JP5572706B2 - コーティング粒子及びコーティング粒子の製造方法 - Google Patents
コーティング粒子及びコーティング粒子の製造方法 Download PDFInfo
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- JP5572706B2 JP5572706B2 JP2012519380A JP2012519380A JP5572706B2 JP 5572706 B2 JP5572706 B2 JP 5572706B2 JP 2012519380 A JP2012519380 A JP 2012519380A JP 2012519380 A JP2012519380 A JP 2012519380A JP 5572706 B2 JP5572706 B2 JP 5572706B2
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Description
核粒子表面に種々の成分をコーティングする方法としては、スプレーコーティング法、ディップコーティング法などの湿式法と、回転式混合法や二軸混練法などの乾式法とが知られている(特許文献1、特許文献2、非特許文献1参照)。
一方、乾式法は、コーティング率が低くなる場合があり、またコーティング層と核粒子との密着性が低く、コーティング層が剥がれやすい場合がある。
そこで、本発明は、上記のような不具合を減らした、胃溶性固形製剤、腸溶性固形製剤、徐放性固形製剤、苦味抑制性固形製剤などに好適なコーティング粒子及びコーティング粒子の製造方法を提供することを課題とするものである。
〈1〉核粒子に、コーティング層が被覆されてなるコーティング粒子であって、該コーティング層がヒドロキシアルキルセルロース、バインダーならびに溶出制御基剤および/またはシリカを含む層であり、該ヒドロキシアルキルセルロースの体積平均粒子径が、0.1〜20μmである、コーティング粒子。
〈2〉前記バインダーが、ポリアルキレングリコール、ポリアルキレングリコール高級脂肪酸エステル、高級脂肪酸、高級アルコール、高級アルコールエステルおよび天然ワックスからなる群から選ばれる少なくとも1種である、前記〈1〉に記載のコーティング粒子。
〈4〉第1工程で得られた粒子に溶出制御基剤およびバインダーを乾式コーティングする第2工程を含む、前記〈3〉に記載のコーティング粒子の製法。
〈5〉第1工程で得られた粒子をシリカでオーバーコーティングする第3工程を含む、前記〈3〉に記載のコーティング粒子の製法。
〈6〉第1工程で得られた粒子に溶出制御基剤およびバインダーを乾式コーティングする第2工程と、第2工程で得られた粒子をシリカでオーバーコーティングする第3工程を含む、前記〈3〉または〈4〉に記載のコーティング粒子の製法。
〈7〉前記〈3〉〜〈6〉のいずれか一つに記載のコーティング粒子の製法により製造されたコーティング粒子。
本発明のコーティング粒子は、核粒子に、コーティング層が被覆されてなるものである。該コーティング層は、ヒドロキシアルキルセルロースおよびバインダーを含む層である。
該核粒子は、速放性製剤および放出持続型製剤(徐放性製剤)などの放出制御型製剤であってもよい。核粒子は、慣用の添加剤を含有していてもよい。該添加剤としては、例えば、賦形剤、崩壊剤、結合剤、滑沢剤、着色剤、pH調整剤、pH緩衝剤、界面活性剤、徐放化剤、安定化剤、酸味料、香料、流動化剤、清涼化剤、甘味料、旨み成分、甘味増強剤などが挙げられる。これら添加剤は、製剤分野において慣用の量が用いられる。
医薬や農薬の有効成分である上記化合物のうち、塩形成部位を有する化合物では、その生理的又は薬学的に許容可能な塩(特に、医薬的または農薬的に許容可能な塩など)なども含まれる。
滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、蔗糖脂肪酸エステル、フマル酸ステアリルナトリウムなどが挙げられる。
pH調整剤としては、クエン酸塩、リン酸塩、炭酸塩、酒石酸塩、フマル酸塩、酢酸塩、アミノ酸塩などが挙げられる。
pH緩衝剤としては、クエン酸−クエン酸ナトリウム緩衝剤などが挙げられる。
