆで打錠し、１錠中ニフェジピンを３．７５ｍｇ含有する重量２５ｍｇの内核錠（直径４ｍｍ、厚さ１.８ｍｍ）を作製した。この内核錠を局方第２法溶出試験（シンカー不使用）で評価したところ、４５分後に約４５％、２時間後には１００％のニフェジピンが溶出していた。
【００６７】
ニフェジピンを５.２重量％含有する外殻部の組成：
ニフェジピン（微粉砕結晶） １２５ｇ （ ５.２０８％）
ＨＰＣ−Ｌ ８８４ｇ （３６.８３３％）
ＨＰＣ−Ｍ ９００ｇ （３７.５００％）
オイドラギットＲＬＰＯ ４８０ｇ （２０.０００％）
ポリソルベート８０ ３ｇ （ ０.１２５％）
軽質無水ケイ酸 ４ｇ （ ０.１６７％）
ステアリン酸マグネシウム ４ｇ （ ０.１６７％）
ステアリン酸マグネシウムを除く上記原料を均一に混合し造粒後、乾燥し、整粒した。これにステアリン酸マグネシウムを加えて混合し、外殻部用打錠末とした。直径７ｍｍの臼と７ｍｍφ１０ｍｍＲの上杵・下杵を取り付けた有核打錠機（菊水クリーンプレスコレクト１８ＤＣ）を用い、前記内核錠と外殻部用打錠末１２０ｍｇとを打錠圧１,０００ｋｇｆにて打錠し、１錠中ニフェジピンを１０ｍｇ含有する重量１４５ｍｇの有核錠（直径７ｍｍ、厚さ４.２ｍｍ）を作製した。
【００６８】
さらに、この有核錠剤の表面に、次の組成を有する遮光性のフィルムコーティングを施し、総重量１５１ｍｇ、体積約１５０ｍｍ³の錠剤を得た（市販品の体積の約４８％）。
【００６９】
１錠当りのフィルムコーティングの組成：
ＨＰＭＣ ２９１０（１５ｃＰ） ３.６ｍｇ （６０.０００％）
ポリエチレングリコール ４０００ １.２ｍｇ （２０.０００％）
三二酸化鉄（赤色） ０.１ｍｇ （ １.６６７％）
三二酸化鉄（黄色） ０.２ｍｇ （ ３.３３３％）
酸化チタン ０.９ｍｇ （１５.０００％）
【００７０】
実施例２
１錠中にニフェジピンを１５重量％含有する芯部の組成：
ニフェジピン（微粉砕結晶） ７５.０ｇ （１５.００％）
ＨＰＭＣ ２９１０、３ｃＰ １７９.０ｇ （３５.８０％）
ＨＰＭＣ ２９０６、４０００ｃＰ １１９.４ｇ （２３.８８％）
ＨＰＣ−Ｌ ２４.４ｇ （ ４.８８％）
オイドラギットＲＬＰＯ １００.０ｇ （２０.００％）
三二酸化鉄（赤色） ０.２ｇ （ ０.０４％）
軽質無水ケイ酸 １.０ｇ （ ０.２０％）
ステアリン酸マグネシウム １.０ｇ （ ０.２０％）
実施例１と同様の方法により、上記原料をもとに１錠中ニフェジピンを３.７５ｍｇ含有する内核錠（重量２５ｍｇ、直径４ｍｍ、厚さ１.８ｍｍ）を作製した。この内核錠を局方第２法溶出試験（シンカー不使用）で評価したところ、４５分後に約４５％、２時間後には１００％のニフェジピンが溶出していた。
【００７１】
この内核錠に、実施例１と同じ組成の外殻部用打錠末１２０ｍｇを同様に圧縮被覆して１錠中ニフェジピンを１０ｍｇ含有する重量１４５ｍｇの有核錠（直径７ｍｍ、厚さ４.２ｍｍ）を作製し、さらに同じく遮光性のフィルムコーティングを施して、総重量１５１ｍｇ、体積約１５０ｍｍ³の錠剤を得た（市販品の体積の約４８％）。
【００７２】
比較例１
１錠中にニフェジピンを１５重量％含有する芯部の組成：
ニフェジピン（微粉砕結晶） ７５.０ｇ （１５.００％）
ＨＰＭＣ ２９１０、３ｃＰ ２３９.０ｇ （４７.８０％）
ＨＰＭＣ ２９０６、４０００ｃＰ １５９.４ｇ （３１.８８％）
ＨＰＣ−Ｌ ２４.４ｇ （ ４.８８％）
三二酸化鉄（赤色） ０.２ｇ （ ０.０４％）
軽質無水ケイ酸 １.０ｇ （ ０.２０％）
ステアリン酸マグネシウム １.０ｇ （ ０.２０％）
実施例１と同様の方法により、上記原料をもとに１錠中ニフェジピンを３.７５ｍｇ含有する内核錠（重量２５ｍｇ、直径４ｍｍ、厚さ１.８ｍｍ）を作製した。この内核錠を局方第２法溶出試験（シンカー不使用）で評価したところ、４５分後に約４５％、２時間後には１００％のニフェジピンが溶出していた。
【００７３】
この内核錠に、実施例１と同じ組成の外殻部用打錠末１２０ｍｇを同様に圧縮被覆して１錠中ニフェジピンを１０ｍｇ含有する重量１４５ｍｇの有核錠（直径７ｍｍ、厚さ４.２ｍｍ）を作製し、さらに同じく遮光性のフィルムコーティングを施して、総重量１５１ｍｇ、体積約１５０ｍｍ³の錠剤を得た（市販品の体積の約４８％）。
【００７４】
実施例３
１錠中にニフェジピンを３０重量％含有する芯部の組成：
ニフェジピン（微粉砕結晶） ３００.０ｇ （３０.００％）
ＨＰＭＣ ２９１０、３ｃＰ ２４９.６ｇ （２４.９６％）
ＨＰＣ−Ｌ ２８４.０ｇ （２８.４０％）
オイドラギットＲＬＰＯ １６０.０ｇ （１６.００％）
ポリソルベート８０ ２.０ｇ （ ０.２０％）
三二酸化鉄（赤色） ０.４ｇ （ ０.０４％）
軽質無水ケイ酸 ２.０ｇ （ ０.２０％）
ステアリン酸マグネシウム ２.０ｇ （ ０.２０％）
実施例１と同様の方法により、上記原料をもとに１錠中ニフェジピンを７.５ｍｇ含有する内核錠（重量２５ｍｇ、直径４ｍｍ、厚さ１.８ｍｍ）を作製した。この内核錠を局方第２法溶出試験（シンカー不使用）で評価したところ、４５分後に約４５％、２時間後には１００％のニフェジピンが溶出していた。
【００７５】
ニフェジピンを１０.４重量％含有する外殻部の組成：
ニフェジピン（微粉砕結晶) ２５０ｇ （１０.４１６％）
ＨＰＣ−Ｌ ７９２ｇ （３３.０００％）
ＨＰＣ−Ｍ ８６０ｇ （３５.８３３％）
オイドラギットＲＬＰＯ ４８０ｇ （２０.０００％）
ポリソルベート８０ １０ｇ （ ０.４１７％）
軽質無水ケイ酸 ４ｇ （ ０.１６７％）
ステアリン酸マグネシウム ４ｇ （ ０.１６７％）
実施例１と同様の方法により、上記組成の外殻部用打錠末を調製した。前記内核錠とこの外殻部用打錠末１２０ｍｇとを実施例１と同様に打錠し、１錠中ニフェジピンを２０ｍｇ含有する重量１４５ｍｇの有核錠（直径７ｍｍ、厚さ４.２ｍｍ）を作製した。
【００７６】
さらに、この有核錠剤の表面に、次の組成を有する遮光性のフィルムコーティングを施し、総重量１５１ｍｇ、体積約１５０mm³の錠剤を得た（市販品の体積の約４８％）。
【００７７】
１錠当りのフィルムコーティングの組成：
ＨＰＭＣ ２９１０（１５ｃＰ） ３.６０ｍｇ （６０.０％）
ポリエチレングリコール ４０００ １.２０ｍｇ （２０.０％）
三二酸化鉄（赤色） ０.２４ｍｇ （ ４.０％）
酸化チタン ０.９６ｍｇ （１６.０％）
【００７８】
実施例４
１錠中にニフェジピンを３０重量％含有する芯部の組成：
ニフェジピン（微粉砕結晶） １５０.０ｇ （３０.００％）
ＨＰＭＣ ２９１０、３ｃＰ １４６.０ｇ （２９.２０％）
ＨＰＭＣ ２９０６、４０００ｃＰ ９７.４ｇ （１９.４８％）
ＨＰＣ−Ｌ ２４.４ｇ （ ４.８８％）
オイドラギットＲＬＰＯ ８０.０ｇ （１６.００％）
三二酸化鉄（赤色） ０.２ｇ （ ０.０４％）
軽質無水ケイ酸 １.０ｇ （ ０.２０％）
ステアリン酸マグネシウム １.０ｇ （ ０.２０％）
実施例３と同様の方法により、上記原料をもとに１錠中ニフェジピンを７.５ｍｇ含有する内核錠（重量２５ｍｇ、直径４ｍｍ、厚さ１.８ｍｍ）を作製した。この内核錠を局方第２法溶出試験（シンカー不使用）で評価したところ、４５分後に約４５％、２時間後には１００％のニフェジピンが溶出していた。
【００７９】
これに実施例３と同じ組成の外殻部用打錠末１２０ｍｇを圧縮被覆して１錠中ニフェジピンを２０ｍｇ含有する重量１４５ｍｇの有核錠（直径７ｍｍ、厚さ４.２ｍｍ）を作製し、さらに実施例３と同様の遮光性のフィルムコーティングを施し、総重量１５１ｍｇ、体積約１５０ｍｍ³の錠剤を得た（市販品の体積の約４８％）。
【００８０】
比較例２
１錠中にニフェジピンを３０重量％含有する芯部の組成：
ニフェジピン（微粉砕結晶） １５０.０ｇ （３０.００％）
ＨＰＭＣ ２９１０、３ｃＰ １９４.０ｇ （３８.８０％）
ＨＰＭＣ ２９０６、４０００ｃＰ １２９.４ｇ （２５.８８％）
ＨＰＣ−Ｌ ２４.４ｇ （ ４.８８％）
三二酸化鉄（赤色） ０.２ｇ （ ０.０４％）
軽質無水ケイ酸 １.０ｇ （ ０.２０％）
ステアリン酸マグネシウム １.０ｇ （ ０.２０％）
実施例３と同様の方法により、上記原料をもとに１錠中ニフェジピンを７.５ｍｇ含有する内核錠（重量２５ｍｇ、直径４ｍｍ、厚さ１.８ｍｍ）を作製した。この内核錠を局方第２法溶出試験（シンカー不使用）で評価したところ、４５分後に約４５％、２時間後には１００％のニフェジピンが溶出していた。
【００８１】
これに実施例３と同じ組成の外殻部用打錠末１２０ｍｇを圧縮被覆して１錠中ニフェジピンを２０ｍｇ含有する重量１４５ｍｇの有核錠（直径７ｍｍ、厚さ４.２ｍｍ）を作製し、さらに実施例３と同様の遮光性のフィルムコーティングを施し、総重量１５１ｍｇ、体積約１５０ｍｍ³の錠剤を得た（市販品の体積の約４８％）。
【００８２】
実施例５
１錠中にニフェジピン６０重量％含有する芯部の組成：
ニフェジピン（微粉砕結晶） ３００.０ｇ （６０.００％）
ＨＰＭＣ ２９１０、３ｃＰ ７１.８ｇ （１４.３６％）
ＨＰＣ−Ｌ ８４.０ｇ （１６.８０％）
オイドラギットＲＬＰＯ ４０.０ｇ （ ８.００％）
ポリソルベート８０ ２.０ｇ （ ０.４０％）
三二酸化鉄（赤色） ０.２ｇ （ ０.０４％）
軽質無水ケイ酸 １.０ｇ （ ０.２０％）
ステアリン酸マグネシウム １.０ｇ （ ０.２０％）
実施例１と同様の方法により、上記原料をもとに１錠中ニフェジピンを１５ｍｇ含有する内核錠（重量２５ｍｇ、直径４ｍｍ、厚さ１.８ｍｍ）を作製した。この内核錠を局方第２法溶出試験（シンカー不使用）で評価したところ、４５分後に約４５％、２時間後には１００％のニフェジピンが溶出していた。
【００８３】
ニフェジピンを２０.８重量％含有する外殻部の組成：
ニフェジピン（微粉砕結晶） ５００ｇ （２０.８３３％）
ＨＰＣ−Ｌ ７０２ｇ （２９.２５０％）
ＨＰＣ−Ｍ ７００ｇ （２９.１６７％）
オイドラギットＲＬＰＯ ４８０ｇ （２０.０００％）
ポリソルベート８０ １０ｇ （ ０.４１７％）
軽質無水ケイ酸 ４ｇ （ ０.１６７％）
ステアリン酸マグネシウム ４ｇ （ ０.１６７％）
実施例１と同様の方法により、上記組成の外殻部用打錠末を調製した。前記内核錠とこの外殻部用打錠末１２０ｍｇとを実施例１と同様に打錠し、１錠中ニフェジピンを４０ｍｇ含有する重量１４５ｍｇの有核錠（直径７ｍｍ、厚さ４.２ｍｍ）を作製した。
【００８４】
さらに、この有核錠剤の表面に、実施例３と同じ組成の遮光性のフィルムコーティングを施し、総重量１５１ｍｇ、体積約１５０ｍｍ³の錠剤を得た（市販品の体積の約４８％）。
【００８５】
実施例６
１錠中にニフェジピンを６０重量％含有する芯部の組成：
ニフェジピン（微粉砕結晶） ３００.０ｇ （６０.００％）
ＨＰＭＣ ２９１０、３ｃＰ ５９.４ｇ （１１.８８％）
ＨＰＭＣ ２９０６、４０００ｃｐ ７０.０ｇ （１４.００％）
ＨＰＣ−Ｌ ２４.４ｇ （ ４.８８％）
オイドラギットＲＬＰＯ ４４.０ｇ （ ８.８０％）
三二酸化鉄（赤色） ０.２ｇ （ ０.０４％）
軽質無水ケイ酸 １.０ｇ （ ０.２０％）
ステアリン酸マグネシウム １.０ｇ （ ０.２０％）
実施例１と同様の方法により、上記原料をもとに１錠中ニフェジピンを１５ｍｇ含有する内核錠（重量２５ｍｇ、直径４ｍｍ、厚さ１.８ｍｍ）を作製した。この内核錠を局方第２法溶出試験（シンカー不使用）で評価したところ、４５分後に約４５％、２時間後には１００％のニフェジピンが溶出していた。
【００８６】
この内核錠と実施例５と同じ外殻部用の打錠末１２０ｍｇとを、実施例１と同様に打錠し、１錠中ニフェジピンを４０ｍｇ含有する重量１４５ｍｇの有核錠（直径７ｍｍ、厚さ４.２ｍｍ）を作製した。さらに、この有核錠剤の表面に、実施例３と同じ組成の遮光性のフィルムコーティングを施し、総重量１５１ｍｇ、体積約１５０ｍｍ³の錠剤を得た（市販品の体積の約４８％）。
【００８７】
比較例３
１錠中にニフェジピンを６０重量％含有する芯部の組成：
ニフェジピン（微粉砕結晶） ３００.０ｇ （６０.００％）
ＨＰＭＣ ２９１０、３ｃＰ ７９.４ｇ （１５.８８％）
ＨＰＭＣ ２９０６、４０００ｃＰ ９４.０ｇ （１８.８０％）
ＨＰＣ−Ｌ ２４.４ｇ （ ４.８８％）
三二酸化鉄（赤色） ０.２ｇ （ ０.０４％）
