JP2004010501A - Solid preparation and method for producing the same - Google Patents
Solid preparation and method for producing the same Download PDFInfo
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- JP2004010501A JP2004010501A JP2002162580A JP2002162580A JP2004010501A JP 2004010501 A JP2004010501 A JP 2004010501A JP 2002162580 A JP2002162580 A JP 2002162580A JP 2002162580 A JP2002162580 A JP 2002162580A JP 2004010501 A JP2004010501 A JP 2004010501A
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- weight
- active ingredient
- pharmacologically active
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- excipient
- Prior art date
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- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims abstract description 20
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、高脂血症や家族性高コレステロール血症などの治療に有用なラクトン環を有する薬理活性成分を含む製剤及びその製造方法に関する。
【０００２】
【従来の技術】
シンバスタチンやロバスタチンなどのラクトン環含有薬理活性成分は、コレステロール生合成系の律速酵素であるＨＭＧ（３−ヒドロキシ−３−メチルグルタリル）−ＣｏＡ還元酵素を特異的かつ拮抗的に阻害し、肝臓のＬＤＬ受容体活性を増強させることによって、血清総コレステロールを速やかにかつ強力に低下させる作用を有する。従って、前記薬理活性成分は、高脂血症や家族性高コレステロール血症などの疾病に対する経口投与製剤として有用である。
【０００３】
経口投与製剤としては、通常、賦形剤、結合剤、崩壊剤などを造粒して打錠した錠剤や顆粒剤などの固形製剤として調製される。しかし、ラクトン環を有する化合物は、温度、湿度、光などの作用によって分解されるため、このような固形製剤中においても安定性が低く、特に、高温及び高湿における非包装状態では安定性が低下する。
【０００４】
このようなラクトン環を有する活性成分のうち、シンバスタチンについて、各種賦形剤との物理化学的相溶性に関する報告が行われている（Ｂｕｌｌ．Ｆａｃ．Ｐｈａｒｍ．Ｃａｉｒｏ Ｕｎｉｖ．，：Ｖｏｌ ３８．Ｎｏ．１．（２０００），ｐ．２１−３２）。この文献では、シンバスタチンは、ポリエチレングリコール、トウモロコシデンプン、セルロースアセテート・フタレート、カルボキシメチルセルロース、ステアリン酸マグネシウム、ラクトースとは相互作用（反応）し、ポリビニルピロリドン、クロスカルメロース、結晶セルロースとは相溶性に優れると記載されている。
【０００５】
一方、３ｒｄＣＥＮＴＲＡＬ ＥＵＲＯＰＥＡＮ ＳＹＭＰＯＳＩＵＭ ＯＮ ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ ＴＥＣＨＮＯＬＯＧＹ（ＦａｒｍＶｅｓｔｎ １９９９；５０）には、プラバスタチンナトリウムと各種賦形剤との相溶性に関する報告が行われている。この文献では、プラバスタチンナトリウムは、ラクトース、ヒドロキシプロピルセルロース、クエン酸ナトリウム水和物などに対しては安定であり、微結晶セルロース、クロスカルメロース、ステアリン酸マグネシウムなどによっても僅かな崩壊を示すのみであるが、リン酸水素ナトリウムの水和物に対しては非常に不安定でラクトン環が形成され易いと記載されている。
【０００６】
特表平７−５０８２８０号公報には、微晶質セルロースを用いずに、荷電樹脂として、ポリアクリル酸ナトリウムなどのアクリル酸系樹脂などを用いて、シンバスタチンやロバスタチンなどの薬剤を球状多粒子に製造する方法が開示されている。この文献には、シンバスタチン８．７重量％、リン酸二ナトリウム７重量％、リン酸モノナトリウム１．７重量％、ドデシル硫酸ナトリウム２１．７重量％、塩化ナトリウム１７．４重量％、ポリビニルピロリドン（商品名：Ｐｏｖｉｄｏｎｅ２９−３２Ｋ）８．７重量％、メタクリル酸ジビニルベンゼン共重合体３４．８重量％及びブチル化ヒドロキシアニソール０．０００２重量％を含む粒子や、メタクリル酸ジビニルベンゼン共重合体３５重量％、クエン酸２５重量％、クエン酸三ナトリウム２５重量％、ポリビニルピロリドン（商品名：Ｐｏｖｉｄｏｎｅ ９０Ｋ）５重量％及びロバスタチン１０重量％を含む粒子などが記載されている。しかし、この粒子も高温及び高湿条件での安定性は充分でない。
【０００７】
【発明が解決しようとする課題】
従って、本発明の目的は、ラクトン環を有する薬理活性成分を長期間に亘り安定化できる固形製剤及びその製造方法を提供することにある。
【０００８】
本発明の他の目的は、高温及び高湿度などの過酷な条件下においても、長期間に亘り、ラクトン環を有する薬理活性成分の分解を抑制して安定化できる固形製剤及びその製造方法を提供することにある。
【０００９】
本発明のさらに他の目的は、溶出性にも優れる固形製剤及びその製造方法を提供することにある。
【００１０】
【課題を解決するための手段】
本発明者は、前記目的を達成するため鋭意検討した結果、クロスポビドンを用いることなく、非セルロース系賦形剤及び安定化剤を用いて固形製剤を調製すると、ラクトン環を含有する薬理活性成分を安定化できることを見出し、本発明を完成した。
