JP4907530B2 - ボツリヌス神経毒を含む治療用組成物 - Google Patents
ボツリヌス神経毒を含む治療用組成物 Download PDFInfo
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- JP4907530B2 JP4907530B2 JP2007523628A JP2007523628A JP4907530B2 JP 4907530 B2 JP4907530 B2 JP 4907530B2 JP 2007523628 A JP2007523628 A JP 2007523628A JP 2007523628 A JP2007523628 A JP 2007523628A JP 4907530 B2 JP4907530 B2 JP 4907530B2
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- botulinum neurotoxin
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- neurotoxin
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Description
Gartlan, M.G., and Hoffman, H.T. Crystalline preparation of botulinum toxin type A (Botox): Degradation in potency with storage., Otolaryngology - Head and Neck Surgery 102(2): 135-140 (1992)。
本発明の目的は、ボツリヌス毒素、又は化学的変性によってか又は遺伝子操作によってボツリヌス毒素から誘導される毒素を含む医薬組成物中で、哺乳類由来の蛋白に代わる非-蛋白性代替物を提供することにある。この新規の製剤は、ヒト患者に注射された場合、低い, そして好ましくはごく僅かな, 免疫原性を有しなければならない。
本明細書において、下記用語又は表現は次の定義を有する。
本発明は、本発明者が安定な神経毒含有医薬組成物が、非蛋白性安定剤を添加することによって, 特にヒアルロン酸又はポリビニルピロリドン又は ポリエチレングリコール又はそれらの2種以上の混合物を添加することによって、あらゆる哺乳類由来の蛋白又はドナープールアルブミンを含むことなく製剤化されることを見出したことを示す。本発明は、ヒアルロン酸又はポリビニルピロリドン又はポリエチレングリコール又はそれらの2種以上の混合物を用いて製剤化される、ボツリヌス毒素組成物の開発に関する。このような組成物は、顕著な安定性を有する、より安全な組成物である。
本発明のボツリヌス毒素調製物, 及びその医薬組成物及びこれを用いる治療方法は、本明細書に記載したような"発明の対象全体"に進歩性があるとする、特定の有利な性質を有することを実証する。
ボツリヌス毒素調製物及びその医薬組成物は、標準的に許容された、信頼のある試験操作で, 下記の重要な性質及び特性を提示する。
ボツリヌス菌A型由来の純神経毒を、DasGupta & Sathyamoorthyの方法に基づく方法によって得る。ボツリヌス菌A型を20 L の醗酵容器で、2% プロテアーゼペプトン, 1% 酵母抽出物, 1% グルコース 及び0.05% チオグリコール酸ナトリウムからなる培地中で培養する。72 時間の増殖後, 毒素を3 N硫酸 (最終 pH = 3.5)の添加によって沈殿させる。沈殿及び遠心分離されたバイオマスを、0.2 M リン酸ナトリウム緩衝剤を用いてpH 6.0で抽出する。
例1の精製した神経毒を使用して、蒸留水mlあたり200Uのボツリヌス毒素調製物及び1 mgのヒアルロン酸を含む溶液を調製する。溶液をバイアルに分注する。
例1の精製した神経毒を使用して、蒸留水mlあたり200Uのボツリヌス毒素調製物及び1 mgのヒアルロン酸を含む溶液を調製し、ついで10 mM 酢酸ナトリウム緩衝剤の添加によってpH 4.5, 5.0 及び5.5に調整する。溶液をバイアルに分注する。
例2の製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 2つの調製物は同一の活性を有する。24及び48時間で, 例2の製剤の安定性はHSA調製物の安定性と、2つのサンプルに生じる初期活性の5%より少ない損失の点で一致する。
例3の製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 本発明の調製物(すべてのpH ポイントで)及びHSA調製物の2つは同一の活性を有する。pH 4.5の調製物は、6日目までに約50%の活性の損失を示す。pH 5.0及び5.5の調製物は6日目までにすべての活性を失う。
例3の製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 本発明の調製物 (pH 4.5で) はHSA調製物と同一の活性を有する。更に重要なことは, 活性の損失が凍結乾燥で検出されなかった。