軽質無水ケイ酸 １.０ｇ （ ０.２０％）
ステアリン酸マグネシウム １.０ｇ （ ０.２０％）
実施例１と同様の方法により、上記原料をもとに１錠中ニフェジピンを１５ｍｇ含有する内核錠（重量２５ｍｇ、直径４ｍｍ、厚さ１.８ｍｍ）を作製した。この内核錠を局方第２法溶出試験（シンカー不使用）で評価したところ、４５分後に約４５％、２時間後には１００％のニフェジピンが溶出していた。
【００８８】
この内核錠と実施例５と同じ組成の外殻部用の打錠末１２０ｍｇとを、実施例１と同様に打錠し、１錠中ニフェジピンを４０ｍｇ含有する重量１４５ｍｇの有核錠（直径７ｍｍ、厚さ４.２ｍｍ）を作製した。さらに、この有核錠剤の表面に、実施例３と同じ組成の遮光性のフィルムコーティングを施し、総重量１５１ｍｇ、体積約１５０ｍｍ³の錠剤を得た（市販品の体積の約４８％）。
【００８９】
実施例１〜６及び比較例１〜３で得られたニフェジピン含有有核錠剤（直径７ｍｍ）の体積はいずれも約１５０ｍｍ³であり、市販品（直径約９ｍｍ）の体積（約３１０ｍｍ³）の約４８％であった。
【００９０】
試験例
実施例１〜６及び比較例１〜３で得られたニフェジピン含有有核錠剤の溶出性を２種類の溶出試験法、すなわち局方第２法溶出試験（シンカー使用）と局方崩壊試験装置法で比較検討した。なお、比較標準品として市販のアダラートＣＲ錠１０ｍｇ、２０ｍｇ又は４０ｍｇ（バイエル薬品株式会社）を用いた。
局方第２法溶出試験（シンカー使用）は以下の条件下で実施されたものである。
【００９１】
・試験液：ラウリル硫酸ナトリウムを１％含有するｐＨ６.８のリン酸緩衝液９００ｍｌ
・温 度：３７℃
・回転数：毎分１００回転
・シンカーの固定位置：試験液の液面と撹拌翼の上端との中間で且つ容器壁から１０ｍｍ離れた位置に、線径１.０ｍｍ以下の耐酸性針金で固定。
また、局方崩壊試験装置法は、下記の条件下で実施されたものである。
【００９２】
・試験液：ラウリル硫酸ナトリウムを１％含有するｐＨ６.８のリン酸緩衝液９００ｍｌ
・温 度：３７℃
・補助盤使用。
局方第２法溶出試験（シンカー使用）の結果：
実施例１〜６及び比較例１〜３の各有核錠はいずれも対応する市販のニフェジピン有核錠剤（アダラートCR錠１０ｍｇ、２０ｍｇ、４０ｍｇ）とほぼ同一の溶出パターンを示した（図１、３、５参照）。
局方崩壊試験装置法による溶出試験の結果：
実施例１〜６の有核錠はいずれも対応する市販のニフェジピン有核錠剤とほぼ同一の溶出パターンを示したが、比較例１〜３の有核錠はいずれも対応する市販のニフェジピン有核錠剤に比べて溶出後半（３時間以降）部分の溶出がかなり速かった（図２、４、６参照）。
【００９３】
以上の試験結果から、崩壊抑制作用物質を芯部に含有することの有用性が示された。
【００９４】
実施例７
ロサルタン・カリウム５０ｍｇを含有する速放部の組成：
ロサルタン・カリウム １５０.０ｇ（２７.７７８％）
乳糖 １２７.８ｇ（２３.６６７％）
結晶セルロース １０８.０ｇ（２０.０００％）
低置換度ヒドロキシプロピルセルロース １３５.０ｇ（２５.０００％）
ラウリル硫酸ナトリウム １.２ｇ（ ０.２２２％）
ＨＰＭＣ ２９１０ ６ｍｍ²／ｓ １２.０ｇ（ ２.２２２％）
軽質無水ケイ酸 ３.０ｇ（ ０.５５６％）
ステアリン酸マグネシウム ３.０ｇ（ ０.５５６％）
ステアリン酸マグネシウムを除く上記原料を均一に混合し造粒後、乾燥し、整粒した。これにステアリン酸マグネシウムを加えて混合し、打錠末とした。この打錠末１８０ｍｇを、直径９.５ｍｍの臼と９.５ｍｍφ１０ｍｍＲの上杵・下杵を取り付けた有核打錠機（菊水クリーンプレスコレクト１８ＤＣ）の臼に充填し、その上に実施例３のニフェジピン含有有核錠剤（直径７ｍｍ；但し、フィルムコーティングなし）を載置して、打錠圧１,５００ｋｇｆで打錠した。得られた錠剤は、ニフェジピン含有有核錠剤の上面が外殻の表面に同心状に露出しており、重量３２５ｍｇ、直径９.５ｍｍ、厚さ５.４ｍｍであった。さらに、この錠剤の表面に、次の組成の遮光性のフィルムコーティングを施し、総重量３３５ｍｇの錠剤を得た。
【００９５】
１錠当りのフィルムコーティングの組成：
ＨＰＭＣ ２９１０（１５ｃＰ） ６.００ｍｇ （６０.０％）
ポリエチレングリコール ４０００ ２.００ｍｇ （２０.０％）
三二酸化鉄（赤色） ０.１５ｍｇ （ １.５％）
三二酸化鉄（黄色） ０.２５ｍｇ （ ２.５％）
酸化チタン １.６０ｍｇ （１６.０％）
この錠剤はニフェジピンを２０ｍｇ及びロサルタン・カリウムを５０ｍｇ含有し、その直径は９.６ｍｍ、厚さは５.５ｍｍ、そして体積は約３２０ｍｍ³であって、ニフェジピン単剤の市販品（アダラートCR錠）とほぼ同等であり、服用可能な大きさであった。
【００９６】
実施例８
バルサルタン８０ｍｇを含有する速放部の組成：
バルサルタン １６０ｇ （４０.０％）
結晶セルロース ６０ｇ （１５.０％）
Ｄ−マンニトール ６０ｇ （１５.０％）
低置換度ヒドロキシプロピルセルロース ６０ｇ （１５.０％）
クロスポビドン ４０ｇ （１０.０％）
ラウリル硫酸ナトリウム ２ｇ （ ０.５％）
軽質無水ケイ酸 ６ｇ （ １.５％）
フマル酸ステアリルナトリウム １２ｇ （ ３.０％）
フマル酸ステアリルナトリウムの一部を含む上記原料を均一に混合し、ローラーコンパクター（フロイント産業製）とロールグラニューレーター（日本ロールグラニューレーター製）を用いて乾式造粒・整粒した。これに残りのフマル酸ステアリルナトリウムを加えて混合し、打錠末とした。この打錠末２００ｍｇを、直径１０ｍｍの臼と１０ｍｍφ１０ｍｍＲの上杵・下杵を取り付けた有核打錠機（菊水クリーンプレスコレクト１８ＤＣ）の臼に充填し、その上に実施例３のニフェジピン含有有核錠剤（直径７ｍｍ；但し、フィルムコーティングなし）を載置して、打錠圧１,８００ｋｇｆで打錠した。
【００９７】
得られた錠剤は、ニフェジピン含有有核錠剤の上面が外殻の表面に同心状に露出しており、重量３４５ｍｇ、直径１０ｍｍ、厚さ５.６ｍｍであった。これにさらに実施例７と同様の遮光性フィルムコーティングを施し、総重量３５５ｍｇの錠剤を得た。この錠剤はニフェジピンを２０ｍｇ及びバルサルタンを８０ｍｇ含有し、直径は１０.１ｍｍ、厚さは５.７ｍｍ、そして体積は約３６０ｍｍ³であって、ニフェジピン単剤の市販品（アダラートＣＲ錠）に比べてもわずか１５％程度の増大であり、服用可能な大きさであった。
【００９８】
実施例９
カンデサルタン・シレキシル８ｍｇを含有する速放部の組成：
カンデサルタン・シレキシル １６.０ｇ （ ５.３３％）
乳糖 ９７.４ｇ （３２.４７％）
結晶セルロース １２０.０ｇ （４０.００％）
ラウリル硫酸ナトリウム ０.６ｇ （ ０.２０％）
低置換度ヒドロキシプロピルセルロース ４５.０ｇ （１５.００％）
Ａｃ−Ｄｉ−Ｓｏｌ １５.０ｇ （ ５.００％）
軽質無水ケイ酸 ３.０ｇ （ １.００％）
フマル酸ステアリルナトリウム ３.０ｇ （ １.００％）
フマル酸ステアリルナトリウムを除く上記原料を均一に混合し造粒後、乾燥し、整粒した。これにステアリン酸マグネシウムを加えて混合し、打錠末とした。この打錠末１５０ｍｇを、直径９ｍｍの臼と９ｍｍφ１０ｍｍＲの上杵・下杵を取り付けた有核打錠機（菊水クリーンプレスコレクト１８ＤＣ）の臼に充填し、その上に実施例３のニフェジピン含有有核錠剤（直径７ｍｍ；但し、フィルムコーティングなし）を載置して、打錠圧１,５００ｋｇｆで打錠した。
【００９９】
得られた錠剤は、ニフェジピン含有有核錠剤の上面が外殻の表面に同心状に露出しており、重量２９５ｍｇ、直径９ｍｍ、厚さ５.３ｍｍであった。これにさらに次の組成の遮光性のフィルムコーティングを施し、総重量３０４ｍｇの錠剤を得た。
【０１００】
１錠当りのフィルムコーティングの組成：
ＨＰＭＣ ２９１０（１５ｃＰ） ５.４０ｍｇ （６０.０％）
ポリエチレングリコール ４０００ １.８０ｍｇ （２０.０％）
三二酸化鉄（赤色） ０.１７ｍｇ （ １.９％）
三二酸化鉄（黄色） ０.１９ｍｇ （ ２.１％）
酸化チタン １.４ｍｇ （１６.０％）
この錠剤はニフェジピンを２０ｍｇ及びカンデサルタン・シレキシルを８ｍｇ含有し、直径は９.１ｍｍ、厚さは５.４ｍｍ、そして体積は約２９０ｍｍ³であって、ニフェジピン単剤の市販品（アダラートＣＲ錠）の約９割であり、十分に服用可能な大きさであった。
【０１０１】
実施例１０
カンデサルタン・シレキシルの含有率が１０重量％である速放部の組成：
カンデサルタン・シレキシル ４０ｇ （１０.００％）
乳糖 １１１ｇ （２７.７５％）
結晶セルロース １６０ｇ （４０.００％）
ラウリル硫酸ナトリウム １ｇ （ ０.２５％）
低置換度ヒドロキシプロピルセルロース ６０ｇ （１５.００％）
Ａｃ−Ｄｉ−Ｓｏｌ ２０ｇ （ ５.００％）
軽質無水ケイ酸 ４ｇ （ １.００％）
フマル酸ステアリルナトリウム ４ｇ （ １.００％）
フマル酸ステアリルナトリウムを除く上記原料を均一に混合し造粒後、乾燥し、整粒した。これにステアリン酸マグネシウムを加えて混合し、速放部用打錠末とした。この打錠末４０ｍｇを、直径７ｍｍの臼と７ｍｍφ１０ｍｍＲの上杵・下杵を取り付けた単発打錠機（Ｋｏｒｓｃｈ ＥＫ−０）の臼に充填し、その上に実施例３のニフェジピン含有有核錠剤（直径７ｍｍ；但し、フィルムコーティングなし）を載置して、打錠圧１,０００ｋｇｆで打錠した。
【０１０２】
得られた錠剤は、ニフェジピン含有有核錠剤部分と速放部が見かけ上平行に２層となっており、重量１８５ｍｇ、直径７ｍｍ、厚さ４.８ｍｍであった。これにさらに次のような組成を有する遮光性のフィルムコーティングを施し、総重量１９２ｍｇの錠剤を得た。
【０１０３】
１錠当りのフィルムコーティングの組成：
ＨＰＭＣ ２９１０（１５ｃＰ） ４.２０ｍｇ （６０％）
ポリエチレングリコール ４０００ １.４０ｍｇ （２０％）
三二酸化鉄（赤色） ０.１４ｍｇ （ ２％）
三二酸化鉄（黄色） ０.１４ｍｇ （ ２％）
酸化チタン １.１２ｍｇ （１６％）
この錠剤はニフェジピンを２０ｍｇ及びカンデサルタン・シレキシルを４ｍｇ含有し、直径は７.１ｍｍ、厚さは４.９ｍｍ、そして体積は約１７０ｍｍ³であって、ニフェジピン単剤の市販品（アダラートＣＲ錠）の約５５％であり、無理なく嚥下できる大きさであった。
【０１０４】
実施例１１
実施例１０で得た錠剤（但し、フィルムコーティングの前）において、さらに同じ打錠末４０ｍｇを上から充填し、打錠圧１,５００ｋｇｆで打錠した。得られた錠剤は、見かけ上ニフェジピン含有有核錠剤の上下両面を第２医薬成分含有速放部が挟んだ３層となっており、重量２２５ｍｇ、直径７ｍｍ、厚さ５.４ｍｍであった。これにさらに実施例１０と同じ組成の遮光性のフィルムコーティングを施し、総重量２３２ｍｇの錠剤を得た。
【０１０５】
この錠剤はニフェジピンを２０ｍｇ及びカンデサルタン・シレキシルを８ｍｇ含有し、直径は７.１ｍｍ、厚さは５.５ｍｍ、また体積は１９６.２ｍｍ³と、ニフェジピン単剤の市販品（アダラートCR錠）の約６３％であり、十分に服用可能な大きさであった。
【０１０６】
実施例１２
直径７.５ｍｍの臼と７.５ｍｍφ１１ｍｍＲの上杵・下杵を取り付けた有核打錠機（菊水クリーンプレスコレクト１８ＤＣ）を用い、実施例１と同様の方法で、１錠中にニフェジピンを１０ｍｇ含有する有核錠剤（重量：１４５ｍｇ、直径：７.５ｍｍ、厚さ：３.８ｍｍ）を調製し、さらに、このニフェジピン含有有核錠剤の底面に、実施例１０と同じ速溶部用打錠末４０ｍｇを同様に層状にプレスコーティング（圧縮成形）した。
【０１０７】
得られた２層錠剤は、重量１８５ｍｇ、直径７.５ｍｍ、厚さ４.３ｍｍであった。これにさらに実施例１０と同じ組成の遮光性のフィルムコーティングを施し、総重量１９２ｍｇの錠剤を得た。
【０１０８】
この錠剤はニフェジピンを１０ｍｇ及びカンデサルタン・シレキシルを４ｍｇ含有し、直径は７.６ｍｍ、厚さは４.４ｍｍ、そして体積は約１７０ｍｍ³であって、ニフェジピン単剤の市販品（アダラートＣＲ錠）の約５５％であり、高齢の患者にも無理なく嚥下できる大きさであった。
【０１０９】
実施例１３
メフルシド １２.５ｍｇを含有する速放部の組成：
メフルシド ２５．０ｇ （ ８．３３％）
乳糖 ８８．４ｇ （２９．４７％）
結晶セルロース １２０．０ｇ （４０．００％）
ラウリル硫酸ナトリウム ０．６ｇ （ ０．２０％）