【００１１】
すなわち、本発明の固形製剤は、ラクトン環を有する薬理活性成分と賦形剤と安定化剤とを含む製剤であって、賦形剤が非セルロース系賦形剤で構成され、かつクロスポビドンを実質的に含有しない。また、前記製剤は、イオン性官能基を有する高分子化合物を実質的に含まず、非イオン性結合剤を含有してもよい。前記製剤において、ラクトン環を有する薬理活性成分はシンバスタチンやロバスタチンなどで構成されている。前記薬理活性成分の粒径は、累積粒度分布において、５０％粒径（メジアン径）３．５μｍ以上、かつ９０％粒径２０μｍ以下であってもよい。前記製剤において、賦形剤が糖類やデンプン類などで構成され、安定化剤が有機酸で構成されていてもよい。前記製剤には、さらに、抗酸化剤などが含まれていてもよい。前記製剤を構成する成分の割合は、例えば、前記薬理活性成分１００重量部に対して、賦形剤５０〜１００００重量部（特に１００〜５０００重量部）程度、安定化剤１〜５０重量部（特に３〜４０重量部）程度である。さらに、安定化剤の割合は、賦形剤１００重量部に対して、０．００１〜５０重量部（特に０．０１〜３０重量部）程度である。
【００１２】
本発明には、ラクトン環を有する薬理活性成分、非セルロース系賦形剤、及び安定化剤を含み、クロスポビドンを実質的に含有しない組成物を造粒して固形製剤を製造する方法も含まれる。
【００１３】
また、本発明には、結晶セルロース及びクロスポビドンを実質的に用いることなく、非セルロース系賦形剤及び安定化剤を用いて固形製剤を調製することにより、ラクトン環を有する薬理活性成分の安定性を改善する方法も含まれる。
【００１４】
【発明の実施の形態】
本発明の固形製剤には、ラクトン環を有する薬理活性成分と賦形剤と安定化剤とが含まれている。本発明の固形製剤には、さらに抗酸化剤が含まれていてもよい。
【００１５】
［ラクトン環を有する薬理活性成分］
ラクトン環を有する薬理活性成分としては、ラクトン環を有する限り特に制限されず、例えば、シンバスタチンやロバスタチンなどのラクトン環を有するスタチン類などが例示できる。シンバスタチン又はロバスタチンは、下記式（１）で表される。
【００１６】
【化１】
（式中、Ｒ１はメチル基を示し、Ｒ２はメチル基又は水素原子を示す）
前記式（１）において、Ｒ１及びＲ２がメチル基である化合物がシンバスタチンで、Ｒ１がメチル基でＲ２が水素原子である化合物がロバスタチンである。シンバスタチン及びロバスタチンは、ＨＭＧ−ＣｏＡ還元酵素阻害剤で、高脂血症や家族性高コレステロール血症などの疾病に対する経口投与製剤として用いられている。
【００１８】
ラクトン環を有する薬理活性成分の粒子径は、製剤化が可能である限り特に制限されず、累積粒度分布における５０％粒径が３．５μｍ以上［好ましくは３．７μｍ以上（例えば、３．７〜９μｍ）、さらに好ましくは４μｍ以上（例えば、４〜７μｍ）］であり、かつ９０％粒径が２０μｍ以下［好ましくは１５μｍ以下（例えば、７〜１５μｍ）、さらに好ましくは１０μｍ以下（例えば、８〜１０μｍ）］程度であるのが好ましい。薬理活性成分の粒径がこの範囲にあると、製剤の溶出性が適度な範囲となり、薬理活性が体内で効果的に発現する。
【００１９】
ラクトン環を有する薬理活性成分の含有量は、製剤に対して、０．１〜５０重量％、好ましくは０．５〜３０重量％、さらに好ましくは１〜２０重量％（特に３〜１０重量％）程度である。
【００２０】
［賦形剤］
賦形剤は非セルロース系賦形剤で構成されている。賦形剤としては、例えば、糖類やデンプン類、タルク、炭酸カルシウム、炭酸マグネシウムなどが例示できる。
【００２１】
糖類としては、例えば、単糖類（アラビノース、キシロース、ブドウ糖、果糖、ガラクトース、マンノース、ソルボースなど）、オリゴ糖類［ショ糖（例えば、白糖や精製白糖、粉糖、グラニュー糖など）、乳糖、麦芽糖、還元麦芽糖、イソマルトースなど］、糖アルコール（キシリトール、エリスリトール、ソルビトール、マンニトールなど）などが挙げられる。これらの糖類は、単独で又は二種以上組み合わせて使用できる。これらの糖類のうち、通常、ブドウ糖や果糖などの単糖類、白糖、乳糖、還元麦芽糖などのオリゴ糖類、マンニトールやソルビトールなどの糖アルコールが使用される。
【００２２】
デンプン類としては、例えば、デンプン（トウモロコシデンプン、小麦デンプン、馬鈴薯デンプン、米デンプン、甘藷デンプンなど）などが挙げられる。これらのデンプン類のうち、通常、トウモロコシデンプン、小麦デンプン、馬鈴薯デンプンなどのデンプンが使用される。
【００２３】
これらの賦形剤は、単独で又は二種以上組み合わせて使用できる。これらの賦形剤のうち、糖類又はデンプン類が好ましく、例えば、乳糖などの糖類と、トウモロコシデンプンなどのデンプン類とを組み合わせて用いてもよい。糖類とデンプン類とを組み合わせて用いる場合は、両者の割合（重量比）は、糖類／デンプン類＝９９／１〜５０／５０、好ましくは９５／５〜６０／４０、さらに好ましくは９０／１０〜７０／３０程度である。
【００２４】
賦形剤の割合は、薬理活性成分１００重量部に対して、５０〜１００００重量部、好ましくは１００〜５０００重量部、さらに好ましくは３００〜３０００重量部（特に５００〜３０００重量部）程度である。
【００２５】
［安定化剤］
安定化剤は、製剤のｐＨを酸性域に保ち、薬理活性成分のラクトン環を保護する役割を有する。安定化剤としては、無機酸（リン酸など）や有機酸などの酸成分を用いてもよいが、有機酸、特に低分子量の有機酸が好ましい。
【００２６】
有機酸としては、例えば、脂肪族オキシカルボン酸（グリコール酸、乳酸、オキシ酪酸、グリセリン酸などのＣ２−６脂肪族オキシカルボン酸など）、脂肪族オキシポリカルボン酸（クエン酸、リンゴ酸、酒石酸などＣ２−６脂肪族オキシポリカルボン酸など）、芳香族オキシカルボン酸（サリチル酸、オキシ安息香酸、没食子酸など）、脂肪族カルボン酸（酢酸、プロピオン酸などのＣ２−１０脂肪族飽和ポリカルボン酸など、ソルビン酸などのＣ４−１０脂肪族不飽和ポリカルボン酸など）、脂肪族ポリカルボン酸（シュウ酸、マロン酸、コハク酸、グルタル酸、アジピン酸などのＣ２−１０脂肪族飽和ポリカルボン酸など、マレイン酸、フマル酸などのＣ４−１０脂肪族不飽和ポリカルボン酸など）、芳香族カルボン酸（安息香酸など）などが挙げられる。これらの有機酸は水和物であってもよい。これらの安定化剤は、単独で又は二種以上組み合わせて使用できる。
