JP2004256545A - ボツリヌス毒素医薬組成物 - Google Patents
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Abstract
【解決手段】 ボツリヌス毒素、塩化ナトリウムまたは水、および多糖(例えばヒドロキシエチルデンプン)および/またはアミノ酸を含有し、血液由来のアルブミンを含有しない、ヒト患者の処置のために投与するのに適当なボツリヌス毒素医薬組成物を提供する。
【選択図】なし
Description
アルブミンは、豊富に存在する小さい血漿タンパク質である。ヒト血清アルブミンは分子量が約69キロダルトン(kD)で、医薬組成物中に不活性成分として用いられており、増量担体として、および医薬組成物中に存在するある種のタンパク質活性成分の安定剤として機能し得る。
嫌気性グラム陽性細菌であるボツリヌス菌(Clostridium botulinum)は、ボツリヌス中毒と呼ばれる神経麻痺性障害をヒトおよび動物において引き起こす強力なポリペプチド神経毒であるボツリヌス毒素を産生する。ボツリヌス菌およびその胞子は通常、土壌中に見出され、滅菌と密閉が不適切な零細缶詰工場の食品容器内で増殖する可能性があり、これが多くのボツリヌス中毒症例の原因である。ボツリヌス中毒の影響は、通例、ボツリヌス菌の培養物または胞子で汚染された食品を飲食した18〜36時間後に現れる。ボツリヌス毒素は、消化管内を弱毒化されないで通過することができ、そして末梢運動ニューロンを攻撃することができるようである。ボツリヌス毒素中毒の症状は、歩行困難、嚥下困難および会話困難から、呼吸筋の麻痺および死にまで進行し得る。
多糖類は、何百または何千もの単糖単位がグリコシド(エーテル)結合したものから成り得る。二つの重要な多糖は、セルロースとデンプンである。セルロースは主たる植物の構成物質で、植物にその堅さと形状を与えている。デンプンは植物の栄養供給貯留を構成し、主に種々の種子および塊茎中に見られる。
本発明において、下記単語または用語の定義は次の通りである。
「約」とは、該当するアイテム、パラメータまたはタームが、そのアイテム、パラメータまたはタームの値よりも10%高い値から10%低い値までの範囲を包含することを意味する。
「多糖」は、同じかまたは異なる2個を越える糖分子モノマーのポリマーを意味する。
多糖によるこれら3種のボツリヌス毒素安定化によって、医薬組成物の注射前にボツリヌス毒素の本来の毒性を維持する。
前記のように、A型ボツリヌス毒素複合体は、N−Zアミンおよび酵母エキスを含有する培地中で培養したボツリヌス菌のHall株の培養物から得られる。A型ボツリヌス毒素複合体を、一連の酸沈殿によって培養液から精製して、活性な高分子量毒素タンパク質および付随するヘマグルチニンタンパク質から成る結晶複合体とする。次いで、結晶複合体を、塩およびアルブミンを含有する溶液に再溶解し、滅菌濾過し(0.2μ)、減圧乾燥する。次いで、BOTOX(登録商標)を、筋肉内注射する前に、防腐していない滅菌塩類液で再構成する。BOTOX(登録商標)の各バイアルは、A型ボツリヌス毒素複合体約100単位(U)、ヒト血清アルブミン0.5mgおよび塩化ナトリウム0.9mgを、防腐剤なしに無菌減圧乾燥形態で含有した。その代わりに、ヒト血清アルブミンを組換え生成したアルブミンで置き換えることができる。
A型ボツリヌス毒素精製神経毒複合体の医薬製剤を、前記実施例1と同様の方法で調製した。ただし、アルブミン0.5mgの代わりにヘタスターチ500μgまたは600μgを使用した。ヘタスターチ含有製剤の調製時に効力が全部維持されることを確認した。すなわち、いずれのヘタスターチ含有製剤でも、アルブミン不含有・ヘタスターチ含有組成物の効力は、凍結乾燥100U(±20U)A型ボツリヌス毒素複合体の再構成時に測定したところ、96〜128単位であった。3つのヘタスターチ・A型ボツリヌス毒素複合体医薬組成物の効力測定値は、再構成時にそれぞれ105単位、111単位および128単位であった。効力測定は、標準的なマウス投与毒素効力アッセイによって行った。
A型ボツリヌス毒素精製神経毒複合体の医薬製剤を、前記実施例1と同様の方法で調製した。ただし、アルブミン0.5mgの代わりにヘタスターチ500μgまたは600μgを使用した。更に、グリシン1mgを製剤に加えた。ヘタスターチとグリシンを含有し、アルブミンを含有しない100UのA型ボツリヌス毒素複合体の医薬組成物を凍結乾燥した後、−5℃で7箇月間貯蔵した。その7箇月の期間終了時に、ヘタスターチとグリシンを含有するこの毒素製剤の効力が実質的に不変である(すなわち、元の効力との効力差が5%未満である)ことを、マウス投与アッセイによって確認した。
100UのA型ボツリヌス毒素精製神経毒複合体の医薬製剤を、前記実施例1と同様の方法で調製する。ただし、アルブミン0.5mgの代わりにヘタスターチ600μgを使用した。更に、リジン1mgを製剤に加える。ヘタスターチとリジンを含有し、アルブミンを含有しない100UのA型ボツリヌス毒素複合体医薬組成物を凍結乾燥した後、−5℃で1年月間貯蔵する。その1年間の期間終了時に、ヘタスターチとリジンを含有するこの毒素製剤の効力が実質的に不変である(すなわち、元の効力との効力差が5%未満である)ことを、マウス投与アッセイによって確認する。