低置換度ヒドロキシプロピルセルロース ４５．０ｇ （１５．００％）
Ac-Di-Sol １５．０ｇ （ ５．００％）
軽質無水ケイ酸 ３．０ｇ （ １．００％）
フマル酸ステアリルナトリウム ３．０ｇ （ １．００％）
フマル酸ステアリルナトリウムを除く上記原料を均一に混合し造粒後、乾燥し、整粒した。これにフマル酸ステアリルナトリウムを加えて混合し、打錠末とした。
【０１１０】
この打錠末１５０mgを、直径９mmの臼と９mmφ１０mmRの上杵・下杵を取り付けた有核打錠機（菊水クリーンプレスコレクト18DC）の臼に充填し、その上に実施例３のニフェジピン含有有核錠剤（直径７ｍｍ；但し、フィルムコーティングなし）を載置して、打錠圧1,500 kgfで打錠した。
得られた錠剤は、ニフェジピン含有有核錠剤の上面が外殻の表面に同心状に露出しており、重量２９５mg、直径９mm、厚さ５．３ｍｍであった。これにさらに実施例１０と同じ組成の遮光性のフィルムコーティングを施し、総重量３０４ｍｇの錠剤を得た。
この錠剤はニフェジピンを２０ｍｇ及びメフルシドを１２．５ｍｇ含有し、直径は９．１mm、厚さは５．４ｍｍ、そして体積は約２９０ mm³であって、ニフェジピン単剤の市販品（アダラートCR錠）の約９割であり、十分に服用可能な大きさであった。
【０１１１】
実施例１４
ヒドロクロロチアジド１２.５ｍｇを含有する速放部の組成：
ヒドロクロロチアジド ２５．０ｇ （ ８．３３％）
乳糖 ８８．４ｇ （２９．４７％）
結晶セルロース １２０．０ｇ （４０．００％）
ラウリル硫酸ナトリウム ０．６ｇ （ ０．２０％）
低置換度ヒドロキシプロピルセルロース ４５．０ｇ （１５．００％）
Ac-Di-Sol １５．０ｇ （ ５．００％）
軽質無水ケイ酸 ３．０ｇ （ １．００％）
フマル酸ステアリルナトリウム ３．０ｇ （ １．００％）
フマル酸ステアリルナトリウムを除く上記原料を均一に混合し造粒後、乾燥し、整粒した。これにフマル酸ステアリルナトリウムを加えて混合し、打錠末とした。
【０１１２】
この打錠末１５０mgを、直径９mmの臼と９mmφ１０mmRの上杵・下杵を取り付けた有核打錠機（菊水クリーンプレスコレクト18DC）の臼に充填し、その上に実施例３のニフェジピン含有有核錠剤（直径７ｍｍ；但し、フィルムコーティングなし）を載置して、打錠圧1,500 kgfで打錠した。
【０１１３】
得られた錠剤は、ニフェジピン含有有核錠剤の上面が外殻の表面に同心状に露出しており、重量２９５mg、直径９mm、厚さ５．３ｍｍであった。これにさらに実施例１０と同じ組成の遮光性のフィルムコーティングを施し、総重量３０４ｍｇの錠剤を得た。
【０１１４】
この錠剤はニフェジピンを２０ｍ、そしてまた体積は約２９０ mm³であって、ニフェジピン単剤の市販品（アダラートCR錠）の約９割であり、十分に服用可能な大きさであった。
【０１１５】
実施例７〜９で得た錠剤の溶出性を以下の局方第２法による溶出試験（５０ｒｐｍ）と局方第２法溶出試験（シンカー使用）の２通りの溶出試験法で比較検討した。
（１） 局方第２法による溶出試験（５０ｒｐｍ）とは、下記の条件下で実施されるもので、錠剤からの第２医薬成分の溶出性を調べるための溶出試験条件である。
【０１１６】
・試験液：ポルソルベート８０を０.３％含有する精製水９００ｍｌ
・温 度：３７℃
・回転数：毎分５０回転。
（２） 局方第２法溶出試験（シンカー使用）は以下の条件下で実施されるもので、錠剤からのニフェジピンの溶出性を調べるための溶出試験条件である。
【０１１７】
・試験液：ラウリル硫酸ナトリウムを１％含有するｐＨ６.８のリン酸緩衝液９００ｍｌ
・温 度：３７℃
・回転数：毎分１００回転
・シンカーの固定位置：試験液の液面と撹拌翼の上端との中間で且つ容器壁から１０ｍｍ離れた位置に、線径１.０ｍｍ以下の耐酸性針金で固定。
局方第２法による溶出試験（５０ｒｐｍ）の結果：
実施例７で得た錠剤からのロサルタン・カリウムの溶出性は市販のニューロタン錠５０ｍｇ（萬有製薬株式会社製）とほぼ同等であり（図７参照）、実施例８で得た錠剤からのバルサルタンの溶出性は市販のディオバン錠８０ｍｇ（ノバルティスファーマ株式会社）とほぼ同等であり（図９参照）、実施例９で得た錠剤からのカンデサルタン・シレキシルの溶出性は市販のブロプレス錠８ｍｇ（武田薬品工業株式会社）とほぼ同等であった（図１１参照）。
局方第２法溶出試験（シンカー使用）の結果：
実施例７〜９で得た錠剤からのニフェジピンの溶出性は市販のアダラートＣＲ錠２０ｍｇ（バイエル薬品株式会社）と同等であった（図８、図１０、図１２参照）。
【０１１８】
以上の結果から、本発明のニフェジピン有核錠剤錠剤は第２医薬成分との合剤にも有用であることが示された。
【０１１９】
【発明の効果】
本発明によりニフェジピン含有有核錠の芯部を小型化することに成功した結果、ニフェジピン含有有核錠としての体積が、従来品（市販品）に比べ体積比で最大約５０％小さくなり、単品での服薬の便宜性が高まった。さらに、本発明の小型化されたニフェジピン含有有核錠剤を用いることにより、従来ニフェジピンと併用投与されることの多かったアンジオテンシンＩＩ受容体拮抗薬やアンジオテンシン変換酵素阻害薬、利尿薬等の第２医薬成分を、それぞれの生物学的同等性を維持しつつ１剤にまとめ、かつ経口投与に適した大きさとしたニフェジピンとこれら第２医薬成分との合剤を簡便に提供することが可能となった。
【図面の簡単な説明】
【図１】アダラートＣＲ錠１０ｍｇ（市販品）を標準製剤とし、実施例１、実施例２及び比較例１で得た有核錠剤の溶出パターンを局方第２法溶出試験（シンカー使用）で比較検討した結果を示すグラフ。
【図２】アダラートＣＲ錠１０ｍｇ（市販品）を標準製剤とし、実施例１、実施例２及び比較例１で得た有核錠剤の溶出パターンを局方崩壊試験装置法で比較検討した結果を示すグラフ。
【図３】アダラートＣＲ錠２０ｍｇ（市販品）を標準製剤とし、実施例３、実施例４及び比較例２で得られた有核錠剤の溶出パターンを局方第２法溶出試験（シンカー使用）で比較検討した結果を示すグラフ。
【図４】アダラートＣＲ錠２０ｍｇ（市販品）を標準製剤とし、実施例３、実施例４及び比較例２で得られた有核錠剤の溶出パターンを局方崩壊試験装置法で比較検討した結果を示すグラフ。
【図５】アダラートＣＲ錠４０ｍｇ（市販品）を標準製剤とし、実施例５、実施例６及び比較例３で得られた有核錠剤の溶出パターンを局方第２法溶出試験（シンカー使用）で比較検討した結果を示すグラフ。
【図６】アダラートＣＲ錠４０ｍｇ（市販品）を標準製剤とし、実施例５、実施例６及び比較例３で得た有核錠剤の溶出パターンを局方崩壊試験装置法で比較検討した結果を示すグラフ。
【図７】ニューロタン錠５０ｍｇ（市販品）を標準製剤とし、実施例７で得た錠剤からのロサルタン・カリウムの溶出パターンを局方第２法溶出試験（シンカー不使用）で比較検討した結果を示すグラフ。
【図８】アダラートＣＲ錠２０ｍｇ（市販品）を標準製剤とし、実施例７で得られた錠剤からのニフェジピンの溶出パターンを局方第２法溶出試験（シンカー使用）で比較検討した結果を示すグラフ。
【図９】ディオバン錠８０ｍｇ（市販品）を標準製剤とし、実施例８で得た錠剤からのバルサルタンの溶出パターンを局方第２法溶出試験（シンカー不使用）で比較検討した結果を示すグラフ。
【図１０】アダラートＣＲ錠２０ｍｇ（市販品）を標準製剤とし、実施例８で得られた錠剤からのニフェジピンの溶出パターンを局方第２法溶出試験（シンカー使用）で比較検討した結果を示すグラフ。
【図１１】ブロプレス錠８ｍｇ（市販品）を標準製剤とし、実施例９で得た錠剤からのカンデサルタン・シレキシルの溶出パターンを局方第２法溶出試験（シンカー不使用）で比較検討した結果を示すグラフ。
【図１２】アダラートＣＲ錠２０ｍｇ（市販品）を標準製剤とし、実施例９で得られた錠剤からのニフェジピンの溶出パターンを局方第２法溶出試験（シンカー使用）で比較検討した結果を示すグラフ。[0001]
[Technology to which the invention belongs]
The present invention relates to a miniaturized once-daily nifedipine-containing nucleated tablet and a combination with a second pharmaceutical ingredient using the tablet.
[0002]
[Prior art and problems]
The inventors previously developed a once-daily nifedipine-containing nucleated tablet and disclosed it in Patent Document 1. The nifedipine-containing nucleated tablet (trade name: Adalat CR tablet) is currently widely used clinically in hypertensive patients in Japan. However, the nucleated tablet has a slightly larger size (a diameter of about 9 mm, a thickness of about 5.5 mm, and a volume of about 310 mm) as a characteristic characteristic of a compression-coated nucleated tablet. ^Three Therefore, it is not always easy to take for elderly people or patients with dysphagia, and miniaturization is desired.
[0003]
Moreover, it is estimated that about half of the hypertensive patients prescribed with the above-mentioned nucleated tablets are administered in combination with other antihypertensive drugs. In fact, according to IMS statistics (2001), the combined use rate of Adalat CR tablets and angiotensin converting enzyme inhibitors such as enalapril and lisinopril is about 15%, combined use with angiotensin II receptor antagonists such as candesartan and valsartan The rate is about 20%. The reasons for such frequent use are as follows: (1) There are many patients who cannot achieve antihypertensive and blood pressure maintenance that can be satisfied with each antihypertensive monotherapy, and (2) they are fully satisfied with antihypertensive monotherapy. If you try to obtain blood pressure and blood pressure maintenance that can be done, you will have to increase the dose, increasing the risk of side effects, and (3) combination therapy combining multiple antihypertensive drugs with different mechanisms of action at multiple low doses. It is considered safe.