【００２７】
これらの安定化剤のうち、通常、乳酸などの脂肪族オキシカルボン酸、クエン酸やリンゴ酸などの脂肪族オキシポリカルボン酸、酢酸やプロピオン酸などの脂肪族カルボン酸、マレイン酸やフマル酸などの脂肪族ポリカルボン酸などが使用され、特に、クエン酸やクエン酸水和物などの脂肪族オキシカルボン酸が好ましく使用される。
【００２８】
安定化剤の割合は、薬理活性成分１００重量部に対して、１〜５０重量部、好ましくは３〜４０重量部、さらに好ましくは５〜３０重量部（特に１０〜３０重量部）程度である。
【００２９】
本発明の固形製剤において、賦形剤と安定化剤との割合（重量比）は、賦形剤１００重量部に対して、安定化剤０．００１〜５０重量部、好ましくは０．０１〜３０重量部、さらに好ましくは０．１〜１０重量部（特に０．３〜５重量部）である。
【００３０】
［抗酸化剤］
抗酸化剤としては、慣用の抗酸化剤が使用でき、例えば、ブチルヒドロキシアニソール（ＢＨＡ）、ジブチルヒドロキシトルエン（ＢＨＴ）、アスコルビン酸、アスコルビン酸ナトリウム、エリソルビン酸、エリソルビン酸ナトリウム、トコフェロール、没食子酸プロピル、グアヤク脂、ノルジヒドログアヤレチック酸、ピロ亜硫酸ナトリウム、亜硫酸水素ナトリウム、ロンガリットなどが挙げられる。
【００３１】
これらの抗酸化剤は、単独で又は二種以上組み合わせて使用できる。
【００３２】
これらの抗酸化剤のうち、ブチルヒドロキシアニソール、ジブチルヒドロキシトルエン、アスコルビン酸、特にブチルヒドロキシアニソールが好ましい。
【００３３】
抗酸化剤の割合は、薬理活性成分に対して、１０〜５０００ｐｐｍ、好ましくは２０〜１０００ｐｐｍ、さらに好ましくは３０〜５００ｐｐｍ程度である。
【００３４】
さらに、本発明の固形製剤には、結合剤が含まれていてもよい。
【００３５】
［結合剤］
結合剤としては、慣用の結合剤が使用でき、例えば、タンパク質類（ゼラチンなど）、多糖類（アラビアゴム、プルラン、デキストリン、トラガント、アルギン酸ナトリウムなど）、加工デンプン（α化デンプン、部分α化デンプン、加水分解デキストリン、エステル化デンプン、エーテル化デンプンなど）、セルロース誘導体（メチルセルロース、エチルセルロースなどのＣ１−４アルキルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシメチルプロピルセルロースなどのヒドロキシＣ１−４アルキルセルロース、カルボキシメチルセルロースなどのカルボキシＣ１−４アルキルセルロースなど）、ビニル系重合体（ポリビニルピロリドン、ポリビニルアルコールなど）などが挙げられる。これらの結合剤のうち、非イオン性結合剤（例えば、ヒドロキシプロピルセルロースのヒドロキシＣ１−４アルキルセルロースや、部分α化デンプンなどの加工デンプンなど）が好ましい。これらの結合剤は、単独で又は二種以上組み合わせて使用できる。
【００３６】
結合剤の割合は、薬理活性成分１００重量部に対して、５〜１００重量部、好ましくは１０〜８０重量部、さらに好ましくは２０〜７０重量部（特に３０〜５０重量部）程度である。
【００３７】
［他の添加剤］
前記組成物には、他の添加剤、例えば、流動化剤（例えば、軽質無水ケイ酸など）、滑沢剤（ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク等）、崩壊剤（低置換度ヒドロキシプロピルセルロースなど）、界面活性剤（例えば、アルキル硫酸ナトリウムなどのアニオン系界面活性剤、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、及びポリオキシエチレンヒマシ油誘導体等の非イオン系界面活性剤等）、脂質（例えば、炭化水素、ワックス類、高級脂肪酸とその塩、高級アルコール、脂肪酸エステル、硬化油等）、着色剤（例えば、タール色素、カラメル、ベンガラ、酸化チタン等）、矯味剤［例えば、甘味剤（ショ糖、乳糖、マンニトール、キシリトール、サッカリン、サッカリンナトリウム、アスパルテーム、ステビオシド等）、香料等］、湿潤剤［例えば、ポリエチレングリコール（マクロゴール）、グリセリン、プロピレングリコール等］、緩衝剤、吸着剤、防腐剤などの保存剤、帯電防止剤、崩壊延長剤等が含まれていてもよい。
【００３８】
これらの添加剤は、単独で又は二種以上組み合わせて使用でき、特に最終製剤中の含量に制限はないが、例えば、薬理活性成分１００重量部に対して、流動化剤１〜５０重量部（特に５〜３０重量部）、滑沢剤０．１〜３０重量部（特に１〜２０重量部）程度である。
【００３９】
なお、本発明の固形製剤は、クロスポビドン（架橋化ポリビニルピロリドン、登録商標：コリドンＣＬ）を実質的に含有しない。さらに、本発明の固形製剤は、イオン性官能基を有する高分子化合物を実質的に含有しない。このような高分子化合物には、カルボキシル基やスルホン酸基、アミノ基などの官能基を有する非糖類系高分子化合物などが含まれ、例えば、カルボキシメチルセルロースカルシウム、デンプングリコール酸ナトリウム（カルボキシメチルスターチナトリウム）、クロスカルメロースナトリウムなどのイオン性崩壊剤や、ポリアクリル酸ナトリウムなどのアクリル酸系樹脂、ポリスチレンスルホン酸ナトリウムなどのスルホン酸基含有樹脂などが例示できる。
【００４０】
［固形製剤］
本発明の固形製剤は、種々の使用形態に使用することが可能であり、特に限定されないが、例えば、錠剤、散剤、細粒剤、顆粒剤、丸剤、カプセル剤、ドライシロップ剤などの経口投与に適した形態で使用できる。これらの形態のうち、錠剤、顆粒剤、細粒剤等、特に錠剤が好ましい。さらに、錠剤は、糖衣錠、ゼラチン被包錠、フィルムコーティング錠、腸溶性コーティング錠、有核錠（圧縮被包錠）、多層錠（二層又は三層錠）などであってもよい。固形製剤の平均粒子径は０．０１〜１０ｍｍ、好ましくは０．０５〜５ｍｍ、さらに好ましくは０．１〜３ｍｍ程度である。錠剤の平均径は、５〜１０ｍｍ程度である。
