JP6849007B2 - 造粒組成物、及びその製造方法 - Google Patents
造粒組成物、及びその製造方法 Download PDFInfo
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- JP6849007B2 JP6849007B2 JP2019071948A JP2019071948A JP6849007B2 JP 6849007 B2 JP6849007 B2 JP 6849007B2 JP 2019071948 A JP2019071948 A JP 2019071948A JP 2019071948 A JP2019071948 A JP 2019071948A JP 6849007 B2 JP6849007 B2 JP 6849007B2
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Description
なお、上記特許文献1以外の先行技術文献としては、下記特許文献2〜5が挙げられる。
1. 核粒子と、被覆粒子と、前記核粒子同士及び前記核粒子と前記被覆粒子とを結合して粒状の形態を保持する結合剤とを具備し、前記核粒子と結合剤とからなる造粒物本体の周囲に前記被覆粒子が付着してなり、前記結合剤は高分子物質を溶媒に溶解又は分散したものであり、前記被覆粒子はアスペクト比11以下で、かつ前記結合剤に不溶なものであり、該被覆粒子の少なくとも一部はそのまま表面に露出しており、前記核粒子及び/又は結合剤に薬効成分又は生体機能性成分が含有され、更に界面の展開面積比Sdrの平均値が150〜700であることを特徴とする造粒組成物。
2. 上記結合剤が、それのみでは粒状の形態を保持し得ないほどゲル強度が弱いか、又はゲル強度を発揮し得ないほど希薄な濃度の高分子物質溶液又は高分子物質分散液である1記載の造粒組成物。
3. 上記核粒子として、粒子状の薬効成分又は生体機能性成分を含有する1又は2記載の造粒組成物。
4. 上記薬効成分又は生体機能性成分が疎水性液体に溶解又は分散され、この疎水性液体の液滴が上記結合剤中に分散している1又は2に記載の造粒組成物。
5. 疎水性液体が、モノカプリル酸プロピレングリコール、ジカプリル酸プロピレングリコール、ジカプリン酸プロピレングリコール、モノラウリン酸プロピレングリコール、モノオレイン酸プロピレングリコール、安息香酸ベンジル、オクチルデシルトリグリセリド、オレイン酸、クエン酸トリエチル、ジメチルポリシロキサン、シンナムアルデヒド、中鎖モノ・ジグリセリド、中鎖脂肪酸トリグリセリド、トリアセチン、ピペロニルブトキシド、フタル酸ジエチル、フタル酸ジブチル、ブチルフタリルブチルグリコレート、ミリスチン酸オクチルドデシル、酪酸エチルから選ばれる1種又は2種以上である4記載の造粒組成物。
6. 上記造粒物本体に、上記核粒子として上記被覆粒子と同じ粒子を含有している1〜5のいずれかに記載の造粒組成物。
7. 上記造粒物本体が、ゲル化作用を有さない高分子物質を水以外の溶媒に溶解した結合剤と、該溶媒に不溶な薬効成分又は生体機能性成分の粒子からなる核粒子とで形成されたものである1〜3のいずれかに記載の造粒組成物。
8. 上記被覆粒子が、エチルセルロース、トウモロコシデンプン、コメデンプン、コムギデンプン、バレイショデンプン、ステアリン酸カルシウム、炭酸マグネシウム、低置換度カルボキシメチルスターチナトリウム、デンプングリコール酸ナトリウム、無水ケイ酸、ケイ酸マグネシウム、ケイソウ土、ベントナイト、ゼオライト、二酸化ケイ素、カンテン末、クロスカルメロースナトリウム、クロスポピドン、タルクから選ばれる1種又は2種以上の粉末である1〜7のいずれかに記載の造粒組成物。
9. 上記結合剤が、ゼラチン、カラギーナン、寒天、ポリエチレングリコール、メチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メタクリル酸コポリマー、アミノアルキルメタクリレートコポリマー、アンモニオアルキルメタクリレートコポリマー、アクリル酸エチル・メタクリル酸メチルコポリマー、ヒプロメロースフタレート、ヒプロメロースアセテートサクシネート、セルロースアセテートフタレート及びポリビニルアセテートフタレートから選ばれる1種又は2種以上の高分子物質を溶媒に溶解又は分散したものである1〜8のいずれかに記載の造粒組成物。
10. 1〜9のいずれかに記載の造粒組成物を製造する方法であって、