例1の精製した神経毒を使用して、蒸留水mlあたり200Uのボツリヌス毒素調製物及び100 mgのポリビニルピロリドンを含む溶液を調製する。溶液をバイアルに分注する。
例1の精製した神経毒を使用して、蒸留水mlあたり200Uのボツリヌス毒素調製物及び100 mgのポリビニルピロリドンを含む溶液を調製し、ついで10 mM 酢酸ナトリウム緩衝剤の添加によってpH 4.5, 5.0 及び5.5に調整する。溶液をバイアルに分注する。
例1の精製した神経毒を使用して、蒸留水mlあたり200Uのボツリヌス毒素調製物、100 mgのポリビニルピロリドン及び20 mgのマンニトールを含む溶液を調製し、ついで10 mM 酢酸ナトリウム緩衝剤の添加によってpH 4.5, 5.0 及び5.5に調整する。溶液をバイアルに分注する。
例1の精製した神経毒を使用して、蒸留水mlあたり200Uのボツリヌス毒素調製物、100 mgのポリビニルピロリドン及び20 mgのソルビトールを含む溶液を調製し、ついで10 mM 酢酸ナトリウム緩衝剤の添加によってpH 4.5, 5.0 及び5.5に調整する。溶液をバイアルに分注する。
例7の製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 2つの調製物は同一の活性を有する。
例8の製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 本発明の調製物(すべてのpH ポイントで)及びHSA調製物の2つは同一の活性を有する。 pH 4.5 及び5.0 ならびにHSA 調製物は、製剤化の24時間内で活性の損失を示さない。pH 5.5の調製物は、24時間以内にHSA 及びその他の調製物に比べて20% 活性を失う。
例8Aの製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 本発明の調製物(すべてのpH ポイントで)及びHSA調製物の2つは同一の活性を有する。 pH 4.5, 5.0 及び 5.5ならびにHSA 調製物は、製剤化の24時間以内に活性の損失を示さない。
例8Bの製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 本発明の調製物(すべてのpH ポイントで)及びHSA調製物の2つは同一の活性を有する。 pH 4.5, 5.0 及び 5.5ならびにHSA 調製物は、製剤化の24時間以内に活性の損失を示さない。
例8の製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 本発明の調製物 (すべてのpH ポイントで) はHSA調製物と同一の活性を有する。更に重要なことは, 10%より少ない活性損失が凍結乾燥で最高6ヶ月間すべての製剤に関して検出される。
例8Aの製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 本発明の調製物 (すべてのpH ポイントで) はHSA調製物と同一の活性を有する。更に重要なことは, 10%より少ない活性損失が凍結乾燥で最高6ヶ月間すべての製剤に関して検出される。
例8Bの製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 本発明の調製物 (すべてのpH ポイントで) はHSA調製物と同一の活性を有する。更に重要なことは, 10%より少ない活性損失が凍結乾燥で最高6ヶ月間すべての製剤に関して検出される。
例1の精製した神経毒を使用して、蒸留水mlあたり200Uのボツリヌス毒素調製物及び100 mgのポリエチレングリコールを含む溶液を調製する。溶液をバイアルに分注する。
例1の精製した神経毒を使用して、蒸留水mlあたり200Uのボツリヌス毒素調製物、100 mgのポリエチレングリコール及び20 mgのマンニトールを含む溶液を調製する。溶液をバイアルに分注する。
例1の精製した神経毒を使用して、蒸留水mlあたり200Uのボツリヌス毒素調製物、100 mgのポリエチレングリコール及び20 mgのソルビトールを含む溶液を調製する。溶液をバイアルに分注する。
例12の製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 2つの調製物は同一の活性を有する。
例 12A及び12Bの製剤を調製し、 ヒト血清アルブミン (HSA)中で製剤化されたボツリヌス毒素と比べる。 製剤化の間, 2つの調製物は同一の活性を有する。本発明の調製物及びHSA 調製物は、製剤化の24時間以内に20 % より少ない活性の損失を示す。
50歳の女性は、眼瞼けいれんための治療を求める。ヒアルロン酸含有ボツリヌス毒素調製物(例 3)約10 U 〜約20 Uを、患者に筋肉内注射する。1-7日以内に,眼瞼けいれんの症状は緩和され、症状の緩和は少なくとも約 2ヶ月〜約 6 ヶ月間継続する。