【００４１】
［固形製剤の製造方法］
本発明の固形製剤は、剤型に応じた慣用の方法、例えば、薬理活性成分、賦形剤及び安定化剤を含む組成物を造粒することにより得ることができる。
【００４２】
造粒には、慣用の造粒法、例えば、押出造粒法、転動造粒法、流動層造粒法、混合・攪拌造粒法、噴霧乾燥造粒法、振動造粒法などの湿式造粒法や、圧縮成形造粒法などの乾式造粒法が採用できる。これらの造粒法のうち、通常、押出造粒法、転動造粒法、流動層造粒法、混合・攪拌造粒法などの湿式造粒法を好ましく利用できる。例えば、錠剤の場合、例えば、薬理活性成分と、賦形剤と、必要により抗酸化剤や安定化剤、結合剤などとを湿式造粒し、乾燥させた後、必要により滑沢剤や流動化剤などの添加剤を加えて打錠して得ることができる。湿式造粒における溶媒は、特に制限されないが、水及び低級アルコール（例えば、エタノールなど）から選択された少なくとも一種の溶液、安全性の面から、特に水やエタノール溶液が好ましく使用できる。
【００４３】
このようにして得られた固形製剤は、シンバスタチンの場合、１日につき１回の投与が通常であり、その投与量は、成人（体重６０ｋｇ）において、薬理活性成分換算で１日当たり５〜２０ｍｇ程度である。
【００４４】
シンバスタチンやロバスタチンなどの薬理活性成分を含む製剤は、ＨＭＧ−ＣｏＡ還元酵素を阻害する作用を有するので、高脂血症や家族性高コレステロール血症などの疾病に対する経口投与製剤として有用である。また、ヒトの他、各種哺乳動物（例えば、マウス、ラット、ウサギ、イヌ、ネコ、ブタ、ウシ、ウマ等）の治療剤としても使用できる。
【００４５】
本発明では、結晶セルロース及びクロスポビドンを実質的に用いることなく、非セルロース系賦形剤及び安定化剤を用いて固形製剤を調製することにより、ラクトン環を有する薬理活性成分の安定性が改善される。
【００４６】
【発明の効果】
本発明では、ラクトン環を有する薬理活性成分を含む固形製剤であっても、長期間に亘り、前記薬理活性成分を安定化できる。特に、高温及び高湿度などの過酷な条件下においても、長期間に亘り、前記薬理活性成分の分解を抑制して安定化できる。さらに、前記固形製剤は溶出性にも優れている。
【００４７】
【実施例】
以下に、実施例に基づいて本発明をより詳細に説明するが、本発明はこれらの実施例により限定されるものではない。なお、以下の例において「％」及び「部」は、重量基準である。また、固形製剤の保存試験及び溶出性試験の方法と、使用した主な成分の内容を以下に示す。
【００４８】
［保存試験］
固形製剤のシンバスタチンの含有量を高速液体クロマトグラフィー（ＨＰＬＣ）で測定した後、密栓したガラス瓶に６０℃、６０％ＲＨの条件下で２週間及び４週間保存した後、２週間後と４週間後とのシンバスタチンの含有量をＨＰＬＣで測定した。初期のシンバスタチン含有量に対する保存後のシンバスタチン含有量の割合を、主剤含量比（重量％）として示した。
【００４９】
［溶出性試験］
固形製剤におけるシンバスタチンの水溶液中での溶出率（１５分後）を、溶出試験機（富山産業（株）製）を用いて、日局一般試験法・溶出試験法第２法（パドル法）に準じて測定した。
【００５０】
［使用した主な成分］
（薬理活性成分）
シンバスタチン−１：累積粒度分布における５０％粒径（Ｄ５０）４．０２μｍ、９０％粒径（Ｄ９０）９．２６μｍ
シンバスタチン−２：Ｄ５０（１．８２μｍ）、Ｄ９０（３．５３μｍ）
シンバスタチン−３：Ｄ５０（３．４１μｍ）、Ｄ９０（６．８２μｍ）
シンバスタチン−４：Ｄ５０（１０μｍ）、Ｄ９０（２３．７μｍ）。
【００５１】
（賦形剤）
乳糖：２００メッシュ
トウモロコシデンプン
結晶セルロース：アビセル（旭化成（株）製）。
【００５２】
（崩壊剤）
クロスポビドン：コリドンＣＬ（ＢＡＳＦ社製）
（安定化剤）
クエン酸一水和物
（抗酸化剤）
ＢＨＡ：ブチルヒドロキシアニソール
（結合剤）
ヒドロキシプロピルセルロース：信越化学（株）製
（流動化剤）
軽質無水ケイ酸：アドソリダー１０１（フロイント産業（株）製）
（滑沢剤）
ステアリン酸マグネシウム。
【００５３】
実施例１
微量のＢＨＡを含有するシンバスタチン−１、乳糖、及びトウモロコシデンプンを均一に攪拌混合し、これにクエン酸一水和物及びヒドロキシプロピルセルロースを含むエタノール溶液を加えて攪拌しながら乳鉢で練合を行った後、８号篩で篩過した後、５０℃で２時間乾燥した。乾燥した造粒物を整粒（２２号篩）し、軽質無水ケイ酸及びステアリン酸マグネシウムを加えて混合した後、打錠機で打錠した。各成分の割合及び保存試験の評価結果を表１に示す。
【００５４】
比較例１〜３
表１に示す成分を用いて、実施例１と同様の方法で固形製剤を製造し、保存試験を行った。結果を表１に示す。
【００５５】
【表１】
表の結果から明らかなように、実施例の製剤は、４週間経過しても安定性に優れている。なお、実施例１で得られた固形製剤の溶出性試験を行ったところ、実施例１の溶出率は２６．７％である。
【００５７】
実施例２
シンバスタチン−１の代わりにシンバスタチン−２を用いる以外は実施例１と同様にして固形製剤を製造し、溶出性試験を行ったところ、１５分後の溶出率は３３％であった。
【００５８】
実施例３
シンバスタチン−１の代わりにシンバスタチン−３を用いる以外は実施例１と同様にして固形製剤を製造し、溶出性試験を行ったところ、１５分後の溶出率は３３．６％であった。
【００５９】
実施例４
シンバスタチン−１の代わりにシンバスタチン−４を用いる以外は実施例１と同様にして固形製剤を製造し、溶出性試験を行ったところ、１５分後の溶出率は２０％であった。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a preparation containing a pharmacologically active ingredient having a lactone ring useful for treating hyperlipidemia, familial hypercholesterolemia, and the like, and a method for producing the same.