界面活性剤として、ラウリル硫酸ナトリウム、ポリソルベート、ポリオキシエチレンポリオキシプロピレングリコールなどが挙げられる。
安定化剤としては、例えば、トコフェロール、エデト酸四ナトリウム、ニコチン酸アミド、シクロデキストリン類などが挙げられる。
香料としては、例えば、メントール、ハッカ油、レモン油、バニリンなどが挙げられる。
流動化剤としては、例えば、軽質無水ケイ酸、含水二酸化ケイ素などが挙げられる。
清涼化剤としては、カンフル及びボルネオールなどのテルペン系化合物(モノテルペンアルコールなど)などの他、この前記テルペン系化合物を含む精油、エッセンス又はパウダー;ペパーミント、スペアミント、クールミントなどの精油、エッセンス又は粉末(パウダー);前記の精油又はエッセンスを粉末状担体(例えば、デキストリンなど)に吸着させたもの、精油又はエッセンスを賦形材(アラビアガムなど)及び液体基剤(水、アルコールなど)と混合し、粉粒化したものなどが挙げられる。
旨み成分としては、アミノ酸系旨み成分(アミノ酸又はその塩、例えば、グルタミン酸、グルタミン酸ナトリウム、グルタミン酸カリウム、グルタミン酸塩酸塩、グアニル酸ナトリウム、イノシン酸、イノシン酸ナトリウム、アルギニン−グルタミン酸塩、アスパラギン酸、アスパラギン酸ナトリウム、グリシン、アラニンなど)、ペプチド系旨み成分(L−グルタミル−L−グルタミン酸、L−グルタミル−L−セリンなどのジペプチド;トリ−L−グルタミン酸、L−グルタミル−L−グリシル−L−セリンなどのトリペプチドなど)、カルボン酸系旨み成分(コハク酸ナトリウムなどのカルボン酸塩など)などが挙げられる。
さらに鹹味(塩味)を有する甘味増強剤(又は鹹味剤)を含有してもよい。このような甘味増強剤としては、塩化ナトリウム、塩化カリウム、リン酸塩(リン酸水素カリウム、リン酸水素ナトリウムなど)などが例示できる。甘味増強剤(又は鹹味剤)は中性塩、例えば、ナトリウムイオン及び/又は塩素イオン(塩化物イオン)として解離する塩である場合が多い。
バインダーとしては、例えば、有機脂肪酸(ラウリン酸、パルミチン酸、ミリスチン酸、ステアリン酸など)、有機脂肪酸のエステル誘導体、高級アルコール(セチルアルコール、ステアリルアルコールなど)、グリセリン脂肪酸エステル(グリセリルモノステアレートなど)、ポリエチレングリコール類(マクロゴール6000など)、天然ワックス(カルナバワックス、ライスワックスなど)などのワックス様物質などが挙げられる。これらのうち、ポリアルキレングリコール、ポリアルキレングリコール高級脂肪酸エステル、高級脂肪酸、高級アルコール、高級アルコールエステルおよび天然ワックスからなる群から選ばれる少なくとも1種が好ましく、ポリエチレングリコールが特に好ましい。バインダーは親水性のものが好ましい。また、融点が、40〜70℃のものが好ましく、50〜65℃のものが特に好ましい。
コーティング層におけるバインダーの含有量は、特に制限されないが、コーティング粒子中に、0.1〜20重量%であることが好ましく、0.5〜15重量%であることがより好ましい。
コーティング層における、ヒドロキシアルキルセルロースとバインダーとの重量比(ヒドロキシアルキルセルロース/バインダー)は特に制限されないが、好ましくは、99/1〜50/50、より好ましくは95/5〜70/30である。
他のコーティング基剤としては、高分子基剤、無機粉粒、薬物などの有効成分、などが挙げられる。また、前記において、核粒子に含有させることができるものとして例示した添加剤を他のコーティング基剤として用いることができる。
アクリル系高分子としては、例えば、アミノアルキルメタアクリレートコポリマーE、メタアクリル酸−メチルメタアクリレートコポリマーなどが挙げられる。生体内分解性高分子としては、例えば、L−乳酸、D−乳酸、DL−乳酸、グリコール酸、ε−カプロラクトン、N−メチルピロリドンなどからなるホモポリマー、コポリマー又はこれらポリマーの混合物、ポリカプロラクタム、キチン、キトサンなどが挙げられる。ポリビニル系高分子としては、例えば、ポリビニルアセタールジエチルアミノアセテート、PVAコポリマーなどが挙げられる。
