JP2019508464A - クロピドグレル及びアスピリンを含む複合製剤 - Google Patents
クロピドグレル及びアスピリンを含む複合製剤 Download PDFInfo
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- JP2019508464A JP2019508464A JP2018548696A JP2018548696A JP2019508464A JP 2019508464 A JP2019508464 A JP 2019508464A JP 2018548696 A JP2018548696 A JP 2018548696A JP 2018548696 A JP2018548696 A JP 2018548696A JP 2019508464 A JP2019508464 A JP 2019508464A
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- clopidogrel
- aspirin
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Abstract
Description
クロピドグレル硫酸水素塩とPEG 6000、マンニトール300 DC、MCC 102及びL−HPCを下記表1の含有量で混合した。表1の含有量は、1錠剤当りの含有量を示す。その後、前記混合物とコロイダルシリコンジオキシド、タルク及びステアリルフマル酸ナトリウム(PRUV(登録商標))を後混合した後、打錠した。その結果、打錠時にスティッキングとキャッピング現象が発生した。
下記表2の成分及び含有量に応じて錠剤を製造した。クロピドグレル硫酸水素塩とコロイダルシリコンジオキシドをまず混合した後、前記混合物とPEG 6000、マンニトール300 DC、MCC 102、及びL−HPCを後混合した。その後、滑沢剤であるタルク及びPRUV(登録商標)を添加した後、打錠した。表2の含有量は、1錠剤当りの含有量を示す。この場合、コロイダルシリコンジオキシドを後混合し、MCC 102を使用した前記比較例1及び2とは異なり、実施例1の錠剤は、打錠時にスティッキングやキャッピングの障害が発生しなかった。前記成分の含有量を表2に示した。
打錠時のスティッキング及びキャッピング障害現象をさらに向上させるために、乾燥減量が低い(1.5重量%)MCC112を使用した。クロピドグレル硫酸水素塩とコロイダルシリコンジオキシドをまず混合した後、前記混合物とPEG 6000、マンニトール300 DC、MCC 112、L−HPC、CL−PVP及びPVP K−30を後混合した。その後、滑沢剤であるPRUV(登録商標)を添加した後、打錠した。前記成分の含有量をそれぞれ表3に示した。表3の含有量は、1錠剤当りの含有量を示す。
コロイダルシリコンジオキシドが崩解剤を含む本願の剤形に及ぼす影響を把握するために、前記実施例2〜7と、主にコロイダルシリコンジオキシドの含有量を変えて下記表4の組成を有する錠剤を製造した。
前記実施例2〜7により製造された錠剤を対象に崩解試験を行った。崩解試験は、大韓薬典の一般試験法中、崩解試験法に従った(試験液:水)。その結果は、下記表5の通りであり、対照群としてプラビックス錠を使用した。実施例2〜7の場合、崩解時間が11分以内と示され、対照群より崩解時間が短縮されることが分かった。実施例2〜7の場合、打錠の障害なしに打錠が可能であった。
前記表4で記載された実施例8〜10及び比較例3〜6のクロピドグレル錠剤をもってスティッキング、キャッピング実験及び崩解時間の実験(本願実験例1と同様の方法を使用)をした結果は下記表6の通りである。
− クロピドグレル硫酸塩コーティング錠の製造
1錠剤当りヒドロキシプロピルセルロース0.5mg及びネオコート8038HP 3.5mgと、有機溶媒である塩化メチレン(有機溶媒中、5重量%)及びエタノール(有機溶媒中、99.5重量%)を混合してフィルムコーティング液を調製した後、前記実施例3で製造したクロピドグレル硫酸塩の裸錠をコーティングした。
これとは別途に、1カプセル当り塩化メチレン600mg及びエタノール300mgの混合溶媒にアスピリン(Rhodia、タイ)100mg及びヒドロキシプロピルメチルセルロース(Shin-Etsu、日本)5.0mgを溶解させた後、平均粒径600〜710μmの球状白糖(IPS、イタリア)顆粒30mgに流動層コーティング機(Glatt GmbH Process Technology、ドイツ)で、前記混合物を噴霧してアスピリン外核を形成した。次いで、塩化メチレン250mg及びエタノール250mgの混合溶媒にヒドロキシプロピルメチルセルロースフタレート(Shin-Etsu、日本、置換度200731、粘度40mPa.s)9.5mg、ヒドロキシプロピルメチルセルロース(置換度2910、粘度15mPa.s)5mg及びトリエチルシトレート(Morimurabros.INC、日本)0.5mgを溶解させた後、前記アスピリン外核に噴霧して腸溶層を形成することにより、アスピリン顆粒を製造した。
前記製剤例1と同様に実施するものの、前記実施例3で製造したクロピドグレル硫酸塩の裸錠を使用し、アスピリン顆粒の製造時に下記成分の含有量を表7のように製剤例1とは異にして、クロピドグレル錠剤75mg及びアスピリン75mgを含む複合製剤を製造した。
− クロピドグレル顆粒の製造