[0002]
[Prior art]
Lactone ring-containing pharmacologically active ingredients such as simvastatin and lovastatin specifically and competitively inhibit HMG (3-hydroxy-3-methylglutaryl) -CoA reductase, which is a rate-limiting enzyme in the cholesterol biosynthesis system. By enhancing LDL receptor activity, it has the effect of rapidly and strongly lowering serum total cholesterol. Therefore, the pharmacologically active ingredient is useful as an oral administration preparation for diseases such as hyperlipidemia and familial hypercholesterolemia.
[0003]
Orally administered preparations are usually prepared as solid preparations such as tablets and granules obtained by granulating and excipients, binders, disintegrants and the like. However, a compound having a lactone ring is degraded by the action of temperature, humidity, light, etc., and therefore has low stability even in such a solid preparation, and particularly has stability in a non-packaged state at high temperature and high humidity. descend.
[0004]
Among such active ingredients having a lactone ring, simvastatin has been reported on the physicochemical compatibility with various excipients (Bull. Fac. Pharm. Cairo Univ.,: Vol 38. No. 1. (2000), pp. 21-32. In this document, simvastatin interacts (reacts) with polyethylene glycol, corn starch, cellulose acetate phthalate, carboxymethyl cellulose, magnesium stearate, and lactose, and has excellent compatibility with polyvinylpyrrolidone, croscarmellose, and crystalline cellulose. It is described.
[0005]
On the other hand, 3 rd CENTRAL EUROPEAN SYMPOSIUM ON PHARMACEUTICAL TECHNOLOGY; in (FarmVestn 1999 50) are reports on compatibility of the pravastatin sodium and the various excipients have been made. In this document, pravastatin sodium is stable against lactose, hydroxypropylcellulose, sodium citrate hydrate, etc., and shows only slight disintegration by microcrystalline cellulose, croscarmellose, magnesium stearate, etc. However, it is described that hydrate of sodium hydrogen phosphate is very unstable and lactone ring is easily formed.
[0006]
Japanese Patent Publication No. Hei 7-508280 discloses that, without using microcrystalline cellulose, an agent such as simvastatin or lovastatin is formed into spherical multiparticles by using an acrylic resin such as sodium polyacrylate as a charged resin. A method of making is disclosed. In this document, 8.7% by weight of simvastatin, 7% by weight of disodium phosphate, 1.7% by weight of monosodium phosphate, 21.7% by weight of sodium dodecyl sulfate, 17.4% by weight of sodium chloride, polyvinylpyrrolidone ( Trade name: Povidone 29-32K) Particles containing 8.7% by weight, 34.8% by weight of divinylbenzene methacrylate copolymer and 0.0002% by weight of butylated hydroxyanisole, and 35% by weight of divinylbenzene methacrylate copolymer And particles containing 25% by weight of citric acid, 25% by weight of trisodium citrate, 5% by weight of polyvinylpyrrolidone (trade name: Povidone 90K), and 10% by weight of lovastatin. However, these particles also have insufficient stability under high temperature and high humidity conditions.
[0007]
[Problems to be solved by the invention]
Accordingly, an object of the present invention is to provide a solid preparation capable of stabilizing a pharmacologically active ingredient having a lactone ring for a long period of time and a method for producing the same.
[0008]
Another object of the present invention is to provide a solid preparation which can suppress and stabilize the decomposition of a pharmacologically active ingredient having a lactone ring for a long period of time even under severe conditions such as high temperature and high humidity, and a method for producing the same. Is to do.
[0009]
Still another object of the present invention is to provide a solid preparation excellent in dissolution and a method for producing the same.
[0010]
[Means for Solving the Problems]
The present inventors have conducted intensive studies to achieve the above object, and as a result, without using crospovidone, preparing a solid preparation using a non-cellulosic excipient and a stabilizer, a pharmacologically active ingredient containing a lactone ring And found that the present invention can be stabilized, and completed the present invention.
[0011]
That is, the solid preparation of the present invention is a preparation containing a pharmacologically active ingredient having a lactone ring, an excipient and a stabilizer, wherein the excipient is composed of a non-cellulosic excipient, and contains crospovidone. Substantially not contained. Further, the preparation may contain a nonionic binder substantially without a polymer compound having an ionic functional group. In the above-mentioned preparation, the pharmacologically active ingredient having a lactone ring is composed of simvastatin, lovastatin and the like. The particle size of the pharmacologically active ingredient may be 3.5% or more in 50% particle size (median size) and 20 μm or less in 90% particle size in a cumulative particle size distribution. In the above formulation, the excipient may be composed of a saccharide or a starch, and the stabilizer may be composed of an organic acid. The preparation may further contain an antioxidant and the like. The ratio of the components constituting the preparation is, for example, about 50 to 10000 parts by weight (particularly 100 to 5000 parts by weight) and 1 to 50 parts by weight of a stabilizing agent with respect to 100 parts by weight of the pharmacologically active ingredient. In particular, about 3 to 40 parts by weight). Further, the ratio of the stabilizer is about 0.001 to 50 parts by weight (particularly 0.01 to 30 parts by weight) based on 100 parts by weight of the excipient.
[0012]
The present invention also includes a method for producing a solid preparation by granulating a composition substantially free of crospovidone, comprising a pharmacologically active ingredient having a lactone ring, a non-cellulosic excipient, and a stabilizer. It is.
[0013]
In addition, the present invention provides a method for stabilizing a pharmacologically active ingredient having a lactone ring by preparing a solid preparation using a non-cellulosic excipient and a stabilizer without substantially using crystalline cellulose and crospovidone. Methods to improve the performance are also included.