水溶性コーティング基剤としては、メチルセルロース、カルボキシメチルセルロースナトリウム、ポリビニルピロリドンなどが挙げられる。
コーティング方法としては、造粒ハンドブック(日本粉体工業技術協会編、オーム社)、経口投与製剤の処方設計(京都大学大学院薬学研究科教授 橋田充編、薬業時報社)、粒子設計工学(粉体工学会編、産業図書)、粒子設計と製剤技術(粉体工学会製剤と粒子設計部会 部会長 川島嘉明編、薬業時報社)のような刊行物に記載されている方法が挙げられるが、本発明では乾式コーティング法が好ましい。
また、コーティング層用粉末を1回の操作で乾式コーティングしてもよいし、コーティング層用粉末を複数回に分けて乾式コーティングしてもよい。
容量50mlの三角フラスコに、粒子径の範囲が75〜106μmのアセトアミノフェン原末2.0gを入れた。該フラスコをロータリーエヴァポレーターに装着した。
それに、体積平均粒子径6.27μmのヒドロキシプロピルセルロース(商品名:HPC−H、日本曹達社製)0.1gと、体積平均粒子径11.23μmのポリエチレングリコール(PEG6000;融点55〜60℃)0.01gとを添加し、室温で1分間混合させた。次いで、55℃の恒温液槽に前記フラスコを浸して、10分間、77rpmで回転させた。この操作を15回繰返した。
なお、コーティング率は、分級後のコーティング粒子の重量からアセトアミノフェンの仕込み重量を差し引き、それをコーティング処理に使用したヒドロキシプロピルセルロース、ポリエチレングリコールおよびメタアクリル酸コポリマーの合計重量で除算することで、求められた値である。
容量50mlの三角フラスコに、粒子径の範囲が75〜106μmのアセトアミノフェン原末2.0gを入れた。該フラスコをロータリーエヴァポレーターに装着した。
それに、体積平均粒子径6.27μmのヒドロキシプロピルセルロース(商品名:HPC−H、日本曹達社製)0.1gと、体積平均粒子径11.23μmのポリエチレングリコール(PEG6000;融点55〜60℃)0.01gとを添加し、室温で1分間混合させた。次いで、55℃の恒温液槽に前記フラスコを浸して、10分間、77rpmで回転させた。この操作を10回繰返した。
なお、コーティング率は、分級後のコーティング粒子の重量からアセトアミノフェンの仕込み重量を差し引き、それをコーティング処理に使用したヒドロキシプロピルセルロース、ポリエチレングリコールおよびメタアクリル酸コポリマーの合計重量で除算することで、求められた値である。
容量50mlの三角フラスコに、粒子径の範囲が75〜106μmのアセトアミノフェン原末2.0gを入れた。該フラスコをロータリーエヴァポレーターに装着した。
それに、体積平均粒子径6.27μmのヒドロキシプロピルセルロース(商品名:HPC−H、日本曹達社製)0.1gと、体積平均粒子径11.23μmのポリエチレングリコール(PEG6000;融点55〜60℃)0.01gとを添加し、室温で1分間混合させた。次いで、55℃の恒温液槽に前記フラスコを浸して、10分間、77rpmで回転させた。この操作を20回繰返した。
なお、コーティング率は、分級後のコーティング粒子の重量からアセトアミノフェンの仕込み重量を差し引き、それをコーティング処理に使用したヒドロキシプロピルセルロース、およびポリエチレングリコールの合計重量で除算することで、求められた値である。
溶出試験は、JP XV パドル法に従って、パドル回転数100rpm、900ml純水、37℃の条件で実施した。アセトアミノフェンの溶出濃度は吸光度(285nm)から求めた。結果を図1に示す。
また、アセトアミノフェン原末をヒドロキシアルキルセルロース溶液でコーティングした固形製剤は、粘着性があり、流動性が悪かった。これに対して、実施例1〜3で得られたコーティング粒子は、いずれも、流動性に優れていた。
本出願は、2010年6月8日出願の日本特許出願2010−130663に基づくものであり、その内容はここに参照として取り込まれる。
Claims (7)
- 核粒子に、コーティング層が被覆されてなるコーティング粒子であって、
該コーティング層がヒドロキシアルキルセルロース、バインダーならびに溶出制御基剤および/またはシリカを含む層であり、
