JP2010532784A - ボツリヌス毒素の安定性が改善された薬学的液状組成物 - Google Patents
ボツリヌス毒素の安定性が改善された薬学的液状組成物 Download PDFInfo
- Publication number
- JP2010532784A JP2010532784A JP2010515962A JP2010515962A JP2010532784A JP 2010532784 A JP2010532784 A JP 2010532784A JP 2010515962 A JP2010515962 A JP 2010515962A JP 2010515962 A JP2010515962 A JP 2010515962A JP 2010532784 A JP2010532784 A JP 2010532784A
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- JP
- Japan
- Prior art keywords
- botulinum toxin
- liquid composition
- polysorbate
- methionine
- pharmaceutical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Classifications
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Abstract
Description
(1)ボツリヌス毒素液状組成物の製造
安定化剤溶液を用いてボツリヌス毒素液を希釈し、最終的にボツリヌス毒素液の濃度を100ユニット/mLとなるようにボツリヌス毒素液状組成物を製造した。
製造されたボツリヌス毒素液状組成物を特定の温度で保管しながら一定期間ごとに1mLサンプリングを行った。サンプリングされた液状組成物1mLに注射用水9mLを入れて10倍に希釈し、希釈されたサンプルを4週齢ICR(Institute of Cancer Research、USA)雌マウス5匹に腹腔注射した(1匹当り0.3mLずつ、すなわち3ユニット/マウス)。腹腔注射後3日間観察しながら、死亡したマウスの数およびそれによる死亡率を確認した。マウスの死亡率が50%以上であれば、ボツリヌス毒素の活性が維持されるものと評価できる。
多様なボツリヌス毒素安定化剤候補を含むボツリヌス毒素液状組成物を製造し、25℃または37℃の温度で保管しながら、保管期間によるボツリヌス毒素液状組成物の安定性を測定した。ボツリヌス毒素安定化剤の選別実験による25℃での安定性実験結果を表1に示し、37℃での安定性実験結果を表2に示した。表1および表2において、HSAはヒト血清アルブミン(Human Serum Albumin)を意味し、PEG8000はポリエチレングリコール8000を意味する。
ボツリヌス毒素の安定化剤として様々な濃度のメチオニンとポリソルベート20を含む液状ボツリヌス毒素組成物の安定性実験を37℃の保管条件で実施した。以下の表3にはメチオニンの濃度変化によるボツリヌス毒素の安定性実験結果を示した。
ボツリヌス毒素の安定化剤としてメチオニンと様々な濃度のポリソルベート20を含む液状ボツリヌス毒素組成物の安定性実験を37℃の保管条件で行った。ポリソルベート20の濃度変化によるボツリヌス毒素の安定性実験結果は表4に示した。
ボツリヌス毒素の安定化剤として、メチオニンおよびポリソルベート20の多様な濃度を含む液状ボツリヌス毒素組成物によるボツリヌス毒素の安定性実験を37℃の保管条件で行った。表5および表6には、30日および60日保管時のメチオニンおよびポリソルベート20の多様な濃度条件(実施例12)におけるボツリヌス毒素の安定性実験結果(死亡率(%))を示した。前記実験のボツリヌス毒素液状組成物において、ボツリヌス毒素の濃度は100ユニット/mLであった。
ボツリヌス毒素を最も安定化させるメチオニンとポリソルベート20の濃度範囲においてpH5.5〜7.0のボツリヌス毒素液状組成物(実施例13)を製造し、ボツリヌス毒素の安定性実験を40℃の保管条件で行った。ボツリヌス毒素液状組成物のpHは塩酸(HCl)または水酸化ナトリウム(NaOH)を用いて調整し、ボツリヌス毒素の濃度は100ユニット/mLであった。表7にはボツリヌス毒素液状組成物のpHによるボツリヌス毒素の安定性実験結果を示した。
ボツリヌス毒素の安定化剤を選別する過程で、メチオニンとポリソルベート20の組み合わせだけでなく、イソロイシンとポリソルベート20の組み合わせもボツリヌス毒素を安定化させる効果を持たと確認されたので、メチオニン、イソロイシンおよびポリソルベート20の組み合わせによるボツリヌス毒素の安定性実験を37℃の保管条件で行った。前記実験のボツリヌス毒素液状組成物におけるボツリヌス毒素の濃度は100ユニット/mLであった。
Claims (12)
- ボツリヌス毒素、ポリソルベート20、およびメチオニンを含む薬学的液状組成物。
- 前記メチオニンが、ボツリヌス毒素100ユニット当り0.5〜100μmoL存在する、請求項1に記載の薬学的液状組成物。
- 前記メチオニンの濃度は0.5〜100mMの範囲である、請求項2に記載の薬学的液状組成物。
- 前記メチオニンの濃度は25〜75mMである、請求項3に記載の薬学的液状組成物。