1カプセル当り無水エタノール300mg、塩化メチレン1000mgを溶媒にしてクロピドグレル硫酸水素塩97.875mg、ヒドロキシプロピルメチルセルロース25.5mgを溶解させた後、平均粒径600〜710μmの球状白糖(IPS、イタリア)顆粒103.625mgに流動層コーティング機(Glatt GmbH Process Technology、ドイツ)で、前記混合物を噴霧してクロピドグレル外核を形成した。次いで、無水エタノール200mg、塩化メチレン500mgにヒドロキシプロピルメチルセルロース20mgとポリエチレングリコール3.0mgを溶解させた後、前記クロピドグレルの外核に噴霧して速放保護層を形成することにより、クロピドグレル顆粒を製造した。
前記製剤例1のアスピリン顆粒と同様の方法で製造した。
製剤例1で製造された複合製剤を使用してカプセルがゼラチンである場合とHPMCである場合に分けて、試験条件40℃、75%RHに露出して過酷試験を行って性状の変化を観察した。その結果は下記表8の通りである(〇:良好な状態、×:不良状態)。
前記製剤例1により製造された本発明の複合製剤に対して6ヶ月間の加速試験(温度40℃、75%RH PEボトル)を行って安定性を評価し、評価の結果を表9に示した。
Claims (16)
- クロピドグレル、その異性体またはその薬学的に許容可能な塩を含むクロピドグレル錠剤;及び
アスピリン、その異性体またはその薬学的に許容可能な塩を含むアスピリンコア、及び前記コアを包む腸溶性コーティング層を含むアスピリン含有粒子を含む複合製剤。 - 前記クロピドグレル錠剤は、崩壊剤をさらに含む、請求項1に記載の複合製剤。
- 前記崩解剤は、クロピドグレル錠剤の総重量基準で2〜8重量%で含まれる、請求項2に記載の複合製剤。
- 前記崩解剤は、澱粉グリコール酸ナトリウム、トウモロコシ澱粉、ジャガイモ澱粉、プレゼラチン化澱粉、ベントナイト、モンモリロナイト、ビーガム(veegum)、微結晶性セルロース、ヒドロキシプロピルセルロース、カルボキシメチルセルロース、アルギン酸ナトリウム、アルギン酸、クロスカルメロース(croscarmellose)ナトリウム、グアーガム、キサンタンガム、架橋ポリビニルピロリドン(crospovidone)及びその混合物からなる群の選択された一つ以上である、請求項2に記載の複合製剤。
- 前記クロピドグレル錠剤は、乾燥減量が5重量%以下の賦形剤をさらに含む、請求項1に記載の複合製剤。
- 前記クロピドグレル錠剤は、乾燥減量が1.5重量%以下の賦形剤をさらに含む、請求項5に記載の複合製剤。
- 前記賦形剤は、微結晶セルロースである、請求項5に記載の複合製剤。
- 前記クロピドグレル錠剤は、コロイド性二酸化ケイ素をさらに含む、請求項1に記載の複合製剤。
- 前記コロイド性二酸化ケイ素の含有量は、クロピドグレル錠剤の総重量基準で2〜10重量%である、請求項8に記載の複合製剤。
- 前記腸溶性コーティング層は、シェラック、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、ヒドロキシプロピルメチルセルロースフタレート、セルロースアセテートフタレート、セルロースアセテート、ポリビニルアルコールフタレート、メタクリル酸−メタクリル酸メチル共重合体、メチルアクリル酸−メタクリル酸メチル−メタクリル酸共重合体、メタクリル酸−エチルアクリル酸共重合体及びその混合物からなる群から選択された一つ以上の腸溶性コーティング剤を含む、請求項1に記載の複合製剤。
- 前記複合製剤は、カプセル剤形である、請求項1〜10のいずれか一項に記載の複合製剤。
- 前記カプセルの素材は、ゼラチンまたはヒドロキシプロピルメチルセルロース(HPMC)である、請求項11に記載の複合製剤。
- 前記クロピドグレル錠剤は、崩解時間が11分以内である、請求項1に記載の複合製剤。
- クロピドグレル、その異性体またはその薬学的に許容可能な塩、及びコロイド性二酸化ケイ素をまず混合した後、崩壊剤を添加してクロピドグレル錠剤を準備する段階;
アスピリン、その異性体またはその薬学的に許容可能な塩を含むアスピリンコアを準備する段階;及び
前記アスピリンコアを腸溶性コーティング剤でコーティングする段階を含む、クロピドグレル錠剤及びアスピリンコアを含む複合製剤の製造方法。 - 前記崩解剤は、クロピドグレル錠剤の総重量基準で2〜8重量%で含まれる、請求項14に記載の複合製剤の製造方法。
- 前記コロイド性二酸化ケイ素の含有量は、クロピドグレル錠剤の総重量基準で2〜10重量%である、請求項14に記載の複合製剤の製造方法。
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US20110038931A1 (en) * | 2008-02-22 | 2011-02-17 | Hanall Biopharma Co., Ltd. | Composite preparation |
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KR101675501B1 (ko) * | 2011-11-02 | 2016-11-14 | 한국유나이티드제약 주식회사 | 클로피도그렐 및 아스피린의 복합제제 |
KR101473268B1 (ko) * | 2012-03-09 | 2014-12-16 | 주식회사유한양행 | 클로피도그렐과 아스피린을 포함하는 약학 조성물 및 그의 제조방법 |
JP6004524B2 (ja) * | 2012-07-11 | 2016-10-12 | 大原薬品工業株式会社 | クロピドグレル硫酸塩含有錠剤の製造方法 |
KR101502588B1 (ko) * | 2013-05-01 | 2015-03-16 | 한국유나이티드제약 주식회사 | 클로피도그렐 및 아스피린의 복합제제 |
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