JP4903900B2 - レベチラセタムを含む医薬組成物 - Google Patents
レベチラセタムを含む医薬組成物 Download PDFInfo
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- JP4903900B2 JP4903900B2 JP2010549160A JP2010549160A JP4903900B2 JP 4903900 B2 JP4903900 B2 JP 4903900B2 JP 2010549160 A JP2010549160 A JP 2010549160A JP 2010549160 A JP2010549160 A JP 2010549160A JP 4903900 B2 JP4903900 B2 JP 4903900B2
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- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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Description
香味剤の例は、チェリーフレーバー、グレープフルーツフレーバー、テトラロームオレンジ及びハッカ油(oleum aurantii)である。好ましくは、液体の香味剤が用いられる。好ましい香味剤は、テトラロームオレンジである。
本発明の医薬組成物は、当業者に知られている慣用的な方法に従って、いずれかのプロセスによって製造することができる。プロセスの例は、直接圧縮、乾式造粒、湿式造粒、溶融造粒である。好ましくは、医薬組成物は、湿式造粒によって製造される。
・500mgのレベチラセタム、平均粒子径が180μmの451mgの顆粒マンニトール(パーリトール(Pearlitol)(登録商標)SD200)、19mgのポリビニルピロリドン(ポビドン(Povidone)K30)、30mgのアスパルテーム、及び1mgのテトラロームオレンジを含むドライシロップ組成物。
本発明はまた、医薬組成物の使用によるヒト患者の治療方法に関する。
本発明の別の利点は、医薬組成物が味をマスクした製剤であるということである。組成物は、可溶化したレベチラセタムの味が実質的になく、口当たりの良く、薬剤の味がしない。
本発明の別の利点は、医薬組成物が、一度、舌の上に置かれると、ザラザラした感じ又は他の目立った残留物なしに、ほとんど即座に分散することである。
ドライシロップAは、本発明に係る湿式造粒プロセスによって製造され、下記の組成を有する(表1)。
<10%の顆粒フラクションは、75μmを下回る。
>90%の顆粒フラクションは、75μmを上回り、500μmを下回る。
0%の顆粒フラクションは、500μmを上回る。
粒度分布の結果は、その1つが本明細書に記載されるように、製剤に関して理想的である。
ドライシロップBは、本発明に係る湿式造粒プロセスによって製造され、下記の組成を有する(表2)。
ドライシロップCは、湿式造粒プロセスによって製造され、下記の組成を有する(表3)。
ドライシロップDは、湿式造粒プロセスによって製造され、下記の組成を有する(表4)。
ドライシロップEは、湿式造粒プロセスによって製造され、下記の組成を有する(表5)。
レベチラセタムは、1回の54mg/kg服用後に、試験した全ての種(マウス、ラット、ウサギ及びイヌ)において十分に吸収され、概して、完全に生体に利用可能である。レベチラセタムは、一般に、服用に比例している血漿レベル及び曝露と共に、これらの種において直線的な動力学を示すが、イヌでは、血漿レベル及び曝露の両方は、嘔吐によりいくつかの試験においてより高い服用量で比例以下であった。マウス及びラットでは、血漿レベル及び曝露は、強制飼養と比較して、飼料投与によって与えられた場合により低かったので、食物は吸収を減少させるようであった。毒性学試験で用いた服用量での繰り返し投与後、血漿レベルは、マウスにおいて安定を維持し、ラットでは増加する傾向にあった。マウス、ラット及びイヌでは、より高い服用量での酵素誘導の兆候がいくつかあった。しかしながら、これは、繰り返し投与後のレベチラセタムの感知できるほどの低い曝露に帰着しなかった。
組織分布試験からの見解と一致して、レベチラセタムは、細胞内及び細胞外の水の体積に対応して0.5〜0.7L/kgの分布体積を有する。レベチラセタムは、血漿タンパク質に結合せず、血液と血漿との間に等しく分布する。
海馬スライスにおけるてんかん応答:ラットの海馬スライスの還流を通常のACSFからHKLCFに変更することにより、定電流線毛刺激に応答して、CA3領域において、てんかんFPを増加的に生じた。HKLCF単独に晒された対照スライスでは、PS1振幅は、次第に増加し、20分以内に水平値(4.250.77mV)に到達し、ACSF還流下で記録されたもののほぼ2倍高かった(2.180.15mV;n=10スライスの平均s.d.)。また、反復的なPS(即ち、PS2、PS3等)の定電流の1回刺激によって誘発したバーストは、統計で顕著に増加し、HKLCF還流の最初の30分で、誘発されたバースト当たり1回のPS1から平均7.62.3PSに増加し、記録の終了まで徐々に増加し続け、HKLCFの80分の還流後には、誘発されたバースト当たり平均8.81.6PSに到達した。ブリバラセタム及びレベチラセタムの両方は、これらのてんかん応答を減少させた。HKLCFの15分の還流により、自然なフィールドバーストが、HKLCF単独に晒された10個の対照スライスのうち4個において発生し、HKLCF中の25分から記録の終結まで、全ての対照スライスは、規則的なフィールドバーストを示した。レベチラセタム(32μM)ではなく、ブリバラセタム(3.2M)は、この自然なバーストの速度を減少させた。