[0014]
BEST MODE FOR CARRYING OUT THE INVENTION
The solid preparation of the present invention contains a pharmacologically active ingredient having a lactone ring, an excipient, and a stabilizer. The solid preparation of the present invention may further contain an antioxidant.
[0015]
[Pharmacologically active ingredient having lactone ring]
The pharmacologically active ingredient having a lactone ring is not particularly limited as long as it has a lactone ring, and examples thereof include statins having a lactone ring such as simvastatin and lovastatin. Simvastatin or lovastatin is represented by the following formula (1).
[0016]
Embedded image
(Wherein, R 1 represents a methyl group, and R 2 represents a methyl group or a hydrogen atom)
In the formula (1), a compound in which R 1 and R 2 are a methyl group is simvastatin, and a compound in which R 1 is a methyl group and R 2 is a hydrogen atom is lovastatin. Simvastatin and lovastatin are HMG-CoA reductase inhibitors and are used as oral preparations for diseases such as hyperlipidemia and familial hypercholesterolemia.
[0018]
The particle size of the pharmacologically active ingredient having a lactone ring is not particularly limited as long as it can be formulated, and the 50% particle size in the cumulative particle size distribution is 3.5 μm or more [preferably 3.7 μm or more (for example, 3.7). To 9 μm), more preferably 4 μm or more (eg, 4 to 7 μm)] and a 90% particle size of 20 μm or less [preferably 15 μm or less (eg, 7 to 15 μm), more preferably 10 μm or less (eg, 8 μm or less). -10 μm)]. When the particle size of the pharmacologically active ingredient is in this range, the dissolution of the preparation is in an appropriate range, and the pharmacological activity is effectively expressed in the body.
[0019]
The content of the pharmacologically active ingredient having a lactone ring is 0.1 to 50% by weight, preferably 0.5 to 30% by weight, more preferably 1 to 20% by weight (particularly 3 to 10% by weight) based on the preparation. ).
[0020]
[Excipient]
Excipients are composed of non-cellulosic excipients. Examples of the excipient include sugars, starches, talc, calcium carbonate, magnesium carbonate and the like.
[0021]
Examples of the saccharides include monosaccharides (arabinose, xylose, glucose, fructose, galactose, mannose, sorbose, etc.), oligosaccharides [sucrose (eg, sucrose, purified sucrose, powdered sugar, granulated sugar, etc.), lactose, maltose, Reduced maltose, isomaltose, etc.], sugar alcohols (xylitol, erythritol, sorbitol, mannitol, etc.). These saccharides can be used alone or in combination of two or more. Among these saccharides, monosaccharides such as glucose and fructose, oligosaccharides such as sucrose, lactose and reduced maltose, and sugar alcohols such as mannitol and sorbitol are usually used.
[0022]
Examples of the starches include starch (corn starch, wheat starch, potato starch, rice starch, sweet potato starch, and the like). Among these starches, starches such as corn starch, wheat starch and potato starch are usually used.
[0023]
These excipients can be used alone or in combination of two or more. Among these excipients, saccharides or starches are preferred. For example, saccharides such as lactose and starches such as corn starch may be used in combination. When a saccharide and a starch are used in combination, the ratio (weight ratio) of both is saccharide / starch = 99/1 to 50/50, preferably 95/5 to 60/40, and more preferably 90/10. About 70/30.
[0024]
The proportion of the excipient is about 50 to 10,000 parts by weight, preferably about 100 to 5,000 parts by weight, more preferably about 300 to 3,000 parts by weight (particularly about 500 to 3,000 parts by weight) based on 100 parts by weight of the pharmacologically active ingredient. .
[0025]
[Stabilizer]
The stabilizer has a role of keeping the pH of the preparation in an acidic range and protecting the lactone ring of the pharmacologically active ingredient. As the stabilizer, an acid component such as an inorganic acid (such as phosphoric acid) or an organic acid may be used, but an organic acid, particularly a low molecular weight organic acid is preferable.
[0026]
Examples of the organic acid include aliphatic oxycarboxylic acids (eg, C 2-6 aliphatic oxycarboxylic acids such as glycolic acid, lactic acid, oxybutyric acid, and glyceric acid), and aliphatic oxypolycarboxylic acids (citric acid, malic acid, such as C 2-6 aliphatic oxy polycarboxylic acids such as tartaric acid), aromatic oxycarboxylic acids (salicylic acid, hydroxybenzoic acid, gallic acid), aliphatic carboxylic acid (acetic acid, C 2-10 aliphatic saturated such as propionic acid such polycarboxylic acids, such as C 4-10 aliphatic unsaturated polycarboxylic acids, such as sorbic acid), aliphatic polycarboxylic acids (oxalic acid, malonic acid, succinic acid, glutaric acid, C 2-10 fats such as adipic acid such families saturated polycarboxylic acid, maleic acid, etc. C 4-10 aliphatic unsaturated polycarboxylic acids such as fumaric acid), aromatic carboxylic acid (benzoic acid Etc.), and the like. These organic acids may be hydrates. These stabilizers can be used alone or in combination of two or more.
[0027]
Among these stabilizers, usually, aliphatic oxycarboxylic acids such as lactic acid, aliphatic oxypolycarboxylic acids such as citric acid and malic acid, aliphatic carboxylic acids such as acetic acid and propionic acid, maleic acid and fumaric acid And the like, and in particular, aliphatic oxycarboxylic acids such as citric acid and citric acid hydrate are preferably used.
[0028]
The proportion of the stabilizer is about 1 to 50 parts by weight, preferably about 3 to 40 parts by weight, more preferably about 5 to 30 parts by weight (particularly about 10 to 30 parts by weight) based on 100 parts by weight of the pharmacologically active ingredient. .
[0029]
In the solid preparation of the present invention, the ratio (weight ratio) between the excipient and the stabilizer is 0.001 to 50 parts by weight, preferably 0.01 to 50 parts by weight, based on 100 parts by weight of the excipient. It is 30 parts by weight, more preferably 0.1 to 10 parts by weight (particularly 0.3 to 5 parts by weight).