100UのA型ボツリヌス毒素精製神経毒複合体の医薬製剤を、前記実施例1と同様の方法で調製する。ただし、アルブミン0.5mgの代わりにヘタスターチ600μgを使用した。更に、ヒスチジン1mgを製剤に加える。ヘタスターチとヒスチジンを含有し、アルブミンを含有しない100UのA型ボツリヌス毒素複合体医薬組成物を凍結乾燥した後、−5℃で1年月間貯蔵する。その1年間の期間終了時に、ヘタスターチとヒスチジンを含有するこの毒素製剤の効力が実質的に不変である(すなわち、元の効力との効力差が5%未満である)ことを、マウス投与アッセイによって確認する。
100UのA型ボツリヌス毒素精製神経毒複合体の医薬製剤を、前記実施例1と同様の方法で調製する。ただし、アルブミン0.5mgの代わりにヘタスターチ600μgを使用した。更に、アルギニン1mgを製剤に加える。ヘタスターチとアルギニンを含有し、アルブミンを含有しない100UのA型ボツリヌス毒素複合体医薬組成物を凍結乾燥した後、−5℃で1年月間貯蔵する。その1年間の期間終了時に、ヘタスターチとアルギニンを含有するこの毒素製剤の効力が実質的に不変である(すなわち、元の効力との効力差が5%未満である)ことを、マウス投与アッセイによって確認する。
A型ボツリヌス毒素精製神経毒複合体の医薬製剤を、前記実施例1と同様の方法で調製した。ただし、アルブミン0.5mgの代わりにアミノ酸(例えばリジン、グリシン、ヒスチジンまたはアルギニン)約1mgを使用し得る。多糖を含有せず、アルブミンを含有せず、グリシンを含有する100UのA型ボツリヌス毒素複合体の医薬組成物を凍結乾燥した後、−5℃で少なくとも1年間貯蔵し得る。その期間の終了時に、この製剤の効力は実質的に不変であり得る(すなわち、元の効力との効力差が5%未満であり得る)。
48歳男性が痙性筋肉症状(例えば頚部ジストニー)があると診断される。約10−3ないし35U/kgのA型ボツリヌス毒素医薬組成物(ヘタスターチ600μgおよびアミノ酸(例えばリジン)1mgを含有する)を、患者に筋肉内注射する。1〜7日以内に痙性筋肉状態の徴候が緩和され、この緩和が少なくとも約2〜6箇月持続する。
1.本発明の医薬組成物は、いかなる血液生成物(例えばアルブミン)も含まないように調製し得、それ故、血液生成物の感染性要素(例えばプリオン)を含有しない。
2.本発明の医薬組成物は、従来の医薬組成物に勝るとも劣らない安定性および高い毒素効力回収率を示す。
従って、特許請求の範囲は、前記の好ましい態様の説明に制限されるべきではない。
Claims (5)
- クロストリジウム神経毒を変性または凝集に対して安定化する方法であって、クロストリジウム神経毒と多糖含有安定化組成物とを接触させる段階を含んで成り、前記接触段階が、クロストリジウム神経毒を含有する水溶液または凍結乾燥もしくは減圧乾燥粉末に、有効量の多糖を加える段階を含んで成る方法。
- (a)神経毒、および
(b)多糖
を含有し、該多糖が該神経毒を安定化する、再構成時または注射時のpHが約5〜7.3である医薬組成物。 - 2つのチャンバーを有する予め充填されたシリンジから成り、シリンジの一方のチャンバーはボツリヌス毒素を含有し、シリンジの第2のチャンバーは希釈剤または緩衝剤を含有する、医薬組成物を注射するための装置。
- 処置効果を達成するために医薬組成物を患者に局所投与する段階を含んで成り、該医薬組成物はボツリヌス毒素、多糖およびアミノ酸を含有する、医薬組成物の使用方法。
- (a)ボツリヌス毒素、および
(c)アミノ酸
を実質的に含有し、アルブミンを含有せず、多糖を含有せず、−5℃で1年間貯蔵した場合、塩類液または水で再構成した際の効力が少なくとも約90%であり、再構成後2℃で72時間貯蔵後の効力が約80%である安定な医薬組成物。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US50014700A | 2000-02-08 | 2000-02-08 |
Related Parent Applications (1)
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JP2001557580A Division JP2003522154A (ja) | 2000-02-08 | 2001-02-05 | ボツリヌス毒素医薬組成物 |
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JP2005079801A Division JP2005179375A (ja) | 2000-02-08 | 2005-03-18 | ボツリヌス毒素医薬組成物 |
JP2007211802A Division JP5080902B2 (ja) | 2000-02-08 | 2007-08-15 | ボツリヌス毒素医薬組成物 |
Publications (2)