顆粒の組成を以下の通りである(表6)。
Claims (19)
- ドライシロップの形態である経口投与可能な医薬組成物であって、有効成分としてレベチラセタム(levetiracetam)、ブリバラセタム(brivaracetam)又はセレトラセタム(seletracetam)、賦形剤として、該組成物の全重量に対して、マンニトール、ソルビトール又はキシリトールの中から選択され、平均粒子径が75〜520μmである、少なくとも10〜90重量%の顆粒希釈剤、及び甘味剤又は香味剤を含む前記医薬組成物。
- 前記有効成分がレベチラセタムである、請求項1に記載の医薬組成物。
- てんかん、パーキンソン病、運動障害及び他の神経障害からなる群から選択される疾患を治療するためのドライシロップの形態である経口投与可能な医薬組成物であって、有効成分としてレベチラセタム、ブリバラセタム又はセレトラセタム、賦形剤として、該組成物の全重量に対して、マンニトール、ソルビトール又はキシリトールの中から選択され、平均粒子径が75〜520μmである、少なくとも10〜90重量%の顆粒希釈剤、及び甘味剤又は香味剤を含む前記医薬組成物。
- 前記希釈剤がマンニトールである、請求項1〜3のいずれか1項に記載の医薬組成物。
- 組成物の全重量に対して、20〜80重量%の希釈剤を含む、請求項1〜4のいずれか1項に記載の医薬組成物。
- 組成物の全重量に対して、40〜60重量%の希釈剤を含む、請求項5に記載の医薬組成物。
- 平均粒子径が75〜450μmである希釈剤を含む、請求項1〜6のいずれか1項に記載の医薬組成物。
- 平均粒子径が150〜200μmである希釈剤を含む、請求項7に記載の医薬組成物。
- 室温で水溶性の少なくとも1つの追加の賦形剤を含む、請求項1〜8のいずれか1項に記載の医薬組成物。
- 結合剤を含む、請求項1〜9のいずれか1項に記載の医薬組成物。
- 前記結合剤がポリビニルピロリドンである、請求項10に記載の医薬組成物。
- 組成物の全重量に対して、0.5〜5.0重量%の結合剤を含む、請求項10又は11に記載の医薬組成物。
- 組成物の全重量に対して、1.5〜2.5重量%の結合剤を含む、請求項12に記載の医薬組成物。
- 前記甘味剤がアルパルテームである、請求項1〜13のいずれか1項に記載の医薬組成物。
- 組成物の全重量に対して、1.0〜30重量%の甘味剤を含む、請求項1〜14のいずれか1項に記載の医薬組成物。
- 前記香味剤がテトラロームオレンジ(Tetrarome Orange)である、請求項1〜15のいずれか1項に記載の医薬組成物。
- 0.01〜2.00重量%の香味剤を含む、請求項1〜16のいずれか1項に記載の医薬組成物。
- 有効成分としてレベチラセタムを含み、組成物の全重量に対して、40〜60重量%のマンニトール、1.5〜2.5重量%のポリビニルピロリドン、1.0〜7.5重量%のアスパルテーム、及び0.08〜1.2重量%のテトラロームオレンジを含む、請求項1〜17のいずれか1項に記載の医薬組成物。
- レベチラセタム500mg、平均粒子径が180μmである顆粒マンニトール(パーリトール(Pearlitol)(登録商標)SD200)451mg、ポリビニルピロリドン(ポビドン(Povidone)K30)19mg、アスパルテーム30mg、及びテトラロームオレンジ1mgを含む、請求項1〜18のいずれか1項に記載の医薬組成物。
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WO2011107855A2 (en) * | 2010-03-04 | 2011-09-09 | Torrent Pharmaceuticals Limited | Sustained release oral liquid suspension dosage form |
WO2011136751A2 (en) * | 2010-04-26 | 2011-11-03 | Mahmut Bilgic | Water soluble pharmaceutical composition |
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EP2076249A2 (en) * | 2006-10-27 | 2009-07-08 | FMC Corporation | Dry granulation binders, products, and use thereof |
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JP2018177657A (ja) * | 2017-04-05 | 2018-11-15 | 東和薬品株式会社 | レベチラセタム含有医薬組成物及びその製造方法 |
JP7023054B2 (ja) | 2017-04-05 | 2022-02-21 | 東和薬品株式会社 | レベチラセタム含有医薬組成物及びその製造方法 |
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