上記核粒子と、上記結合剤と、上記薬効成分又は生体機能性成分とを含む造粒溶液の液滴を、上記被覆粒子を流動させた流動床に滴下して、該液滴からなる粒子状の造粒物本体の表面に上記被覆粒子を付着させ、該被覆粒子に前記結合剤の溶媒を吸収させて粒状に造粒することにより、前記造粒物本体の周囲に前記被覆粒子が付着してなる造粒組成物を得ることを特徴とする造粒組成物の製造方法。
本発明の造粒組成物は、上記のとおり、核粒子と結合剤とからなる造粒物本体の周囲に被覆粒子が付着して当該被覆粒子の粒子形状に応じた凹凸を有する形態を有し、上記造粒物本体を形成する上記核粒子及び/又は結合剤に薬効成分又は機能性成分が含有されたものである。
なお、薬効成分又は生体機能性成分は、これらに限定されるものではなく、本発明の造粒組成物に適用可能なものであれば、いずれのものも使用することができる。
精製水40gにパラオキシ安息香酸ブチル10mgを加え、95℃の水浴上で加温してパラオキシ安息香酸ブチルを溶解させた。室温まで冷却後、ゼラチン5gを加え、55〜65℃に加温して、ゼラチン水溶液(結合剤)を得た。
[界面の展開面積比Sdrの測定法]
粒子を両面テープに固定して白金蒸着を行った試料を白色光干渉顕微鏡(Bruker Nano Inc. 製、Contour GT−K)で観察して、無作為に選択した2粒の粒子についてそれぞれ計測を行い、解析ソフトウェアVision64(Ver.5.41)によりStatic Filter処理(Type=Median、size=6)およびMask Data処理(0.05mm×0.05mm)を行って、Sdrを求めた。
精製水35gにゼラチン4gを加え、55〜65℃に加温して、ゼラチン水溶液(結合剤)を得た。一方、クエン酸トリエチル3gにシクロスポリン(薬効成分)1gとパラオキシ安息香酸ブチル10mgを加え、55〜65℃に加温してシクロスポリンとパラオキシ安息香酸ブチルを溶解させ、薬効成分溶液を得た。
クエン酸トリエチル及びシクロスポリンを配合せず、かつ核粒子のトウモロコシデンプンの配合量を1gに減量したこと以外は実施例2と同様にして造粒溶液を調製した。この造粒溶液を用い実施例2と同様にして造粒粒子を得、同様に粒度分布を測定したところ、平均粒径はd50が269μmで、d10は140μm、d90は435μmであり、粒径の均一性が高いものであった。このように、核粒子が少量で、かつ被覆粒子と同一材料であっても、均一な被覆粒子が得られることが確認された。
使用するゼラチンとメトトレキサートの質量をともに2.5gに減じて、造粒溶液に核粒子として2.5gのエチルセルロース(日新化成株式会社、製品名:エトセル100FP、d50=19μm、形状:鱗片状、アスペクト比:1.81)を加えたこと以外は実施例1と同様にして造粒溶液を得、また流動床にも核粒子と同じエチルセルロースを用いたこと以外は実施例1と同様にして造粒粒子を製した。この造粒粒子の粒度分布を測定したところ、平均粒径はd50が230μmで、d10は166μm、d90は294μmであり、粒径の均一性が高いものであった。また、得られた造粒粒子の界面の展開面積比Sdrを、実施例1と同様にして求めたところ、測定1回目:268、測定2回目:328、平均値:298であった。
核粒子として造粒溶液に2.5gのタルク(富士タルク工業株式会社、製品名:タルクML115、d50=6.3μm、形状:略球状乃至鱗片状、アスペクト比:1.3)を加えたこと以外は実施例3と同様にして造粒溶液を得、また流動床にも核粒子と同じタルクを用いたこと以外は実施例3と同様にして造粒粒子を製した。この造粒粒子の粒度分布を測定したところ、平均粒径はd50が248μmで、d10は202μm、d90は300μmであり、粒径の均一性が高いものであった。また、得られた造粒粒子の界面の展開面積比Sdrを、実施例1と同様にして求めたところ、測定1回目:186、測定2回目:240、平均値:213であった。
流動床に結晶セルロース(日本製紙株式会社、製品名:KCフロックW−200G、d50=13μm、形状:柱状乃至針状、アスペクト比:13.9)を用いたこと以外は実施例1と同様にして造粒粒子を得、粒度分布を測定したところ、平均粒径はd50が159μmで、d10は88μm、d90は296μmであり、粒径の均一性が高いものであった。また、得られた造粒粒子の界面の展開面積比Sdrを、実施例1と同様にして求めたところ、測定1回目:757、測定2回目:3500、平均値:2129であった。