- 前記ポリソルベート20が、ボツリヌス毒素100ユニット当り0.01〜50mg存在する、請求項1〜4のいずれか1項に記載の薬学的液状組成物。
- 前記ポリソルベート20の濃度は0.01〜50mg/mLの範囲である、請求項5に記載の薬学的液状組成物。
- 前記ポリソルベート20の濃度は0.1〜2.5mg/mLの範囲である、請求項6に記載の薬学的液状組成物。
- 前記ボツリヌス毒素は、ボツリヌス毒素血清型A、B、C、D、E、FおよびGよりなる群から選択される、請求項1〜4のいずれか1項に記載の薬学的液状組成物。
- 前記ボツリヌス毒素は複合体化タンパク質を含有しない形態、または複合体化タンパク質を含有する複合体形態である、請求項8に記載の薬学的液状組成物。
- 前記薬剤学的組成物のpHは5.5〜7.0の範囲である、請求項1〜4のいずれか1項に記載の薬学的液状組成物。
- 前記薬学的液状組成物はイソロイシンをさらに含む、請求項1〜4のいずれか1項に記載の薬学的液状組成物。
- 前記ボツリヌス毒素の濃度は50〜5,000ユニット/mLである、請求項1または2に記載の薬学的液状組成物。
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JP2019517481A (ja) * | 2016-05-27 | 2019-06-24 | ネスレ スキン ヘルス エス アー | トリプトファンまたはチロシンで安定化された液体神経毒素製剤 |
JP7053498B2 (ja) | 2016-05-27 | 2022-04-12 | ガルデルマ・ホールディング・エスアー | トリプトファンまたはチロシンで安定化された液体神経毒素製剤 |
JP7217700B2 (ja) | 2016-09-13 | 2023-02-03 | アラーガン、インコーポレイテッド | 安定化非タンパク質クロストリジウム毒素組成物 |
JP2019526609A (ja) * | 2016-09-13 | 2019-09-19 | アラーガン、インコーポレイテッドAllergan,Incorporated | 安定化非タンパク質クロストリジウム毒素組成物 |
US11185503B2 (en) | 2017-01-20 | 2021-11-30 | Daewoong Co., Ltd. | Stable liquid composition comprising botulinum toxin |
JP2020505382A (ja) * | 2017-01-20 | 2020-02-20 | テウン カンパニー リミテッドDaewoong Co., Ltd. | ボツリヌス毒素を含む安定した液状組成物 |
JP2022509150A (ja) * | 2018-11-30 | 2022-01-20 | ヒュオンス バイオファーマ カンパニー リミテッド | ボツリヌス毒素の安定化液状組成物 |
JP7244959B2 (ja) | 2018-11-30 | 2023-03-23 | ヒュオンス バイオファーマ カンパニー リミテッド | ボツリヌス毒素の安定化液状組成物 |
JP2023521123A (ja) * | 2020-04-08 | 2023-05-23 | メディトックス インク. | 吐出速度調節が容易であり、安定したボツリヌム毒素事前充填の注射器剤形 |
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US8617568B2 (en) | 2013-12-31 |
CA2690773C (en) | 2013-09-17 |
US20160206710A1 (en) | 2016-07-21 |
US20210379165A1 (en) | 2021-12-09 |
US20190298813A1 (en) | 2019-10-03 |
KR101087017B1 (ko) | 2011-12-09 |
EP2170400A4 (en) | 2010-09-08 |
RU2440825C2 (ru) | 2012-01-27 |
EP2170400B1 (en) | 2012-07-25 |
ES2391798T3 (es) | 2012-11-30 |
US9220780B2 (en) | 2015-12-29 |
WO2009008595A1 (en) | 2009-01-15 |
US10293034B2 (en) | 2019-05-21 |
BRPI0813948B1 (pt) | 2019-08-06 |
KR20090005963A (ko) | 2009-01-14 |
CN101687046A (zh) | 2010-03-31 |
CA2690773A1 (en) | 2009-01-15 |
US20100291136A1 (en) | 2010-11-18 |
US20140161783A1 (en) | 2014-06-12 |
CN101687046B (zh) | 2012-12-26 |
EP2170400A1 (en) | 2010-04-07 |
BRPI0813948A2 (pt) | 2016-06-28 |
RU2009148286A (ru) | 2011-06-27 |
JP5259710B2 (ja) | 2013-08-07 |
BRPI0813948B8 (pt) | 2021-05-25 |
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