[0030]
[Antioxidant]
As the antioxidant, a conventional antioxidant can be used, for example, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), ascorbic acid, sodium ascorbate, erythorbic acid, sodium erysorbate, tocopherol, propyl gallate Guaiac fat, nordihydroguaiaretic acid, sodium pyrosulfite, sodium bisulfite, Rongalit and the like.
[0031]
These antioxidants can be used alone or in combination of two or more.
[0032]
Of these antioxidants, butylhydroxyanisole, dibutylhydroxytoluene, ascorbic acid, especially butylhydroxyanisole, are preferred.
[0033]
The ratio of the antioxidant is about 10 to 5000 ppm, preferably about 20 to 1000 ppm, and more preferably about 30 to 500 ppm, based on the pharmacologically active ingredient.
[0034]
Further, the solid preparation of the present invention may contain a binder.
[0035]
[Binder]
As the binder, conventional binders can be used, for example, proteins (eg, gelatin), polysaccharides (eg, gum arabic, pullulan, dextrin, tragacanth, sodium alginate), modified starch (pregelatinized starch, partially pregelatinized starch). hydrolysis dextrin, esterified starch, etc. etherified starch), C 1-4 alkyl celluloses such as cellulose derivatives (methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl C 1-4 alkyl celluloses such as hydroxymethyl cellulose and carboxy C 1-4 alkyl celluloses such as carboxymethyl cellulose), vinyl polymer (polyvinylpyrrolidone, polyvinyl alcohol, etc.) and the like. Among these binders, nonionic binders (for example, hydroxy C 1-4 alkyl cellulose of hydroxypropyl cellulose and modified starch such as partially pregelatinized starch) are preferred. These binders can be used alone or in combination of two or more.
[0036]
The proportion of the binder is about 5 to 100 parts by weight, preferably about 10 to 80 parts by weight, more preferably about 20 to 70 parts by weight (particularly about 30 to 50 parts by weight) based on 100 parts by weight of the pharmacologically active ingredient.
[0037]
[Other additives]
The composition may contain other additives such as a fluidizing agent (eg, light anhydrous silicic acid), a lubricant (eg, stearic acid, magnesium stearate, calcium stearate, talc), a disintegrant (eg, a low degree of substitution). Nonionic surfactants such as hydroxypropylcellulose, surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, and polyoxyethylene castor oil derivatives) Agents), lipids (e.g., hydrocarbons, waxes, higher fatty acids and salts thereof, higher alcohols, fatty acid esters, hardened oils, etc.), colorants (e.g., tar dyes, caramels, red peppers, titanium oxide, etc.), flavoring agents [For example, sweeteners (sucrose, lactose, mannitol, xylitol, saccharin Saccharin sodium, aspartame, stevioside, etc.), flavors, etc., wetting agents [eg, polyethylene glycol (macrogol), glycerin, propylene glycol, etc.], buffers, adsorbents, preservatives such as preservatives, antistatic agents, disintegration prolongation Agents and the like may be included.
[0038]
These additives can be used alone or in combination of two or more, and there is no particular limitation on the content in the final preparation. For example, 1 to 50 parts by weight of a fluidizing agent with respect to 100 parts by weight of the pharmacologically active ingredient ( About 5 to 30 parts by weight) and about 0.1 to 30 parts by weight (particularly 1 to 20 parts by weight) of a lubricant.
[0039]
The solid preparation of the present invention does not substantially contain crospovidone (crosslinked polyvinylpyrrolidone, registered trademark: Kollidon CL). Further, the solid preparation of the present invention does not substantially contain a polymer compound having an ionic functional group. Such high molecular compounds include non-saccharide high molecular compounds having a functional group such as a carboxyl group, a sulfonic acid group, and an amino group, and include, for example, calcium carboxymethylcellulose, sodium starch glycolate (sodium carboxymethyl starch). ), An ionic disintegrant such as croscarmellose sodium, an acrylate resin such as sodium polyacrylate, and a sulfonic acid group-containing resin such as sodium polystyrene sulfonate.
[0040]
[Solid preparation]
The solid preparation of the present invention can be used in various use forms, and is not particularly limited. For example, oral administration such as tablets, powders, fine granules, granules, pills, capsules, and dry syrups It can be used in a form suitable for Among these forms, tablets, granules, fine granules and the like, particularly tablets, are preferred. Furthermore, tablets may be sugar-coated tablets, gelatin-coated tablets, film-coated tablets, enteric-coated tablets, dry coated tablets (compressed tablets), multilayer tablets (two-layer or three-layer tablets) and the like. The average particle size of the solid preparation is about 0.01 to 10 mm, preferably about 0.05 to 5 mm, and more preferably about 0.1 to 3 mm. The average diameter of the tablet is about 5 to 10 mm.
[0041]
[Method for producing solid preparation]
The solid preparation of the present invention can be obtained by a conventional method according to the dosage form, for example, by granulating a composition containing a pharmacologically active ingredient, an excipient and a stabilizer.
[0042]
For granulation, conventional granulation methods, for example, wet granulation methods such as extrusion granulation method, tumbling granulation method, fluidized bed granulation method, mixing and stirring granulation method, spray drying granulation method, vibration granulation method, etc. A dry granulation method such as a granulation method and a compression molding granulation method can be employed. Of these granulation methods, usually, wet granulation methods such as an extrusion granulation method, a tumbling granulation method, a fluidized bed granulation method and a mixing / stirring granulation method can be preferably used. For example, in the case of tablets, for example, a pharmacologically active ingredient, an excipient and, if necessary, an antioxidant, a stabilizer, a binder, etc. are wet-granulated, dried, and then, if necessary, a lubricant or a fluid. It can be obtained by adding an additive such as an agent and tableting. The solvent in the wet granulation is not particularly limited, but at least one solution selected from water and a lower alcohol (for example, ethanol), and particularly from the viewpoint of safety, a water or ethanol solution can be preferably used.
[0043]
In the case of simvastatin, the solid preparation thus obtained is usually administered once a day, and the dose is about 5 to 20 mg per day in terms of pharmacologically active ingredients in an adult (body weight 60 kg). It is.
[0044]
Since a preparation containing a pharmacologically active ingredient such as simvastatin or lovastatin has an action of inhibiting HMG-CoA reductase, it is useful as an oral preparation for diseases such as hyperlipidemia and familial hypercholesterolemia. In addition, it can be used as a therapeutic agent for various mammals (eg, mice, rats, rabbits, dogs, cats, pigs, cows, horses, etc.) in addition to humans.