50歳の女性は、眼瞼けいれんための治療を求める。ポリビニルピロリドン含有ボツリヌス毒素調製物(例 8)約10 U 〜約20 Uを、患者に筋肉内注射する。1-7日以内に,眼瞼けいれんの症状は緩和され、症状の緩和は少なくとも約 2ヶ月〜約 6 ヶ月間継続する。
50歳の女性は、眼瞼けいれんための治療を求める。ポリエチレングリコール含有ボツリヌス毒素調製物(例 12)約10 U 〜約20 Uを、患者に筋肉内注射する。1-7日以内に,眼瞼けいれんの症状は緩和され、症状の緩和は少なくとも約 2ヶ月〜約 6 ヶ月間継続する。
50歳の女性は、眼瞼けいれんための治療を求める。ポリエチレングリコール含有ボツリヌス毒素調製物(例 12A)約10 U 〜約20 Uを、患者に筋肉内注射する。1-7日以内に,眼瞼けいれんの症状は緩和され、症状の緩和は少なくとも約 2ヶ月〜約 6ヶ月間継続する。
50歳の女性は、眼瞼けいれんための治療を求める。ポリエチレングリコール含有ボツリヌス毒素調製物(例 12B)約10 U 〜約20 Uを、患者に筋肉内注射する。1-7日以内に,眼瞼けいれんの症状は緩和され、症状の緩和は少なくとも約 2ヶ月〜約 6ヶ月間継続する。
Claims (23)
- ボツリヌス神経毒との複合体を自然に生じる複合体形成蛋白(the complexing proteins)を含まない、A,B,C1,D,E,F又はG型ボツリヌス菌(Clostridium botulinum)由来のボツリヌス神経毒あるいは2種以上のボツリヌス神経毒の混合物、及び水溶液中でボツリヌス神経毒の生物学的活性を保持する、ヒアルロン酸である非蛋白性(non−proteinaceous)安定剤を含む医薬組成物であって、この組成物がアルブミン及びゼラチンから選ばれる、ボツリヌス神経毒のための、哺乳類由来の蛋白性安定剤を含まない、上記医薬組成物。
- ボツリヌス神経毒が化学的に変性されているか又は遺伝子操作によって変性されているか、あるいはその混合物である、請求項1記載の医薬組成物。
- pH緩衝剤を含む、請求項1記載の医薬組成物。
- pH緩衝剤が酢酸ナトリウムである、請求項3記載の医薬組成物。
- 抗凍結剤を含む、請求項1記載の医薬組成物。
- 抗凍結剤がポリアルコールである、請求項5記載の医薬組成物。
- ポリアルコールが1種以上のイノシトール,マンニトール及びソルビトールから選ばれる、請求項6記載の医薬組成物。
- 凍結乾燥されている、請求項5−7のいずれか1つに記載の医薬組成物。
- 美容コンディション、眼瞼けいれん、片側顔面けいれん、痙性斜頸、痙縮、ジストニア、偏頭痛、腰痛、頚椎障害、斜視、多汗症及び過流涎の治療に有効な量で、ヒトを含む動物に投与するための、請求項1記載の医薬組成物。
- 美容コンディションが目立つしわである、請求項9記載の医薬組成物。
- ボツリヌス神経毒との複合体を自然に生じる複合体形成蛋白を含まない、A,B,C1,D,E,F又はG型ボツリヌス菌(Clostridium botulinum)由来のボツリヌス神経毒あるいは2種以上のボツリヌス神経毒の混合物、及び水溶液中でボツリヌス神経毒の生物学的活性を保持する、ヒアルロン酸である非蛋白性安定剤を含むボツリヌス神経毒調製物であって、この調製物がアルブミン及びゼラチンから選ばれる、ボツリヌス神経毒のための、哺乳類由来の蛋白性安定剤を含まない、上記ボツリヌス神経毒調製物。
- ボツリヌス神経毒が化学的に変性されているか又は遺伝子操作によって変性されているか,あるいはその混合物である、請求項11記載のボツリヌス神経毒調製物。
- 水溶液がpH緩衝剤を含む、請求項11記載のボツリヌス神経毒調製物。
- pH緩衝剤が酢酸ナトリウムである、請求項13記載のボツリヌス神経毒調製物。
- 調製物が凍結乾燥されている、請求項11記載のボツリヌス神経毒調製物。
- ボツリヌス神経毒との複合体を自然に生じる複合体形成蛋白を含まない、A,B,C1,D,E,F又はG型ボツリヌス菌由来のボツリヌス神経毒あるいは2種以上のボツリヌス神経毒の混合物を安定化する方法において、ボツリヌス神経毒を生物学的活性を保持するのに有効な量で、上記神経毒と、ヒアルロン酸である非蛋白性安定剤とを水溶液中で混合することからなり、そして得られた混合物がアルブミン及びゼラチンから選ばれる、ボツリヌス神経毒のための、哺乳類由来の蛋白性安定剤を含まない、上記安定化する方法。
- ボツリヌス神経毒が化学的に変性されているか又は遺伝子操作によって変性されているか,あるいはその混合物である、請求項16記載の方法。
- 水溶液がpH緩衝剤を含む、請求項16記載の方法。
- pH緩衝剤が酢酸ナトリウムである、請求項18記載の方法。
- 水溶液が抗凍結剤を含む、請求項16記載の方法。
- 水溶液が凍結乾燥されている、請求項20記載の方法。
- 調製物が凍結乾燥されている、請求項16記載の方法。
- 美容コンディション、眼瞼けいれん、片側顔面けいれん、痙性斜頸、痙縮、ジストニア、偏頭痛、腰痛、頚椎障害、斜視、多汗症及び過流涎の治療用薬剤の製造への、請求項11〜14のいずれか1つに記載のボツリヌス神経毒調製物の使用。
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