造粒溶液に核粒子としてトウモロコシデンプンを加えないこと以外は実施例2と同様にして造粒溶液を得た。この造粒溶液のゼラチン濃度は9.3%であることからゲル強度を発揮し得ないほど希薄な溶液であった。この造粒溶液40gを、実施例2と同様にトウモロコシデンプン粉末の流動床に射出したところ、流動床のトウモロコシデンプン粉末が互いに結着し始めて様々な形状の約1cm大の無数の塊が形成された。これは、射出した液滴が実質的な粒子強度を持たなかったために不定形となって、流動床のトウモロコシデンプン粉末を単に湿潤させて、互いに結着させたものと推察された。
エタノール40gに、ヒドロキシプロピルセルロース(HPC)4g及びパラオキシ安息香酸ブチル0.01gを加えて溶解させHPCエタノール溶液(結合剤)を得た。このHPCエタノール溶液に薬効成分としてメトトレキサート(粒径:d50=22μm)4gを加えて混合し、造粒溶液を得た。この造粒溶液は、パラオキシ安息香酸ブチル及びHPCが完全に溶解したHPCエタノール溶液中に、薬効成分のメトトレキサート粒子が均一に分散されたものであった。
核粒子として造粒溶液に2.5gのウォラストナイト(関西マテック株式会社、製品名:KGP−H65、d50=6.3μm、形状:針状、アスペクト比:10.6)を加えたこと以外は実施例3と同様にして造粒溶液を得、また流動床にも核粒子と同じウォラストナイトを用いたこと以外は実施例3と同様にして造粒粒子を製した。この造粒粒子の粒度分布を測定したところ、平均粒径はd50が382μmで、d10は252μm、d90は496μmであり、粒径の均一性が高いものであった。また、得られた造粒粒子の界面の展開面積比Sdrを、実施例1と同様にして求めたところ、測定1回目:690、測定2回目:557、平均値:624であった。
上記各実施例及び比較例で得られた造粒粒子を用い、下記評価条件に従って、錠剤に製剤する際に用いられる賦形剤と混合したときの粉末の分散性を目視により評価し、下記基準により造粒粒子が偏析を引き起こさないかを判定した。結果を表1に示す。
(評価基準)
◎:全体にわたって均一に分散しており偏析していない。
○:造粒粒子同士が隣接することなく分散しているが、分散の密度にはわずかにムラが認められる。
△:造粒粒子同士が凝集して局在している箇所が認められる。
×:複数の相に分離して偏析している。
賦形剤であるD−マンニトール(製品名:グラニュトールS、d 50 は83μm)又は乳糖水和物(製品名:ダイラクトーズR、d 50 は171μm)に、実施例1及び3〜6並びに比較例1及び下記比較例3,4の造粒組成物を、5重量%又は15重量%加えて5分間振とう混合し、造粒粒子の分散度合を目視で評価し、判定した。試験方法をより具体的に説明すると、50mLの透明なポリプロピレン性ねじ付遠沈管に9.5g又は8.5gのD−マンニトール又は乳糖水和物を量りとり、さらに0.5g又は1.5gの造粒組成物を上方から重層してねじ付フタを締め、50mLチューブ用チューブローテーターに固定し、毎分20回転の速度で10分間回転させた。その際、比較例3としてレボフロキサシン細粒10%「DSEP」(第一三共株式会社、実施例1と同様にして測定した界面の展開面積比Sdrは測定1回目:21、測定2回目:50、平均値:36)、比較例4としてフトラフール腸溶顆粒50%(大鵬薬品株式会社、実施例1と同様にして測定した界面の展開面積比Sdrは測定1回目:4、測定2回目:5、平均値:5)を用いた。目視による分散度合は、実施例1及び3〜6並びに比較例1についてはメトトレキサートに特徴的な黄色粒子の色味を指標に、比較例3については特徴的な淡黄色粒子の色味を指標に、比較例4については押出し造粒粒子に特徴的な粒子形状を指標に評価した。
実施例1,3〜6及び比較例1で製した造粒組成物につき、参考として、被覆粒子の大きさ(平均粒径d50)及び顕微鏡による撮像画像上での形状(アスペクト比)と造粒粒子のSdr値との関係を下記表2に示す。
上記参考例で得られた造粒粒子を用いて、下記方法により表3に示す組成の口腔内崩壊錠を製した。得られた口腔内崩壊錠について、水を服用せずに口腔内で崩壊させたときの舌触りを5人のパネリストにより官能評価し、本発明の造粒粒子が不快なザラザラ感を引き起こさないかを判定した。いずれのパネリストにおいても、この口腔内崩壊錠は口腔内で約50〜65秒後に崩壊し、崩壊途中も崩壊後も、口腔内に固い粒の感触や不快なザラザラ感を感じなかった。