[0004]
In the case of such combination therapy, in addition to the nifedipine-containing nucleated tablet having a larger tablet size, at least one additional drug will be taken, and the burden on the patient will be further increased. Therefore, the size of the nifedipine-containing nucleated tablet will be reduced. The need is particularly high in combination therapy. If the once-daily nifedipine-containing nucleated tablet can be sufficiently miniaturized, it becomes possible to combine nifedipine and the second pharmaceutical component as described above into one so-called combination, It is expected to greatly contribute to reducing the physical burden on patients.
[0005]
In the case of a nucleated tablet by compression coating, the size depends on the core size (usually the thickness of the outer shell coated on the core is at least 1.5 mm in the tablet diameter direction and 1 in the side direction). In order to reduce the size, the core portion must first be reduced. On the other hand, since the final tablet size desirable for the patient is estimated to have a diameter of 7 to 8 mm and a thickness of about 4 to 5 mm, it is required that the size of the core is kept to a diameter of about 4 mm and a thickness of about 2 mm. In addition, to ensure the effectiveness and safety of once-daily nifedipine preparations, even if they are downsized, they must not differ from the nifedipine dissolution characteristics of commercially available nifedipine nucleated tablets. It is necessary to keep this as it is.
[0006]
In the core of the dry-coated tablet of Patent Document 1, nifedipine is dissolved by combining nifedipine with hydrophilic gel-forming polymer substances having various viscosities, or by adding other additives such as excipients as appropriate. However, in order to reduce the size, it is necessary to refrain as much as possible from the hydrophilic gel-forming polymer substance and other additives (such as lactose) to be blended. Select a hydrophilic gel-forming polymer material with an appropriate viscosity according to a conventional method, or combine it or reduce the blending amount of other additives, etc. to reduce its size while maintaining the elution characteristics required for the core. It was possible to reduce the size to the above target. However, when the outer shell was compression coated to make a finished tablet and its dissolution was examined, the second dissolution method (using a sinker) achieved the desired dissolution characteristics, but the local disintegration test. In the apparatus method, rapid dissolution of nifedipine was observed in the latter half of the dissolution (after about 3 to 4 hours), and the reproducibility was poor, making it unsuitable as a once-daily administration type nucleated tablet. The cause of this is thought to be that the miniaturized core portion became brittle during a long-time dissolution test and collapsed without exhibiting the expected dissolution properties of nifedipine. It was concluded that as long as a core made of a hydrophilic gel-forming polymer substance was used, it was difficult to achieve both a reduction in the size of the core and maintenance of the nifedipine dissolution characteristics of the finished tablet.
[Patent Document 1]
Japanese Patent No. 3,220,373
[0007]
[Means for Solving the Problems]
Accordingly, as a result of intensive studies on the downsizing of the once-daily nifedipine-containing nucleated tablet described in Patent Document 1, the present inventors have now incorporated a hydrophilic gel-forming polymer substance into the core. If the “disintegration-inhibiting substance”, which was previously thought to be added only to the outer shell, is added to the core instead of reducing the amount, it is surprising that the core does not affect the elution of nifedipine. It was found that the part can be reduced in size, and the core part is compression-coated with the same outer shell part as in the past. The present invention was completed by successfully obtaining a single-dose nifedipine-containing nucleated tablet.
[0008]
Thus, the present invention comprises nifedipine 8 to 80% by weight, hydrophilic gel-forming polymer material 15 to 80% by weight, and water-insoluble polymer that forms a matrix with nifedipine and the hydrophilic gel-forming polymer material. Nifedipine 5 to 50 wt%, hydrophilic gel-forming property, formed by compression coating on the core with delayed dissolution of nifedipine containing 2 to 30 wt% of the anti-collapse agent And 30 to 90% by weight of a polymer substance, and an outer shell portion containing 5 to 50% by weight of a collapse-inhibiting substance composed of a water-insoluble polymer that forms a matrix together with nifedipine and the hydrophilic gel-forming polymer substance. Nifedipine-containing nucleated tablet, wherein the dissolution rate of nifedipine from the tablet is
(A) In dissolution test using sinker by Japanese Pharmacopoeia dissolution test method 2
10-40% after 2 hours,
4 to 30% to 65% later,
More than 55% after 6 hours
And
(B) In the dissolution test by the Japanese Pharmacopoeia disintegration test method,
After 3 hours 20-45%,
4 to 30% to 65%
A nifedipine-containing nucleated tablet is provided.
[0009]
The miniaturized nifedipine dry-coated tablet of the present invention further comprises a disintegration-inhibiting agent added to the core of the dry-coated tablet composed of the core described in Patent Document 1 and the outer shell covering the core. Except for this point, each compounding component that can be used can be basically used as described in Patent Document 1, and its production method is basically as it is. Can be used.
[0010]
Hereinafter, the present invention will be described in more detail.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
The core part of the nifedipine dry-coated tablet of the present invention contains three components of nifedipine, a hydrophilic gel-forming polymer substance, and a disintegration-inhibiting substance as essential components.
[0012]
The properties of nifedipine used for the core are not particularly limited. Usually, in the sedimentation method or laser diffraction scattering type particle size distribution measurement, the median diameter is about 1 to 30 μm, or the specific surface area is measured by the gas adsorption method. 0.5-10m ² A finely ground nifedipine crystal of about / g is preferably used. Further, nifedipine that has been made amorphous or solid solution with polyvinyl pyrrolidone or the like and pulverized, or nifedipine once dissolved in an organic solvent and adsorbed on a porous substance such as light anhydrous silicic acid can be used.
[0013]
The content of nifedipine in the core part can be in the range of 8 to 80% by weight, preferably 10 to 70% by weight, more preferably 12 to 65% by weight, based on the weight of the core part.
[0014]
Examples of the hydrophilic gel-forming polymer substance used for the core include cellulose derivatives such as methylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose, polyvinyl alcohol, and the like. Of these, HPC or HPMC is preferable. These hydrophilic gel-forming polymer materials can be used alone or in combination, and a plurality of hydrophilic gel-forming polymer materials of different viscosity grades may be used in combination.
[0015]
The blending amount of these hydrophilic gel-forming polymer substances is in the range of 15 to 80% by weight, preferably 25 to 70% by weight, more preferably 30 to 65% by weight, based on the weight of the core. can do.
[0016]
The disintegration-inhibiting substance used for the core according to the present invention is a substance composed of a water-insoluble polymer that forms a pH-independent matrix together with nifedipine and the hydrophilic gel-forming polymer, and is suitable for the core. This makes it possible to have a stable disintegration in an environment with a strong mechanical stimulus such as the digestive tract, and by incorporating this into the core, there is no change in the elution characteristics of nifedipine. The blending amount of the hydrophilic gel-forming polymer substance and other additives can be reduced, and as a result, the core volume can be reduced to about 50%.
[0017]
As the disintegration inhibitory substance to be blended in the core part, the same substances used in the outer shell part in the dry-coated tablet described in Patent Document 1 can be used alone or in combination. Examples thereof include specific pH-independent water-insoluble polymers usually used as a base or film for sustained-release preparations. Preferably, water-insoluble methacrylate copolymers can be used. Of these, an ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer (hereinafter referred to as “aminoalkyl”) composed of three repeating units represented by the following formulas (I), (II) and (III): Particularly preferred are "methacrylate copolymers".
[0018]
[Chemical 1]

[0019]
The aminoalkyl methacrylate copolymer has a weight ratio (I) / (II) / (III) of the repeating units of the above formulas (I), (II) and (III) of 1/2 / 0.1 to 0. .2 are preferred, and those with viscosities in the range of about 1 to about 4 centistokes are preferred. Such aminoalkyl methacrylate copolymers are commercially available and can be obtained under the trade name Eudragit RS or RL [Roehm Pharma GmbH, Germany].
[0020]
The disintegration-inhibiting agent compounded in the core may be within the range of 2 to 30% by weight, preferably 5 to 25% by weight, more preferably 8 to 20% by weight, based on the weight of the core. it can.
[0021]
In order to improve the wetting of nifedipine crystals and promote the penetration of water and gastrointestinal tract fluid into the core, and to promote the dissolution of nifedipine from the core, a surfactant is added to the core. Is preferred. Examples of the surfactant that can be blended include polysorbate 80, polysorbate 60, polysorbate 20, sodium lauryl sulfate, various sucrose fatty acid esters, etc., and these can be used alone or in combination of two or more. May be used. The amount of these surfactants is usually from 0.03 to 3% by weight, preferably from 0.05 to 2% by weight, more preferably from 0.1 to 0.5% by weight, based on the weight of the core. Can be within the range.
[0022]
In addition, a fluidizing agent can be blended in the core as necessary. Examples of the fluidizing agent that can be blended include light anhydrous silicic acid, heavy anhydrous silicic acid, hydrous silicon dioxide, and synthetic aluminum silicate. And magnesium aluminate metasilicate. The blending amount of these fluidizing agents is usually 0.02 to 2% by weight, preferably 0.05 to 1% by weight, more preferably 0.1 to 0.5% by weight based on the weight of the core. %.
[0023]
A lubricant can be blended in the core portion as necessary. Examples of the lubricant that can be blended include magnesium stearate, stearic acid, sodium stearyl fumarate, and sucrose fatty acid ester. . The blending amount of these lubricants is usually 0.02 to 2% by weight, preferably 0.05 to 1% by weight, more preferably 0.1 to 0.5% by weight based on the weight of the core. %.
[0024]
Furthermore, in the core, depending on circumstances, starches such as corn starch, potato starch, alpha starch, dextrin, carboxymethyl starch, saccharides such as lactose, sucrose, glucose, mannitol, sorbitol, light anhydrous silicic acid, synthetic silicic acid Inorganic salts such as aluminum, magnesium aluminate metasilicate, calcium phosphate and calcium carbonate, paraffin, wax, fats and oils such as higher fatty acids, excipients such as cellulose; starches, croscarmellose sodium, carboxymethyl starch sodium, carboxy Disintegrants such as methylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crystalline cellulose, and crosslinked polyvinylpyrrolidone; various food colors and coloring agents such as iron sesquioxide (face ); It can be blended excipients such.
[0025]
However, it goes without saying that it is desirable to keep the blending amount of these pharmaceutical additives to the minimum necessary in order to reduce the size of the core.
[0026]
The final composition of the core part is a dissolution test in which the dissolution rate of nifedipine from a tablet having the same composition as the core part is a dissolution test that does not use a sinker according to the second dissolution method of the Japanese Pharmacopoeia Test (referred to as “no sinker”)), generally 20 to 70% after 45 minutes, preferably 25 to 65%, more preferably 30 to 60%, more than 65% after 2 hours, preferably 70% or more, more It is desirable to adjust so that it may become 75% or more preferably.
[0027]
Here, the pharmacopoeia second method dissolution test (without sinker) was carried out under the following conditions.
[0028]
Test solution: 900 ml of phosphate buffer solution with pH 6.8 containing 1% sodium lauryl sulfate
・ Temperature: 37 ℃
-Number of revolutions: 75 revolutions per minute.
In addition, as a tablet having the same composition as the core used in the dissolution test, those prepared by tableting under the same conditions as the tableting conditions of the core of the dry-coated tablet are used.
[0029]
On the other hand, the outer shell part formed by compression coating on the surface of the core part has nifedipine and a hydrophilic gel-forming polymer substance as well as nifedipine and pH together with nifedipine and the hydrophilic gel-forming polymer substance. Contains a disintegration-inhibiting substance consisting of a water-insoluble polymer that forms an independent matrix as an essential component, and optionally contains surfactants, fluidizing agents, lubricants, and other pharmaceutical additives. To do.
[0030]
These nifedipine, hydrophilic gel-forming polymer substance, disintegration-inhibiting substance, surfactant, fluidizing agent, lubricant, and other pharmaceutical additives in the outer shell part are all used for the core part. The same or different ones from those described above can be appropriately selected and used.
[0031]
The content of nifedipine in the outer shell can be within the range of 5 to 50% by weight, preferably 5 to 40% by weight, more preferably 5 to 30% by weight, based on the weight of the outer shell. The blending amount of the hydrophilic gel-forming polymer substance is within the range of 30 to 90% by weight, preferably 45 to 85% by weight, more preferably 55 to 75% by weight, based on the weight of the outer shell. The blending amount of the disintegration inhibiting substance is 5 to 50% by weight, preferably 7.5 to 40% by weight, more preferably 10 to 30% by weight, based on the weight of the outer shell. Can be within range.
[0032]
In order to improve the wetting of the nifedipine crystals and promote the penetration of water and gastrointestinal fluid into the tablet to promote the dissolution of nifedipine, it is preferable to add a surfactant to the outer shell. The blending amount is usually in the range of 0.02 to 2% by weight, preferably 0.05 to 1% by weight, more preferably 0.1 to 0.5% by weight, based on the weight of the outer shell. It can be.
[0033]
When blending the fluidizing agent in the outer shell, the blending amount is usually 0.02 to 2% by weight, preferably 0.05 to 1% by weight, more preferably based on the weight of the outer shell. It can be in the range of 0.1 to 0.5% by weight.
[0034]
When a lubricant is blended in the outer shell part, the blending amount is usually 0.02 to 2% by weight, preferably 0.05 to 1% by weight, more preferably based on the weight of the outer shell part. It can be in the range of 0.1 to 0.5% by weight.
[0035]
Furthermore, in addition to the above-mentioned components, the outer shell portion can be blended with various pharmaceutical additives similar to those for the core portion, if necessary.
[0036]
The final composition of the outer shell is determined by the dissolution rate of nifedipine from the tablet having the same composition as the outer shell.
(A) In a dissolution test using a sinker according to the second method of dissolution test of the Japanese Pharmacopoeia (hereinafter referred to as “Pharmacopoeia Second Method dissolution test (using sinker)”),
After 2 hours 20-50%, preferably 25-45%, more preferably 30-40%,
After 4 hours 40-90%, preferably 45-85%, more preferably 50-80%,
After 6 hours 75% or more, preferably 80% or more, more preferably 85% or more, and
(B) In the dissolution test by the Japanese Pharmacopoeia disintegration test method (hereinafter referred to as the “Pharmacopoeia disintegration test apparatus method”),
After 3 hours 30-60%, preferably 35-55%, more preferably 40-50%,
4 hours later 40-90%, preferably 45-85%, more preferably 50-80%
It is desirable to adjust so that.