[0045]
In the present invention, the stability of a pharmacologically active ingredient having a lactone ring is improved by preparing a solid preparation using a non-cellulosic excipient and a stabilizer without substantially using crystalline cellulose and crospovidone. Is done.
[0046]
【The invention's effect】
In the present invention, even a solid preparation containing a pharmacologically active ingredient having a lactone ring can stabilize the pharmacologically active ingredient for a long period of time. In particular, even under severe conditions such as high temperature and high humidity, the decomposition of the pharmacologically active ingredient can be suppressed and stabilized for a long period of time. Further, the solid preparation is excellent in dissolution property.
[0047]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. In the following examples, “%” and “parts” are based on weight. The methods of the storage test and the dissolution test of the solid preparation and the contents of the main components used are shown below.
[0048]
[Storage test]
After measuring the content of simvastatin in the solid preparation by high-performance liquid chromatography (HPLC), it was stored in a sealed glass bottle at 60 ° C. and 60% RH for 2 weeks and 4 weeks, and after 2 weeks and 4 weeks The content of simvastatin was determined by HPLC. The ratio of the simvastatin content after storage to the initial simvastatin content was shown as the main agent content ratio (% by weight).
[0049]
[Dissolution test]
Using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.), the dissolution rate (after 15 minutes) of simvastatin in a solid preparation in an aqueous solution was determined by the Japanese Pharmacopoeia General Test Method and Dissolution Test Method 2 (paddle method). It measured according to.
[0050]
[Main ingredients used]
(Pharmacologically active ingredients)
Simvastatin-1: 50% particle size (D50) 4.02 μm, 90% particle size (D90) 9.26 μm in cumulative particle size distribution
Simvastatin-2: D50 (1.82 μm), D90 (3.53 μm)
Simvastatin-3: D50 (3.41 μm), D90 (6.82 μm)
Simvastatin-4: D50 (10 μm), D90 (23.7 μm).
[0051]
(Excipient)
Lactose: 200 mesh corn starch crystalline cellulose: Avicel (manufactured by Asahi Kasei Corporation).
[0052]
(Disintegrant)
Crospovidone: Kollidon CL (manufactured by BASF)
(Stabilizer)
Citric acid monohydrate (antioxidant)
BHA: butylhydroxyanisole (binder)
Hydroxypropylcellulose: Shin-Etsu Chemical Co., Ltd. (plasticizer)
Light anhydrous silicic acid: Adsolider 101 (manufactured by Freund Corporation)
(lubricant)
Magnesium stearate.
[0053]
Example 1
Simvastatin-1, lactose, and corn starch containing a trace amount of BHA are uniformly stirred and mixed, and an ethanol solution containing citric acid monohydrate and hydroxypropylcellulose is added thereto, and the mixture is kneaded in a mortar with stirring. Then, the mixture was sieved with a No. 8 sieve and dried at 50 ° C. for 2 hours. The dried granulated product was sized (No. 22 sieve), light anhydrous silicic acid and magnesium stearate were added and mixed, followed by tableting with a tableting machine. Table 1 shows the proportions of the components and the evaluation results of the storage test.
[0054]
Comparative Examples 1-3
Using the components shown in Table 1, a solid preparation was produced in the same manner as in Example 1, and a storage test was performed. Table 1 shows the results.
[0055]
[Table 1]
As is clear from the results in the table, the formulations of Examples are excellent in stability even after 4 weeks. When the dissolution test of the solid preparation obtained in Example 1 was performed, the dissolution rate in Example 1 was 26.7%.
[0057]
Example 2
A solid preparation was produced in the same manner as in Example 1 except that simvastatin-1 was used instead of simvastatin-1, and a dissolution test was performed. As a result, the dissolution rate after 15 minutes was 33%.
[0058]
Example 3
A solid preparation was produced in the same manner as in Example 1 except that simvastatin-3 was used instead of simvastatin-1, and a dissolution test was performed. As a result, the dissolution rate after 15 minutes was 33.6%.
[0059]
Example 4
A solid preparation was produced in the same manner as in Example 1 except that simvastatin-4 was used instead of simvastatin-1, and a dissolution test was performed. As a result, the dissolution rate after 15 minutes was 20%.
Claims (10)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002162580A JP2004010501A (en) | 2002-06-04 | 2002-06-04 | Solid preparation and method for producing the same |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002162580A JP2004010501A (en) | 2002-06-04 | 2002-06-04 | Solid preparation and method for producing the same |
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| JP2004010501A true JP2004010501A (en) | 2004-01-15 |
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| JP2002162580A Withdrawn JP2004010501A (en) | 2002-06-04 | 2002-06-04 | Solid preparation and method for producing the same |
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| JP (1) | JP2004010501A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005077359A1 (en) * | 2004-02-17 | 2005-08-25 | Sankyo Company, Limited | Stabilized pharmaceutical composition containing indoline compound |
| JP2006008543A (en) * | 2004-06-23 | 2006-01-12 | Eisai Co Ltd | Ampiroxicam-containing pharmaceutical composition, its stabilizing method and its manufacturing method |
| JP2007277270A (en) * | 2005-06-17 | 2007-10-25 | Nippon Zoki Pharmaceut Co Ltd | Dried product and production method thereof |
| CN116121925A (en) * | 2022-12-19 | 2023-05-16 | 宿迁市柯信纺织品股份有限公司 | Solid wax smearing method for yarn production |
-
2002
- 2002-06-04 JP JP2002162580A patent/JP2004010501A/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005077359A1 (en) * | 2004-02-17 | 2005-08-25 | Sankyo Company, Limited | Stabilized pharmaceutical composition containing indoline compound |
| JP2006008543A (en) * | 2004-06-23 | 2006-01-12 | Eisai Co Ltd | Ampiroxicam-containing pharmaceutical composition, its stabilizing method and its manufacturing method |
| JP2007277270A (en) * | 2005-06-17 | 2007-10-25 | Nippon Zoki Pharmaceut Co Ltd | Dried product and production method thereof |
| CN116121925A (en) * | 2022-12-19 | 2023-05-16 | 宿迁市柯信纺织品股份有限公司 | Solid wax smearing method for yarn production |
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