表3に示した各成分を秤量し、40cm×70cmの透明ポリエチレン袋に入れて封をし、手で10分間転倒混合して打錠用混合末を調製し、ロータリー式打錠機(PICCOLA D8)で、円形扁平型(直径7mm、1錠あたりの重量120mg)の口腔内崩壊錠を製した。
2 結合剤
3 造粒物本体
4 被覆粒子
m 薬効成分又は生体機能性成分
h 薬効成分又は生体機能性成分が分散又は溶解した疎水性液体の液滴
Claims (10)
- 核粒子と、被覆粒子と、前記核粒子同士及び前記核粒子と前記被覆粒子とを結合して粒状の形態を保持する結合剤とを具備し、前記核粒子と結合剤とからなる造粒物本体の周囲に前記被覆粒子が付着してなり、前記結合剤は高分子物質を溶媒に溶解又は分散したものであり、前記被覆粒子はアスペクト比11以下で、かつ前記結合剤に不溶なものであり、該被覆粒子の少なくとも一部はそのまま表面に露出しており、前記核粒子及び/又は結合剤に薬効成分又は生体機能性成分が含有され、更に界面の展開面積比Sdrの平均値が150〜700であることを特徴とする造粒組成物。
- 上記結合剤が、それのみでは粒状の形態を保持し得ないほどゲル強度が弱いか、又はゲル強度を発揮し得ないほど希薄な濃度の高分子物質溶液又は高分子物質分散液である請求項1記載の造粒組成物。
- 上記核粒子として、粒子状の薬効成分又は生体機能性成分を含有する請求項1又は2記載の造粒組成物。
- 上記薬効成分又は生体機能性成分が疎水性液体に溶解又は分散され、この疎水性液体の液滴が上記結合剤中に分散している請求項1又は2記載の造粒組成物。
- 疎水性液体が、モノカプリル酸プロピレングリコール、ジカプリル酸プロピレングリコール、ジカプリン酸プロピレングリコール、モノラウリン酸プロピレングリコール、モノオレイン酸プロピレングリコール、安息香酸ベンジル、オクチルデシルトリグリセリド、オレイン酸、クエン酸トリエチル、ジメチルポリシロキサン、シンナムアルデヒド、中鎖モノ・ジグリセリド、中鎖脂肪酸トリグリセリド、トリアセチン、ピペロニルブトキシド、フタル酸ジエチル、フタル酸ジブチル、ブチルフタリルブチルグリコレート、ミリスチン酸オクチルドデシル、酪酸エチルから選ばれる1種又は2種以上である請求項4記載の造粒組成物。
- 上記造粒物本体に、上記核粒子として上記被覆粒子と同じ粒子を含有している請求項1〜5のいずれか1項に記載の造粒組成物。
- 上記造粒物本体が、ゲル化作用を有さない高分子物質を水以外の溶媒に溶解した結合剤と、該溶媒に不溶な薬効成分又は生体機能性成分の粒子からなる核粒子とで形成されたものである請求項1〜3のいずれか1項に記載の造粒組成物。
- 上記被覆粒子が、エチルセルロース、トウモロコシデンプン、コメデンプン、コムギデンプン、バレイショデンプン、ステアリン酸カルシウム、炭酸マグネシウム、低置換度カルボキシメチルスターチナトリウム、デンプングリコール酸ナトリウム、無水ケイ酸、ケイ酸マグネシウム、ケイソウ土、ベントナイト、ゼオライト、二酸化ケイ素、カンテン末、クロスカルメロースナトリウム、クロスポピドン、タルクから選ばれる1種又は2種以上の粉末である請求項1〜7のいずれか1項に記載の造粒組成物。
- 上記結合剤が、ゼラチン、カラギーナン、寒天、ポリエチレングリコール、メチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メタクリル酸コポリマー、アミノアルキルメタクリレートコポリマー、アンモニオアルキルメタクリレートコポリマー、アクリル酸エチル・メタクリル酸メチルコポリマー、ヒプロメロースフタレート、ヒプロメロースアセテートサクシネート、セルロースアセテートフタレート及びポリビニルアセテートフタレートから選ばれる1種又は2種以上の高分子物質を溶媒に溶解又は分散したものである請求項1〜8のいずれか1項に記載の造粒組成物。
- 請求項1〜9のいずれか1項に記載の造粒組成物を製造する方法であって、
上記核粒子と、上記結合剤と、上記薬効成分又は生体機能性成分とを含む造粒溶液の液滴を、上記被覆粒子を流動させた流動床に滴下して、該液滴からなる粒子状の造粒物本体の表面に上記被覆粒子を付着させ、該被覆粒子に前記結合剤の溶媒を吸収させて粒状に造粒することにより、前記造粒物本体の周囲に前記被覆粒子が付着してなる造粒組成物を得ることを特徴とする造粒組成物の製造方法。
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