[0037]
In this specification, the pharmacopoeia second method dissolution test (using a sinker) was carried out under the following conditions.
[0038]
Test solution: 900 ml of phosphate buffer solution with pH 6.8 containing 1% sodium lauryl sulfate
・ Temperature: 37 ℃
・ Rotation speed: 100 revolutions per minute
Fixing position of sinker: Fixing with acid-resistant wire having a wire diameter of 1.0 mm or less at a position between the liquid surface of the test solution and the upper end of the stirring blade and at a distance of 10 mm from the vessel wall.
[0039]
Moreover, the pharmacopeiale test apparatus method was implemented on condition of the following.
[0040]
Test solution: 900 ml of phosphate buffer solution with pH 6.8 containing 1% sodium lauryl sulfate
・ Temperature: 37 ℃
・ Use auxiliary panel.
[0041]
The tablets with the same composition as the outer shell used in the dissolution test are those prepared by tableting under the same conditions as the tableting conditions of the nucleated tablet, but without using the core. To do.
[0042]
The cored tablet composed of the core part and the outer shell part described above is prepared by, for example, producing an inner core tablet as the core part by a method known per se, and then using a cored tableting machine (press coater). It can be produced by coating the inner core tablet with the outer shell part having the composition described above. The tableting conditions at that time are not strictly limited, and can be changed according to the elution characteristics desired for the final tablet, but the tableting pressure of the core core tablet is usually about 100 to 1000 kgf. The tableting pressure of the dry-coated tablet is suitably about 500 to 2000 kgf.
[0043]
Thus, according to the present invention, the core can be made smaller than the dry-coated tablet described in Patent Document 1, and the diameter of the core is 2.5 to 4.8 mm, preferably 3 to 4.7 mm. More preferably, it is in the range of 3.5 to 4.5 mm, and the thickness of the core is 1.0 to 2.5 mm, preferably 1.3 to 2.2 mm, more preferably 1.5 to 2.5. It can be in the range of 0 mm. And the dry-coated tablet (bare tablet) produced by compression-coating (tableting) the outer shell on this generally has a diameter of 4.5 to 8.5 mm, preferably 5.0 to 8 mm, more preferably The thickness can be in the range of 5.5 to 7.5 mm, and the thickness is 3.5 to 5.5 mm, preferably 3.8 to 5.2 mm, more preferably 4.0 to 5.0 mm. Can be within range.
[0044]
Prior to coating the core with the outer shell, a thin film coating may be applied. Examples of the film coating base include cellulose-based water-soluble coating bases such as HPC, HPMC, hydroxyethylcellulose, and methylhydroxyethylcellulose; hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate And other enteric film coating bases such as methacrylic acid copolymer and shellac.
[0045]
The dry-coated tablet produced as described above may be further provided with at least one light-shielding film coating on the outside after being formed into a dry-coated tablet. Examples of such a light-shielding film coating include a cellulose-based water-soluble coating in which an appropriate amount of a light-shielding agent such as iron sesquioxide and / or titanium oxide is blended. As the cellulose-based water-soluble coating, it is preferable to use HPMC from the viewpoint of film-forming property, and HPMC having a 2% aqueous solution viscosity at 20 ° C. of 100 cp or less, particularly 15 cp or less is particularly preferable. A plasticizer such as polyethylene glycol can be added to these film coating bases as necessary.
[0046]
Although the nifedipine nucleated tablet of the present invention prepared in this manner is downsized, the nifedipine nucleated tablet equivalent to the once-daily nifedipine nucleated tablet disclosed in Patent Document 1 Demonstrate elution characteristics. That is, the dissolution rate of nifedipine from the miniaturized nifedipine nucleated tablet of the present invention is:
(A) In the Pharmacopeia Method 2 (using sinker) dissolution test,
2 hours later 10-40%, preferably 15-35%, more preferably 20-29%,
4 hours later 30-65%, preferably 35-60%, more preferably 39-56%,
After 6 hours 55% or more, preferably 60% or more, more preferably 65% or more, and
(B) In the collateral decay test apparatus method,
After 3 hours 20-45%, preferably 25-40%, more preferably 28-35%,
4 hours later 30-65%, preferably 35-60%, more preferably 40-55%
It is.
[0047]
The nifedipine-containing nucleated tablet of the present invention can not only maintain the effective blood concentration of nifedipine over a long period of time (at least 24 hours), but is also miniaturized, so that the patient's swallowing compared to conventional commercial products・ It is very easy to take.
[0048]
In addition, since the nifedipine-containing nucleated tablet provided by the present invention can be reduced in size as described above, an immediate-release part containing the second pharmaceutical ingredient is provided on the nifedipine-containing nucleated tablet, and nifedipine and It can be combined with the second pharmaceutical ingredient. Thus, according to the present invention, the nifedipine-containing dry tablet described above is partially compression-coated with the immediate-release part containing the second pharmaceutical ingredient so that at least a part of the surface is exposed. A tablet (hereinafter referred to as a combination) is provided.
[0049]
The combination of the present invention is a tablet comprising the miniaturized nifedipine-containing nucleated tablet of the present invention and an immediate release part containing a second pharmaceutical ingredient, wherein the top, bottom and side surfaces of the nifedipine-containing nucleated tablet The at least one of the three surfaces is exposed to the outside, and the quick release portion is arranged.
[0050]
Specifically, such a tablet is based on the above-mentioned miniaturized nifedipine-containing nucleated tablet, and further, a simple parallel two-layer or three-layer structure in which either one or both surfaces of the bottom surface is compression-coated with a quick release part. A layered tablet or the above-mentioned miniaturized nifedipine-containing dry tablet is used as a core, and the bottom and side surfaces thereof are surrounded by a second drug component-containing quick release part, and the top of the dry tablet is on the top of the quick release part Mention may be made of tablets that have been compressed so as to be exposed substantially concentrically (also known as “bull's eye table”). The above-mentioned miniaturized nifedipine-containing nucleated tablet can be used as a core, and the entire surface can be compressed and coated with a second drug component-containing quick release part to form a nucleated triple tablet, but this increases the size. Too much may harm patient convenience.
[0051]
The second pharmaceutical ingredient that can be used in the combination of the present invention is a drug that does not have a harmful interaction with nifedipine, requires fast solubility, and is orally administered once a day. Although not particularly limited, drugs that act synergistically when used in combination with nifedipine are desirable.
Examples of such second pharmaceutical ingredient include candesartan cilexetil, losartan potassium, valsartan, olmesartan medoxomil, telmisartan and irbesartan; angiotensin II receptor antagonist; enalapril maleate, lisinopril, cilazapril and And an angiotensin converting enzyme inhibitor selected from the group consisting of delapril hydrochloride. Among them, candesartan cilexetil and enalapril maleate are particularly suitable for the combination with the miniaturized nifedipine nucleated tablet of the present invention because the dose is small and the volume of the immediate release part can be reduced.
In addition, diuretics that have been used as antihypertensive drugs for a long time because they have a moderate antihypertensive effect can also be used as the second pharmaceutical ingredient. Diuretics used for this purpose include, for example, ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, polythiazide, methycrothiazide, penflutide, chlorothiazide, cyclothiazide, flumethiazide, Thiazide diuretics such as benzthiazide and bendroflumethiazide; acetazolamide, azosemide, ethacrynic acid, sodium ethacrynate, kinesazone, clofenamide, chlorthalidone, spironolactone, triamterene, piretanide, bumetanide, furosemide, metralide, mefluridamidamide , Trypamide, torsemide, methiclan, aminophylline and other non-thiazide diuretics And the like.
[0052]
The amount of the second pharmaceutical ingredient used in the combination of the present invention depends on the dosage, formability, bulk density, etc. of the second pharmaceutical ingredient, but is usually 150 mg or less, preferably 120 mg or less, more preferably Is 100 mg or less, and more preferably 80 mg or less.
[0053]
Necessary pharmaceutical additives such as a disintegrant, a binder, a surfactant, and a lubricant are blended in the immediate release part containing the second pharmaceutical ingredient. As these pharmaceutical additives, those similar to those described above for the miniaturized nifedipine-containing nucleated tablet can be used. The quick release part is characterized in that after taking, it disintegrates within a short time in the stomach and releases the second pharmaceutical ingredient. For this reason, necessary pharmaceutical additives such as disintegrants, binders, surfactants, lubricants and the like are appropriately selected or combined to determine the composition of the immediate release part. The content rate of the second pharmaceutical component in the immediate release part can be determined in consideration of the dose of the second pharmaceutical component, physicochemical properties, particularly solubility and wettability.
[0054]
It is desirable to design the formulation so that the dissolution rate of the second pharmaceutical ingredient from the immediate release part is 80% or more after 1 hour in the dissolution test (50 rpm) by the second method of dissolution test of Japanese Pharmacopoeia. Here, the dissolution test (50 rpm) according to the second method of the Japanese Pharmacopoeia is carried out under the following conditions.
[0055]
Test liquid: 900 ml of purified water containing 0.3% porsorbate 80
・ Temperature: 37 ℃
-Number of revolutions: 50 revolutions per minute.
[0056]
For joining the miniaturized nifedipine-containing nucleated tablet of the present invention to the immediate-release part containing the second pharmaceutical ingredient, the nucleated tablet press (press) used in the production of the miniaturized nifedipine-containing nucleated tablet is used. The same or similar tablet press as the coater can be used. A commercially available machine may be used as it is, or may be used after being modified. Specifically, for example, tableting can be performed by any one of the following three methods, and may be appropriately selected according to the performance of the nucleated tableting machine (press coater) to be used.
(1) Nucleated tablet press (press coater) in which a mortar and punch having the same or slightly larger (+0.05 to 0.2 mm) diameter are set as the diameter of the nifedipine-containing nucleated tablet of the present invention Is prepared, and the tablet for the immediate release part is filled into the die, the nifedipine-containing nucleated tablet is placed thereon, and compression molding is performed in the die without the second filling.
[0057]
In this method, the immediate release part containing the second pharmaceutical ingredient is joined in a layered manner only to the bottom surface of the nifedipine-containing nucleated tablet, and a tablet in which the top and side surfaces of the nifedipine-containing nucleated tablet are exposed to the outside is obtained. This method is particularly useful when the dose of the second pharmaceutical ingredient is sufficiently small (for example, 10 mg or less) and the quick release part can be designed to be small.
(2) Nucleated tablet press (press coater) in which a mortar and pestle having the same or slightly larger (+0.05 to 0.2 mm) diameter are set as the diameter of the nifedipine-containing nucleated tablet of the present invention The quick-release part tableting powder is filled into the mortar, the nifedipine-containing nucleated tablet is placed on it, and the quick-release part tableting powder is filled into the mortar, followed by compression molding in the mortar. Method.
[0058]
In this method, a tablet in which the second pharmaceutical component-containing immediate release part is joined in layers to the top and bottom surfaces of the nifedipine-containing nucleated tablet, and only the side surface of the nifedipine-containing nucleated tablet is exposed to the outside is obtained. This method is particularly useful when the dose of the second pharmaceutical ingredient is sufficiently small (for example, 10 mg or less) and the quick release part can be designed to be small.
(3) A nucleated tableting machine (press coater) in which a mortar and pestle of a size larger than the nifedipine-containing nucleated tablet of the present invention (usually having a diameter of +2.4 mm or more; can be round or oval) is set. A method of preparing, filling a tablet for a quick-release part into a mortar, placing a nifedipine-containing nucleated tablet on the mortar, and compressing it in the mortar without a second filling.
[0059]
In this method, the second drug component-containing rapid release part is joined to the bottom and side surfaces of the nifedipine-containing nucleated tablet in a concave shape, and substantially only the top surface of the nifedipine-containing nucleated tablet is concentrically exposed on the top surface of the rapid release part. A tablet in a finished state is obtained. This method is not limited by the dose of the second pharmaceutical ingredient, and has the advantage that the combination can be designed flexibly. Therefore, it is possible to target more types of the second pharmaceutical ingredient, and the most extensive This is an available method.
[0060]
In any case of the above (1) to (3), in order to obtain a good joint between the nifedipine-containing nucleated tablet and the second pharmaceutical component-containing immediate release part, avoid film-coating the nifedipine-containing nucleated tablet in advance. Is desirable.
[0061]
The tableting pressure for compression coating (press coating) may be adjusted so that the rapid release part exhibits appropriate hardness and disintegration within a pressure range that does not substantially destroy the nifedipine-containing dry tablet. Usually, the tableting pressure required for press coating can be about 500 to 2000 kgf.
[0062]
In addition, if the size of the final mixture is large, swallowing may be difficult particularly for elderly patients. Therefore, it is desirable to design the size so that the patient can swallow it without difficulty. In the case of a round tablet, the final tablet diameter is usually 12 mm or less, preferably 10 mm or less, more preferably 9.5 mm or less, and the tablet thickness is usually 6 mm or less, preferably 5.8 mm or less, more preferably. Is within the range of 5.6 mm or less. When it is necessary to enlarge the quick release part, it is desirable to design an oblong type or an oval (ellipse) type with a minor axis of about 9 mm.
[0063]
The mixture comprising the miniaturized nifedipine-containing nucleated tablet of the present invention and the second pharmaceutical ingredient-containing immediate-release part can be subjected to normal film coating, if necessary. The composition of the film coating may be the same as that used for the above-mentioned miniaturized nifedipine-containing nucleated tablet.
[0064]
A combination of the nifedipine-containing nucleated tablet and the immediate-release part containing the second pharmaceutical component produced as described above, when orally administered to humans, the immediate-release part rapidly disintegrates first. Two pharmaceutical ingredients are eluted. Subsequently, nifedipine is stably eluted from the nifedipine-containing nucleated tablet (as described in Patent Document 1), and the effective blood concentration is maintained for 24 hours.