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JP2004256545A true JP2004256545A (ja) | 2004-09-16 |
JP4118830B2 JP4118830B2 (ja) | 2008-07-16 |
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JP2001557580A Pending JP2003522154A (ja) | 2000-02-08 | 2001-02-05 | ボツリヌス毒素医薬組成物 |
JP2004084590A Expired - Lifetime JP4118830B2 (ja) | 2000-02-08 | 2004-03-23 | ボツリヌス毒素医薬組成物 |
JP2005079801A Pending JP2005179375A (ja) | 2000-02-08 | 2005-03-18 | ボツリヌス毒素医薬組成物 |
JP2005196335A Withdrawn JP2005336201A (ja) | 2000-02-08 | 2005-07-05 | ボツリヌス毒素医薬組成物 |
JP2007211802A Expired - Lifetime JP5080902B2 (ja) | 2000-02-08 | 2007-08-15 | ボツリヌス毒素医薬組成物 |
JP2011160451A Pending JP2011251988A (ja) | 2000-02-08 | 2011-07-22 | ボツリヌス毒素医薬組成物 |
JP2011233808A Pending JP2012031194A (ja) | 2000-02-08 | 2011-10-25 | ボツリヌス毒素医薬組成物 |
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JP2001557580A Pending JP2003522154A (ja) | 2000-02-08 | 2001-02-05 | ボツリヌス毒素医薬組成物 |
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JP2005079801A Pending JP2005179375A (ja) | 2000-02-08 | 2005-03-18 | ボツリヌス毒素医薬組成物 |
JP2005196335A Withdrawn JP2005336201A (ja) | 2000-02-08 | 2005-07-05 | ボツリヌス毒素医薬組成物 |
JP2007211802A Expired - Lifetime JP5080902B2 (ja) | 2000-02-08 | 2007-08-15 | ボツリヌス毒素医薬組成物 |
JP2011160451A Pending JP2011251988A (ja) | 2000-02-08 | 2011-07-22 | ボツリヌス毒素医薬組成物 |
JP2011233808A Pending JP2012031194A (ja) | 2000-02-08 | 2011-10-25 | ボツリヌス毒素医薬組成物 |
Country Status (19)
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US (2) | US20020064536A1 (ja) |
EP (4) | EP1253932B1 (ja) |
JP (7) | JP2003522154A (ja) |
KR (3) | KR100753765B1 (ja) |
CN (2) | CN1331532C (ja) |
AR (1) | AR027391A1 (ja) |
AT (2) | ATE519494T1 (ja) |
AU (2) | AU2001233315B2 (ja) |
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Cited By (3)
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JP2010514781A (ja) * | 2006-12-29 | 2010-05-06 | ルバンス セラピュティックス インク. | Hiv−tatに由来するポリペプチド断片を用いて安定化されるボツリヌス毒素を局所適用及び経皮送達する組成物及び方法 |
JP2021503322A (ja) * | 2017-11-17 | 2021-02-12 | スウェーディッシュ オーファン バイオヴィトルム エービー(ピーユービーエル) | イオン交換材料を有するシリンジアセンブリ |
JP7227971B2 (ja) | 2017-11-17 | 2023-02-22 | スウェディッシュ オーファン バイオビトラム アクティエボラーグ (ペーウーベーエル) | イオン交換材料を有するシリンジアセンブリ |
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