該ヒドロキシアルキルセルロースの体積平均粒子径が、0.1〜20μmである、コーティング粒子。 - 前記バインダーが、ポリアルキレングリコール、ポリアルキレングリコール高級脂肪酸エステル、高級脂肪酸、高級アルコール、高級アルコールエステルおよび天然ワックスからなる群から選ばれる少なくとも1種である、請求項1に記載のコーティング粒子。
- 核粒子に、ヒドロキシアルキルセルロースおよびバインダーを乾式コーティングする第1の工程を含む、コーティング粒子の製法。
- 第1工程で得られた粒子に溶出制御基剤およびバインダーを乾式コーティングする第2の工程を含む、請求項3に記載のコーティング粒子の製法。
- 第1の工程で得られた粒子をシリカでオーバーコーティングする第3の工程を含む、請求項3に記載のコーティング粒子の製法。
- 第1工程で得られた粒子に溶出制御基剤およびバインダーを乾式コーティングする第2工程と、第2工程で得られた粒子をシリカでオーバーコーティングする第3工程を含む、請求項3または4に記載のコーティング粒子の製法。
- 請求項3〜6のいずれか一項に記載のコーティング粒子の製法により製造されたコーティング粒子。
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US9107851B2 (en) * | 2012-10-15 | 2015-08-18 | New Jersey Institute Of Technology | Solventless mixing process for coating pharmaceutical ingredients |
JP6624662B2 (ja) * | 2017-11-09 | 2019-12-25 | 日本臓器製薬株式会社 | アセトアミノフェン製剤及びその製造方法 |
EP3927313A1 (en) * | 2019-02-22 | 2021-12-29 | Catalent U.K. Swindon Zydis Limited | Preserving functionally-coated api particles produced by solventless mixing processes in aqueous suspension |
EP3975999A4 (en) * | 2019-06-03 | 2023-07-19 | Theriva Biologics, Inc. | ALKALINE PHOSPHATASE FORMULATIONS AND THEIR USES |
KR102159576B1 (ko) * | 2020-07-28 | 2020-09-24 | 전남대학교산학협력단 | 핑거프린트 기반의 빔 간섭 제거 시스템 및 방법 |
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ES2654643T3 (es) | 2018-02-14 |
SI2570120T1 (en) | 2018-04-30 |
KR20130018908A (ko) | 2013-02-25 |
HUE035763T2 (en) | 2018-05-28 |
HRP20180026T1 (hr) | 2018-02-23 |
CN102933204A (zh) | 2013-02-13 |
EP2570120A4 (en) | 2014-03-19 |
EP2570120A1 (en) | 2013-03-20 |
US20130071481A1 (en) | 2013-03-21 |
WO2011155451A1 (ja) | 2011-12-15 |
JPWO2011155451A1 (ja) | 2013-08-01 |
KR101445957B1 (ko) | 2014-09-29 |
PT2570120T (pt) | 2018-01-09 |
US10888520B2 (en) | 2021-01-12 |
EP2570120B1 (en) | 2017-10-25 |
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