[0065]
【Example】
Hereinafter, preferred embodiments of the present invention will be described in more detail with reference to Examples and Comparative Examples. However, the present invention is not limited only to these examples. Note that HPC L and HPC M used in Examples and Comparative Examples are hydroxypropyl cellulose, a viscosity of 6.0 to 10.0 cp (2% aqueous solution, 20 ° C.) and Nippon Soda, respectively, manufactured by Nippon Soda Co., Ltd. Hydroxypropyl cellulose manufactured by Co., Ltd., with a viscosity of 150 to 400 cp (2% aqueous solution, 20 ° C.). As HPMC, various viscosity grades of hydroxypropyl methylcellulose manufactured by Shin-Etsu Chemical Co., Ltd. were used. “Eudragit RL PO” is a trade name of Rehm Pharma, Germany, for ethyl acrylate / methyl methacrylate / methacrylate trimethylammonium ethyl copolymer.
[0066]
Example 1
Composition of core containing 15% by weight of nifedipine in one tablet:
Nifedipine (finely pulverized crystals) 150.0 g (15.00%)
HPMC 2910, 3cP 264.4 g (26.44%)
HPC-L 340.0 g (34.00%)
Eudragit RLPO 240.0g (24.00%)
Polysorbate 80 1.2g (0.12%)
Ferric sesquioxide (red) 0.4g (0.04%)
Light anhydrous silicic acid 2.0g (0.20%)
Magnesium stearate 2.0g (0.20%)
The above raw materials excluding magnesium stearate were mixed uniformly, granulated, dried and sized. Magnesium stearate was added thereto and mixed, and then tableted using a rotary press (tablet press) with a tableting pressure of 400 kgf. A 25 mg inner core tablet (diameter 4 mm, 4 mm diameter) containing 3.75 mg of nifedipine in one tablet. A thickness of 1.8 mm) was produced. When this inner core tablet was evaluated by a pharmacopoeia second method dissolution test (without sinker), about 45% of nifedipine was dissolved after 45 minutes and after 2 hours.
[0067]
Composition of the outer shell containing 5.2% by weight of nifedipine:
Nifedipine (finely ground crystals) 125g (5.208%)
HPC-L 884g (36.833%)
HPC-M 900g (37.500%)
Eudragit RLPO 480g (20.000%)
Polysorbate 80 3g (0.125%)
Light anhydrous silicic acid 4g (0.167%)
Magnesium stearate 4g (0.167%)
The above raw materials excluding magnesium stearate were mixed uniformly, granulated, dried and sized. To this, magnesium stearate was added and mixed to obtain a tableting powder for the outer shell. Using a dry-coated tableting machine (Kikusui Clean Press Collect 18DC) equipped with a 7 mm diameter mortar and 7 mmφ10 mmR upper and lower punches, the inner core tablet and the outer shell tableting powder 120 mg were compressed into a tableting pressure of 1,000 kgf. The tablet was pressed to prepare a 145 mg dry-coated tablet (diameter 7 mm, thickness 4.2 mm) containing 10 mg of nifedipine in one tablet.
[0068]
Furthermore, the surface of this dry-coated tablet is coated with a light-shielding film coating having the following composition, total weight 151 mg, volume about 150 mm ^Three Tablets (about 48% of the volume of the commercial product).
[0069]
Composition of film coating per tablet:
HPMC 2910 (15 cP) 3.6 mg (60.000%)
Polyethylene glycol 4000 1.2mg (20.000%)
Ferric sesquioxide (red) 0.1mg (1.667%)
Ferric sesquioxide (yellow) 0.2mg (3.333%)
Titanium oxide 0.9mg (15,000%)
[0070]
Example 2
Composition of core containing 15% by weight of nifedipine in one tablet:
Nifedipine (finely ground crystals) 75.0 g (15.00%)
HPMC 2910, 3cP 179.0 g (35.80%)
HPMC 2906, 4000 cP 119.4 g (23.88%)
HPC-L 24.4g (4.88%)
Eudragit RLPO 100.0g (20.00%)
Ferric sesquioxide (red) 0.2g (0.04%)
Light anhydrous silicic acid 1.0g (0.20%)
Magnesium stearate 1.0 g (0.20%)
By the same method as in Example 1, an inner core tablet (weight 25 mg, diameter 4 mm, thickness 1.8 mm) containing 3.75 mg of nifedipine in 1 tablet was prepared based on the above raw materials. When this inner core tablet was evaluated by a pharmacopoeia second method dissolution test (without sinker), about 45% of nifedipine was dissolved after 45 minutes and after 2 hours.
[0071]
The inner core tablet was similarly compression coated with 120 mg of outer shell tableting powder having the same composition as in Example 1 and 10 mg of nifedipine contained in one tablet. The weighted tablet had a weight of 145 mg (diameter 7 mm, thickness 4.2 mm). ), And also with a light-shielding film coating, total weight 151 mg, volume of about 150 mm ^Three Tablets (about 48% of the volume of the commercial product).
[0072]
Comparative Example 1
Composition of core containing 15% by weight of nifedipine in one tablet:
Nifedipine (finely ground crystals) 75.0 g (15.00%)
HPMC 2910, 3cP 239.0 g (47.80%)
HPMC 2906, 4000 cP 159.4 g (31.88%)
HPC-L 24.4g (4.88%)
Ferric sesquioxide (red) 0.2g (0.04%)
Light anhydrous silicic acid 1.0g (0.20%)
Magnesium stearate 1.0 g (0.20%)
By the same method as in Example 1, an inner core tablet (weight 25 mg, diameter 4 mm, thickness 1.8 mm) containing 3.75 mg of nifedipine in 1 tablet was prepared based on the above raw materials. When this inner core tablet was evaluated by a pharmacopoeia second method dissolution test (without sinker), about 45% of nifedipine was dissolved after 45 minutes and after 2 hours.
[0073]
This inner core tablet was similarly compression coated with 120 mg of outer shell tableting powder having the same composition as in Example 1 and 10 mg of nifedipine contained in one tablet, and a weighted 145 mg cored tablet (diameter 7 mm, thickness 4.2 mm). ), And also with a light-shielding film coating, total weight 151 mg, volume of about 150 mm ^Three Tablets (about 48% of the volume of the commercial product).
[0074]
Example 3
Composition of core containing 30% by weight of nifedipine in one tablet:
Nifedipine (finely pulverized crystals) 30.0 g (30.00%)
HPMC 2910, 3cP 249.6 g (24.96%)
HPC-L 284.0g (28.40%)
Eudragit RLPO 160.0g (16.0%)
Polysorbate 80 2.0g (0.20%)
Ferric sesquioxide (red) 0.4g (0.04%)
Light anhydrous silicic acid 2.0g (0.20%)
Magnesium stearate 2.0g (0.20%)
By the same method as in Example 1, an inner core tablet (weight 25 mg, diameter 4 mm, thickness 1.8 mm) containing 7.5 mg of nifedipine in one tablet was prepared based on the above raw materials. When this inner core tablet was evaluated by a pharmacopoeia second method dissolution test (without sinker), about 45% of nifedipine was dissolved after 45 minutes and after 2 hours.
[0075]
Composition of outer shell containing 10.4% by weight of nifedipine:
Nifedipine (finely ground crystal) 250g (10.416%)
HPC-L 792g (33.000%)
HPC-M 860g (35.833%)
Eudragit RLPO 480g (20.000%)
Polysorbate 80 10g (0.417%)
Light anhydrous silicic acid 4g (0.167%)
Magnesium stearate 4g (0.167%)
In the same manner as in Example 1, an outer shell tableting powder having the above composition was prepared. The inner core tablet and the outer shell tableting powder 120 mg were tableted in the same manner as in Example 1, and a 145 mg cored tablet (diameter 7 mm, thickness 4.2 mm) containing 20 mg of nifedipine in one tablet. Produced.
[0076]
Further, the surface of the dry-coated tablet is coated with a light-shielding film coating having the following composition, and has a total weight of 151 mg and a volume of about 150 mm. ^Three Tablets (about 48% of the volume of the commercial product).
[0077]
Composition of film coating per tablet:
HPMC 2910 (15 cP) 3.60 mg (60.0%)
Polyethylene glycol 4000 1.20mg (20.0%)
Iron trioxide (red) 0.24mg (4.0%)
Titanium oxide 0.96mg (16.0%)
[0078]
Example 4
Composition of core containing 30% by weight of nifedipine in one tablet:
Nifedipine (finely ground crystals) 150.0 g (30.00%)
HPMC 2910, 3cP 146.0 g (29.20%)
HPMC 2906, 4000 cP 97.4 g (19.48%)
HPC-L 24.4g (4.88%)
Eudragit RLPO 80.0g (16.0%)
Ferric sesquioxide (red) 0.2g (0.04%)
Light anhydrous silicic acid 1.0g (0.20%)
Magnesium stearate 1.0 g (0.20%)
By the same method as in Example 3, an inner core tablet (weight 25 mg, diameter 4 mm, thickness 1.8 mm) containing 7.5 mg of nifedipine in one tablet was prepared based on the above raw materials. When this inner core tablet was evaluated by a pharmacopoeia second method dissolution test (without sinker), about 45% of nifedipine was dissolved after 45 minutes and after 2 hours.
[0079]
This was compression coated with 120 mg of outer shell tableting powder having the same composition as in Example 3 to produce a 145 mg dry-coated tablet (diameter 7 mm, thickness 4.2 mm) containing 20 mg of nifedipine in one tablet, Furthermore, the same light-shielding film coating as in Example 3 was applied, and the total weight was 151 mg, and the volume was about 150 mm. ^Three Tablets (about 48% of the volume of the commercial product).
[0080]
Comparative Example 2
Composition of core containing 30% by weight of nifedipine in one tablet:
Nifedipine (finely ground crystals) 150.0 g (30.00%)
HPMC 2910, 3cP 194.0 g (38.80%)
HPMC 2906, 4000 cP 129.4 g (25.88%)
HPC-L 24.4g (4.88%)
Ferric sesquioxide (red) 0.2g (0.04%)
Light anhydrous silicic acid 1.0g (0.20%)
Magnesium stearate 1.0 g (0.20%)
By the same method as in Example 3, an inner core tablet (weight 25 mg, diameter 4 mm, thickness 1.8 mm) containing 7.5 mg of nifedipine in one tablet was prepared based on the above raw materials. When this inner core tablet was evaluated by a pharmacopoeia second method dissolution test (without sinker), about 45% of nifedipine was dissolved after 45 minutes and after 2 hours.
[0081]
This was compression coated with 120 mg of outer shell tableting powder having the same composition as in Example 3 to produce a 145 mg dry-coated tablet (diameter 7 mm, thickness 4.2 mm) containing 20 mg of nifedipine in one tablet, Furthermore, the same light-shielding film coating as in Example 3 was applied, and the total weight was 151 mg, and the volume was about 150 mm. ^Three Tablets (about 48% of the volume of the commercial product).
[0082]
Example 5
Composition of core containing 60% by weight of nifedipine in one tablet:
Nifedipine (finely pulverized crystals) 30.0 g (60.00%)
HPMC 2910, 3cP 71.8 g (14.36%)
HPC-L 84.0g (16.80%)
Eudragit RLPO 40.0g (8.00%)
Polysorbate 80 2.0g (0.40%)
Ferric sesquioxide (red) 0.2g (0.04%)
Light anhydrous silicic acid 1.0g (0.20%)
Magnesium stearate 1.0 g (0.20%)
By the same method as in Example 1, an inner core tablet (weight 25 mg, diameter 4 mm, thickness 1.8 mm) containing 15 mg of nifedipine in one tablet was prepared based on the above raw materials. When this inner core tablet was evaluated by a pharmacopoeia second method dissolution test (without sinker), about 45% of nifedipine was dissolved after 45 minutes and after 2 hours.
[0083]
Composition of outer shell containing 20.8% by weight of nifedipine:
Nifedipine (finely pulverized crystals) 500g (20.833%)
HPC-L 702g (29.250%)
HPC-M 700g (29.167%)
Eudragit RLPO 480g (20.000%)
Polysorbate 80 10g (0.417%)
Light anhydrous silicic acid 4g (0.167%)
Magnesium stearate 4g (0.167%)
In the same manner as in Example 1, an outer shell tableting powder having the above composition was prepared. The inner core tablet and the outer shell tableting powder 120 mg were tableted in the same manner as in Example 1, and a 145 mg cored tablet (diameter 7 mm, thickness 4.2 mm) containing 40 mg of nifedipine in one tablet. Produced.
[0084]
Further, the surface of the dry-coated tablet was subjected to a light-shielding film coating having the same composition as in Example 3, and the total weight was 151 mg and the volume was about 150 mm. ^Three Tablets (about 48% of the volume of the commercial product).
[0085]
Example 6
Composition of core containing 60% by weight of nifedipine in one tablet:
Nifedipine (finely pulverized crystals) 30.0 g (60.00%)
HPMC 2910, 3cP 59.4g (11.88%)
HPMC 2906, 4000cp 70.0g (14.00%)
HPC-L 24.4g (4.88%)
Eudragit RLPO 44.0g (8.80%)
Ferric sesquioxide (red) 0.2g (0.04%)
Light anhydrous silicic acid 1.0g (0.20%)
Magnesium stearate 1.0 g (0.20%)
By the same method as in Example 1, an inner core tablet (weight 25 mg, diameter 4 mm, thickness 1.8 mm) containing 15 mg of nifedipine in one tablet was prepared based on the above raw materials. When this inner core tablet was evaluated by a pharmacopoeia second method dissolution test (without sinker), about 45% of nifedipine was dissolved after 45 minutes and after 2 hours.
[0086]
This inner core tablet and the same tableting powder 120 mg for the outer shell as in Example 5 were tableted in the same manner as in Example 1, and 145 mg of a dry-coated tablet (diameter 7 mm, thickness) containing 40 mg of nifedipine in one tablet. 4.2 mm). Further, the surface of the dry-coated tablet was subjected to a light-shielding film coating having the same composition as in Example 3, and the total weight was 151 mg and the volume was about 150 mm. ^Three Tablets (about 48% of the volume of the commercial product).
[0087]
Comparative Example 3
Composition of core containing 60% by weight of nifedipine in one tablet:
Nifedipine (finely pulverized crystals) 30.0 g (60.00%)
HPMC 2910, 3cP 79.4 g (15.88%)
HPMC 2906, 4000cP 94.0g (18.80%)
HPC-L 24.4g (4.88%)
Ferric sesquioxide (red) 0.2g (0.04%)
Light anhydrous silicic acid 1.0g (0.20%)
Magnesium stearate 1.0 g (0.20%)
By the same method as in Example 1, an inner core tablet (weight 25 mg, diameter 4 mm, thickness 1.8 mm) containing 15 mg of nifedipine in one tablet was prepared based on the above raw materials. When this inner core tablet was evaluated by a pharmacopoeia second method dissolution test (without sinker), about 45% of nifedipine was dissolved after 45 minutes and after 2 hours.
[0088]
This inner core tablet and 120 mg of tableting powder for the outer shell part having the same composition as in Example 5 were tableted in the same manner as in Example 1, and a 145 mg dry-coated tablet (diameter 7 mm in diameter) containing 40 mg of nifedipine in one tablet. , Thickness 4.2 mm). Further, the surface of the dry-coated tablet was subjected to a light-shielding film coating having the same composition as in Example 3, and the total weight was 151 mg and the volume was about 150 mm. ^Three Tablets (about 48% of the volume of the commercial product).
[0089]
The volume of the nifedipine-containing dry tablet (diameter 7 mm) obtained in Examples 1 to 6 and Comparative Examples 1 to 3 is about 150 mm. ^Three The volume (about 310 mm) of a commercial product (diameter about 9 mm) ^Three ) About 48%.
[0090]
Test example
The dissolution properties of the nifedipine-containing nucleated tablets obtained in Examples 1 to 6 and Comparative Examples 1 to 3 were analyzed using two types of dissolution test methods, namely, the pharmacopeia method 2 dissolution test (using sinker) and the collateral disintegration test method. And compared. In addition, 10 mg, 20 mg or 40 mg (Bayer Pharmaceutical Co., Ltd.) commercially available Adalato CR tablets were used as comparative standard products.
The pharmacopeia method 2 dissolution test (using sinker) was conducted under the following conditions.
[0091]
Test solution: 900 ml of phosphate buffer solution with pH 6.8 containing 1% sodium lauryl sulfate
・ Temperature: 37 ℃
・ Rotation speed: 100 revolutions per minute
Fixing position of sinker: Fixing with acid-resistant wire having a wire diameter of 1.0 mm or less at a position between the liquid surface of the test solution and the upper end of the stirring blade and at a distance of 10 mm from the vessel wall.
Moreover, the pharmacopeiale test apparatus method was implemented on condition of the following.
[0092]
Test solution: 900 ml of phosphate buffer solution with pH 6.8 containing 1% sodium lauryl sulfate
・ Temperature: 37 ℃
・ Use auxiliary panel.
Results of Pharmacopeia Method 2 dissolution test (using sinker):
Each of the dry-coated tablets of Examples 1 to 6 and Comparative Examples 1 to 3 showed almost the same dissolution pattern as the corresponding commercially available nifedipine dry-coated tablets (Adalate CR tablets 10 mg, 20 mg, 40 mg) (FIG. 1, 3, 5).
Results of dissolution test by the collateral disintegration test method:
All of the dry-coated tablets of Examples 1 to 6 showed almost the same dissolution pattern as the corresponding commercially available nifedipine dry-coated tablets, but all of the dry-coated tablets of Comparative Examples 1 to 3 correspond to the commercially available nifedipine dry-coated tablets. Compared with the tablet, the dissolution in the latter half (after 3 hours) was considerably faster (see FIGS. 2, 4 and 6).
[0093]
From the above test results, the usefulness of containing a decay-inhibiting agent in the core was shown.
[0094]
Example 7
Composition of immediate release part containing 50 mg losartan potassium:
Losartan potassium 150.0 g (27.778%)
Lactose 127.8g (23.667%)
Crystalline cellulose 108.0g (20.000%)
Low substituted hydroxypropylcellulose 135.0 g (25,000%)
Sodium lauryl sulfate 1.2g (0.222%)
HPMC 2910 6mm ² / S 12.0g (2.222%)
Light anhydrous silicic acid 3.0g (0.556%)
Magnesium stearate 3.0 g (0.556%)
The above raw materials excluding magnesium stearate were mixed uniformly, granulated, dried and sized. To this, magnesium stearate was added and mixed to obtain a tableting powder. 180 mg of this tableting powder was filled into a mortar of a nucleated tableting machine (Kikusui Clean Press Collect 18DC) equipped with a 9.5 mm diameter mortar and an upper arm and lower arm of 9.5 mmφ10 mmR. Nifedipine-containing nucleated tablets (diameter 7 mm; but without film coating) were placed and tableted with a tableting pressure of 1,500 kgf. In the obtained tablet, the upper surface of the nifedipine-containing nucleated tablet was concentrically exposed on the surface of the outer shell, and the weight was 325 mg, the diameter was 9.5 mm, and the thickness was 5.4 mm. Furthermore, the surface of this tablet was coated with a light-shielding film having the following composition to obtain a tablet having a total weight of 335 mg.
[0095]
Composition of film coating per tablet:
HPMC 2910 (15 cP) 6.00 mg (60.0%)
Polyethylene glycol 4000 2.00 mg (20.0%)
Iron trioxide (red) 0.15mg (1.5%)
Iron sesquioxide (yellow) 0.25mg (2.5%)
Titanium oxide 1.60mg (16.0%)
This tablet contains 20 mg of nifedipine and 50 mg of losartan potassium, its diameter is 9.6 mm, its thickness is 5.5 mm, and its volume is about 320 mm ^Three However, it was almost the same as the commercial product of Nifedipine alone (Adalate CR tablets), and it was a size that could be taken.
[0096]
Example 8
Composition of immediate release part containing valsartan 80mg:
Valsartan 160g (40.0%)
Crystalline cellulose 60g (15.0%)
D-mannitol 60g (15.0%)
Low substituted hydroxypropylcellulose 60g (15.0%)
Crospovidone 40g (10.0%)
Sodium lauryl sulfate 2g (0.5%)
Light anhydrous silicic acid 6g (1.5%)
Sodium stearyl fumarate 12g (3.0%)
The above-mentioned raw material containing a part of sodium stearyl fumarate was uniformly mixed, and dry granulation / size control was performed using a roller compactor (Freund Sangyo) and a roll granulator (Nihon Roll Granulator). The remaining sodium stearyl fumarate was added and mixed to obtain a tableting powder. 200 mg of this tableting powder is filled into a mortar of a dry-coated tableting machine (Kikusui Clean Press Collect 18DC) equipped with a 10 mm diameter mortar and 10 mmφ10 mmR upper and lower punches. A core tablet (diameter 7 mm; no film coating) was placed and tableted with a tableting pressure of 1,800 kgf.
[0097]
In the obtained tablet, the upper surface of the nifedipine-containing nucleated tablet was concentrically exposed on the surface of the outer shell, and the weight was 345 mg, the diameter was 10 mm, and the thickness was 5.6 mm. This was further subjected to the same light-shielding film coating as in Example 7 to obtain tablets having a total weight of 355 mg. This tablet contains 20 mg of nifedipine and 80 mg of valsartan, the diameter is 10.1 mm, the thickness is 5.7 mm, and the volume is about 360 mm ^Three However, it was an increase of only about 15% compared to the commercial product of Nifedipine alone (Adalat CR Tablet), and it was a size that could be taken.
[0098]
Example 9
Composition of immediate release part containing 8 mg of candesartan cilexil:
Candesartan cilexil 16.0g (5.33%)
Lactose 97.4g (32.47%)
Crystalline cellulose 120.0g (40.00%)
Sodium lauryl sulfate 0.6g (0.20%)
Low substituted hydroxypropylcellulose 45.0g (15.00%)
Ac-Di-Sol 15.0g (5.00%)
Light anhydrous silicic acid 3.0g (1.00%)
Sodium stearyl fumarate 3.0 g (1.00%)
The above raw materials excluding sodium stearyl fumarate were uniformly mixed, granulated, dried and sized. To this, magnesium stearate was added and mixed to obtain a tableting powder. 150 mg of this tableting powder is filled into a mortar of a dry-coated tableting machine (Kikusui Clean Press Collect 18DC) equipped with a 9 mm diameter mortar and 9 mmφ10 mmR upper and lower rivets. A core tablet (diameter 7 mm; no film coating) was placed and tableted with a tableting pressure of 1,500 kgf.
[0099]
In the obtained tablet, the upper surface of the nifedipine-containing nucleated tablet was concentrically exposed on the surface of the outer shell, and the weight was 295 mg, the diameter was 9 mm, and the thickness was 5.3 mm. This was further coated with a light-shielding film having the following composition to obtain tablets having a total weight of 304 mg.
[0100]
Composition of film coating per tablet:
HPMC 2910 (15 cP) 5.40 mg (60.0%)
Polyethylene glycol 4000 1.80mg (20.0%)
Ferric sesquioxide (red) 0.17mg (1.9%)
Ferric sesquioxide (yellow) 0.19mg (2.1%)
Titanium oxide 1.4mg (16.0%)
This tablet contains 20 mg of nifedipine and 8 mg of candesartan cilexyl, the diameter is 9.1 mm, the thickness is 5.4 mm, and the volume is about 290 mm ^Three However, it was about 90% of the commercial product of Nifedipine alone (Adalat CR tablet), and it was a size that could be taken sufficiently.
[0101]
Example 10
Composition of immediate release part with a content of 10% by weight of candesartan cilexyl:
Candesartan cilexil 40g (10.00%)
Lactose 111g (27.75%)
Crystalline cellulose 160g (40.00%)
Sodium lauryl sulfate 1g (0.25%)
Low substituted hydroxypropylcellulose 60g (15.00%)
Ac-Di-Sol 20g (5.00%)
Light anhydrous silicic acid 4g (1.00%)
Sodium stearyl fumarate 4g (1.00%)
The above raw materials excluding sodium stearyl fumarate were uniformly mixed, granulated, dried and sized. To this, magnesium stearate was added and mixed to obtain a tablet for a quick release part. 40 mg of this tableting powder was filled into a mortar of a single-punch tablet machine (Korsch EK-0) equipped with a 7 mm diameter mortar and 7 mmφ10 mmR upper and lower rivets. (7 mm in diameter; however, without film coating) was placed and tableted with a tableting pressure of 1,000 kgf.
[0102]
The obtained tablet had a nifedipine-containing nucleated tablet portion and a quick-release portion in two layers, seemingly in parallel, and had a weight of 185 mg, a diameter of 7 mm, and a thickness of 4.8 mm. This was further subjected to a light-shielding film coating having the following composition to obtain a tablet having a total weight of 192 mg.
[0103]
Composition of film coating per tablet:
HPMC 2910 (15 cP) 4.20 mg (60%)
Polyethylene glycol 4000 1.40mg (20%)
Ferric sesquioxide (red) 0.14mg (2%)
Ferric sesquioxide (yellow) 0.14mg (2%)
Titanium oxide 1.12mg (16%)
This tablet contains 20 mg of nifedipine and 4 mg of candesartan cilexil, the diameter is 7.1 mm, the thickness is 4.9 mm, and the volume is about 170 mm ^Three However, it was about 55% of the commercially available nifedipine single agent (Adalate CR tablet), and it was a size that could be swallowed without difficulty.
[0104]
Example 11
The tablet obtained in Example 10 (but before film coating) was further filled with 40 mg of the same tableting powder from above, and tableted with a tableting pressure of 1,500 kgf. The obtained tablet apparently had three layers with the second pharmaceutical component-containing immediate release part sandwiched between the upper and lower surfaces of the nifedipine-containing nucleated tablet, and had a weight of 225 mg, a diameter of 7 mm, and a thickness of 5.4 mm. This was further subjected to a light-shielding film coating having the same composition as in Example 10 to obtain a tablet having a total weight of 232 mg.
[0105]
This tablet contains 20 mg of nifedipine and 8 mg of candesartan cilexyl, the diameter is 7.1 mm, the thickness is 5.5 mm, and the volume is 196.2 mm ^Three It was about 63% of the commercially available nifedipine single agent (Adalate CR tablet), and it was a size that could be taken sufficiently.
[0106]
Example 12
Using a dry-coated tableting machine (Kikusui Clean Press Collect 18DC) equipped with a 7.5mm diameter mortar and 7.5mmφ11mmR upper and lower punches, 10mg of nifedipine in one tablet was carried out in the same manner as in Example 1. Nucleated tablets containing (weight: 145 mg, diameter: 7.5 mm, thickness: 3.8 mm) were prepared, and the tablet for a fast dissolving part as in Example 10 was further formed on the bottom of the nifedipine-containing nucleated tablets. Similarly, 40 mg was press-coated (compression-molded) in layers.
[0107]
The obtained bilayer tablet had a weight of 185 mg, a diameter of 7.5 mm, and a thickness of 4.3 mm. This was further subjected to a light-shielding film coating having the same composition as in Example 10 to obtain a tablet having a total weight of 192 mg.
[0108]
This tablet contains 10 mg of nifedipine and 4 mg of candesartan cilexil, the diameter is 7.6 mm, the thickness is 4.4 mm, and the volume is about 170 mm ^Three However, it was about 55% of the commercially available nifedipine single agent (Adalato CR tablet), and it was a size that could be swallowed even by elderly patients without difficulty.
[0109]
Example 13
Composition of immediate release part containing 12.5 mg of mefluside:
Mefluside 25.0g (8.33%)
Lactose 88.4g (29.47%)
Crystalline cellulose 120.0 g (40.00%)
Sodium lauryl sulfate 0.6g (0.20%)
Low substituted hydroxypropylcellulose 45.0g (15.00%)
Ac-Di-Sol 15.0g (5.00%)
Light anhydrous silicic acid 3.0g (1.00%)
Sodium stearyl fumarate 3.0 g (1.00%)
The above raw materials excluding sodium stearyl fumarate were uniformly mixed, granulated, dried and sized. To this, sodium stearyl fumarate was added and mixed to obtain a tableting powder.
[0110]
150 mg of this tableting powder is filled into a die of a dry-coated tableting machine (Kikusui Clean Press Collect 18DC) equipped with a 9 mm diameter mortar and 9 mmφ10 mmR upper and lower punches. A core tablet (diameter 7 mm; no film coating) was placed and tableted with a tableting pressure of 1,500 kgf.
In the obtained tablet, the upper surface of the nifedipine-containing nucleated tablet was concentrically exposed on the surface of the outer shell, and the weight was 295 mg, the diameter was 9 mm, and the thickness was 5.3 mm. This was further coated with a light-shielding film coating having the same composition as in Example 10 to obtain a tablet having a total weight of 304 mg.
This tablet contains 20 mg of nifedipine and 12.5 mg of mefluside, has a diameter of 9.1 mm, a thickness of 5.4 mm, and a volume of about 290 mm ^Three However, it was about 90% of the commercial product of Nifedipine single agent (Adalato CR Tablet), and it was a size that could be taken sufficiently.
[0111]
Example 14
Composition of immediate release part containing 12.5 mg of hydrochlorothiazide:
Hydrochlorothiazide 25.0 g (8.33%)
Lactose 88.4g (29.47%)
Crystalline cellulose 120.0 g (40.00%)
Sodium lauryl sulfate 0.6g (0.20%)
Low substituted hydroxypropylcellulose 45.0g (15.00%)
Ac-Di-Sol 15.0g (5.00%)
Light anhydrous silicic acid 3.0g (1.00%)
Sodium stearyl fumarate 3.0 g (1.00%)
The above raw materials excluding sodium stearyl fumarate were uniformly mixed, granulated, dried and sized. To this, sodium stearyl fumarate was added and mixed to obtain a tableting powder.
[0112]
150 mg of this tableting powder is filled into a die of a dry-coated tableting machine (Kikusui Clean Press Collect 18DC) equipped with a 9 mm diameter mortar and 9 mmφ10 mmR upper and lower punches. A core tablet (diameter 7 mm; no film coating) was placed and tableted with a tableting pressure of 1,500 kgf.
[0113]
In the obtained tablet, the upper surface of the nifedipine-containing nucleated tablet was concentrically exposed on the surface of the outer shell, and the weight was 295 mg, the diameter was 9 mm, and the thickness was 5.3 mm. This was further coated with a light-shielding film coating having the same composition as in Example 10 to obtain a tablet having a total weight of 304 mg.
[0114]
This tablet has nifedipine 20m and also has a volume of about 290mm ^Three However, it was about 90% of the commercial product of Nifedipine single agent (Adalato CR Tablet), and it was a size that could be taken sufficiently.
[0115]
The dissolution properties of the tablets obtained in Examples 7 to 9 were compared and examined by the following two dissolution test methods: dissolution test by the second method of pharmacopoeia (50 rpm) and dissolution test by the second method of pharmacopoeia (using sinker).
(1) The dissolution test (50 rpm) by the pharmacopoeia second method is carried out under the following conditions, and is a dissolution test condition for examining the dissolution property of the second pharmaceutical ingredient from the tablet.
[0116]
Test liquid: 900 ml of purified water containing 0.3% porsorbate 80
・ Temperature: 37 ℃
-Number of revolutions: 50 revolutions per minute.
(2) The pharmacopoeia second method dissolution test (using a sinker) is performed under the following conditions, and is a dissolution test condition for examining the dissolution property of nifedipine from a tablet.
[0117]
Test solution: 900 ml of phosphate buffer solution with pH 6.8 containing 1% sodium lauryl sulfate
・ Temperature: 37 ℃
・ Rotation speed: 100 revolutions per minute
Fixing position of sinker: Fixing with acid-resistant wire having a wire diameter of 1.0 mm or less at a position between the liquid surface of the test solution and the upper end of the stirring blade and at a distance of 10 mm from the vessel wall.
Results of dissolution test (50 rpm) by Pharmacopeia Method 2:
The dissolution of losartan / potassium from the tablet obtained in Example 7 was almost equivalent to 50 mg of commercially available neurotan tablet (manufactured by Ariyu Pharmaceutical Co., Ltd.) (see FIG. 7). Valsartan from the tablet obtained in Example 8 Is approximately the same as 80 mg of commercially available Diovan tablet (Novatis Pharma Co., Ltd.) (see FIG. 9), and the dissolution of candesartan cilexyl from the tablet obtained in Example 9 is 8 mg of commercially available Blopress tablet (Takeda Pharmaceutical). Kogyo Co., Ltd.) (see FIG. 11).
Results of Pharmacopeia Method 2 dissolution test (using sinker):
The dissolution properties of nifedipine from the tablets obtained in Examples 7 to 9 were equivalent to 20 mg of commercially available Adalato CR tablets (Bayer Pharmaceutical Co., Ltd.) (see FIGS. 8, 10, and 12).
[0118]
From the above results, it was shown that the nifedipine nucleated tablet of the present invention is also useful in combination with the second pharmaceutical ingredient.
[0119]
【The invention's effect】
As a result of successful miniaturization of the core of the nifedipine-containing dry tablet according to the present invention, the volume as the nifedipine-containing dry tablet is reduced by up to about 50% in volume ratio compared to the conventional product (commercially available product). Convenience of taking medicine in Japan has increased. Furthermore, by using the miniaturized nifedipine-containing nucleated tablet of the present invention, second pharmaceuticals such as angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, diuretics and the like that have been conventionally administered in combination with nifedipine. It is possible to easily provide a combination of nifedipine and these second pharmaceutical ingredients, which are combined into one agent while maintaining the bioequivalence of each component, and having a size suitable for oral administration. .
[Brief description of the drawings]
FIG. 1 shows the dissolution pattern of nucleated tablets obtained in Example 1, Example 2 and Comparative Example 1 as a standard formulation using 10 mg adalate CR tablets (commercial product) as a standard second method dissolution test (using sinker). The graph which shows the result of comparative examination.
FIG. 2 shows the results of comparative examination of dissolution patterns of nucleated tablets obtained in Example 1, Example 2 and Comparative Example 1 using 10 mg of Adalato CR Tablet (commercial product) as a standard preparation. Graph showing.
FIG. 3 shows the dissolution pattern of the nucleated tablets obtained in Example 3, Example 4 and Comparative Example 2 using Adalat CR tablets 20 mg (commercially available product) as a standard formulation. The graph which shows the result of having examined in comparison.
FIG. 4 is a result of comparative examination of dissolution patterns of nucleated tablets obtained in Example 3, Example 4 and Comparative Example 2 using 20 mg of adalate CR tablets (commercially available product) as a standard formulation. Graph showing.
FIG. 5 shows the dissolution pattern of the nucleated tablets obtained in Example 5, Example 6 and Comparative Example 3 using the adalate CR tablet 40 mg (commercially available product) as a standard preparation, and the second method dissolution test (using sinker). The graph which shows the result of having examined in comparison.
FIG. 6 shows the results of comparative examination of dissolution patterns of the nucleated tablets obtained in Example 5, Example 6 and Comparative Example 3 using 40 mg of adalate CR tablets (commercial product) as a standard preparation. Graph showing.
FIG. 7 shows the results of comparative examination of the dissolution pattern of losartan / potassium from the tablet obtained in Example 7 using the Neurotan Tablet 50 mg (commercially available product) in a pharmacopeia method 2 dissolution test (without sinker). Graph showing.
FIG. 8 shows the results of comparative examination of the dissolution pattern of nifedipine from the tablets obtained in Example 7 using a pharmacopoeia second method dissolution test (using a sinker) with 20 mg of adalate CR tablets (commercially available product) as a standard formulation. Graph.
FIG. 9 is a graph showing the results of comparative examination of the dissolution pattern of valsartan from the tablets obtained in Example 8 using the Diovan tablet 80 mg (commercially available product) in the pharmacopoeia second method dissolution test (without sinker). .
FIG. 10 shows the results of a comparative examination of the dissolution pattern of nifedipine from the tablet obtained in Example 8 using a pharmacopoeia second method dissolution test (using a sinker), with 20 mg of adalate CR tablet (commercial product) as a standard preparation. Graph.
FIG. 11 shows the results of comparative examination of the dissolution pattern of candesartan cilexyl from the tablets obtained in Example 9 using a pharmacopoeia second method dissolution test (without sinker), using 8 mg of bropress tablet (commercial product) as a standard preparation. Graph showing.
FIG. 12 shows the results of comparative examination of the dissolution pattern of nifedipine from the tablet obtained in Example 9 using a pharmacopoeia second method dissolution test (using a sinker) with 20 mg of adalate CR tablet (commercial product) as a standard preparation. Graph.

Claims (19)

Slow release , forming a matrix with nifedipine 8 to 80% by weight, a hydrophilic gel-forming polymer substance selected from cellulose derivatives and polyvinyl alcohol 15 to 80% by weight, and nifedipine and the hydrophilic gel-forming polymer substance elution of nifedipine containing the disintegration suppression substance 2-30% by weight consisting of pH-independent water-insoluble polymer used as the base or film formulation has been delaying, 2 in diameter. 5-4. 8mm in and and thickness 1. 0 to 2. 5 mm and the core portion is formed by compressing coated onto core portion, nifedipine 5-50 wt%, hydrophilicity selected from cellulose derivatives and polyvinyl alcohol 30-90% by weight of the water-soluble gel-forming polymer material, and matrix together with nifedipine and the hydrophilic gel-forming polymer material. Forming a scan, Ri Do and an outer shell containing 5 to 50 wt% disintegration suppression substance consisting of pH-independent water-insoluble polymer used as the base or film sustained release formulations, naked in tablets state, a is 3. 5 to 5. 5mm der Ru nifedipine-containing press coated tablet diameter from 4.5 to 8. a 5mm and thickness, the dissolution rate of the nifedipine from said tablet,
(A) In dissolution test using sinker by Japanese Pharmacopoeia dissolution test method 2
10-40% after 2 hours,
4 to 30% to 65% later,
6 hours later, 55% or more, and (b) in the dissolution test by the Japanese Pharmacopoeia disintegration test method,
After 3 hours 20-45%,
4 to 30% to 65%
A nifedipine-containing nucleated tablet characterized by   The nifedipine-containing dry-coated tablet according to claim 1, wherein the content of nifedipine in the core is in the range of 10 to 70% by weight based on the weight of the core.   The nifedipine-containing dry-coated tablet according to claim 1 or 2, wherein the hydrophilic gel-forming polymer substance is hydroxypropylcellulose or hydroxypropylmethylcellulose.   The nifedipine-containing dry tablet according to any one of claims 1 to 3, wherein the content of the hydrophilic gel-forming polymer substance in the core is 25 to 70% by weight based on the weight of the core.   The nifedipine-containing dry-coated tablet according to any one of claims 1 to 4, wherein the decay-suppressing agent is an ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer.   The nifedipine-containing dry-coated tablet according to any one of claims 1 to 5, wherein the content of the disintegration-inhibiting agent in the core is 5 to 25% by weight based on the weight of the core.   The nifedipine-containing dry-coated tablet according to any one of claims 1 to 6, wherein the core part and / or the outer shell part further contains a surfactant. In the dissolution test in which the dissolution rate of nifedipine from a tablet having the same composition as the core is not using a sinker according to the second method of dissolution test of the Japanese Pharmacopoeia,
20-70% after 45 minutes,
The nifedipine-containing dry tablet according to any one of claims 1 to 7 , which is 65% or more after 2 hours. The nifedipine-containing dry-coated tablet according to any one of claims 1 to 8 , wherein the content of nifedipine in the outer shell is in the range of 5 to 40% by weight based on the weight of the outer shell. The nifedipine-containing dry tablet according to any one of claims 1 to 9 , wherein the content of the hydrophilic gel-forming polymer substance in the outer shell is 45 to 85% by weight based on the weight of the outer shell. . The nifedipine-containing dry-coated tablet according to any one of claims 1 to 10 , wherein the content of the decay-inhibiting agent in the outer shell is 7.5 to 40% by weight based on the weight of the outer shell. The dissolution rate of nifedipine from a tablet having the same composition as the outer shell part
(A) In dissolution test using sinker by Japanese Pharmacopoeia dissolution test method 2
20-50% after 2 hours,
40-90% after 4 hours,
More than 75% after 6 hours,
And (b) in the dissolution test by the Japanese Pharmacopoeia disintegration test method,
30-60% after 3 hours,
40-90% after 4 hours,
The nifedipine-containing dry tablet according to any one of claims 1 to 11 , wherein The dissolution rate of nifedipine from the tablet
(A) In dissolution test using sinker by Japanese Pharmacopoeia dissolution test method 2
15-35% after 2 hours,
After 4 hours 35-60%,
60% or more after 6 hours,
And (b) in the dissolution test by the disintegration test method of the Japanese Pharmacopoeia,
After 3 hours 25-40%,
After 4 hours 35-60%,
The nifedipine-containing dry-coated tablet according to any one of claims 1 to 12 . The fast dissolving part containing the second pharmaceutical ingredient is partially compression-coated on the nifedipine-containing dry tablet according to any one of claims 1 to 13 so that at least a part of the surface of the dry tablet is exposed. The tablet characterized by comprising. The tablet according to claim 14 , comprising a structure in which at least one of an upper surface, a bottom surface, and a side surface of the nifedipine-containing nucleated tablet is exposed to the outside and a quick release part is disposed. The tablet according to claim 14 or 15 , wherein the second pharmaceutical ingredient is an angiotensin II receptor antagonist, an angiotensin converting enzyme inhibitor or a diuretic. The tablet according to any one of claims 14 to 16 , wherein the second pharmaceutical ingredient is candesartan cilexetil or enalapril maleate. Dissolution rate of the second pharmaceutically active ingredient from the immediate release portion containing a second pharmaceutically active ingredient in a dissolution test according to the dissolution test second method of Japanese Pharmacopoeia, one of the claims 14-17 is 80% or more after 1 hour The tablet according to crab. The tablet according to any one of claims 14 to 18 , wherein the tablet has a diameter of 12 mm or less and a thickness of 6 mm or less.

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