JP2018500881A - ボツリヌス毒素の製造のための培地組成物 - Google Patents
ボツリヌス毒素の製造のための培地組成物 Download PDFInfo
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- JP2018500881A JP2018500881A JP2017524478A JP2017524478A JP2018500881A JP 2018500881 A JP2018500881 A JP 2018500881A JP 2017524478 A JP2017524478 A JP 2017524478A JP 2017524478 A JP2017524478 A JP 2017524478A JP 2018500881 A JP2018500881 A JP 2018500881A
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- medium
- peptone
- hydrolyzate
- clostridium botulinum
- strain
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Abstract
Description
[数1]
B≧−0.625*A+12.5、B≦−1.019*A+53・・・(1)
A:500Da以下のペプチドを約54.91〜60.69重量%含有する加水分解物の含量(0〜5.2w/v%(0〜52g/L));
B:500Da以下のペプチドを約38.48〜42.53重量%含有する加水分解物の含量(0〜5.3w/v%(0〜53g/L))。
1−1:培養に使用した既存培地の組成
本発明で使用された試薬および培地成分は、シグマ社(Sigma、米国)、ケリー社(Kerry Inc、米国)、BD社(BD Biosciences、米国)、Gibco社(Gibco Life Technologies、米国)およびクエスト社(Quest、米国)から購入して使用した。
クロストリジウム・ボツリヌス培養用既存培地(original media)でカゼイン加水分解物(Casein hydrolysate)、酵母抽出物(Yeast extract)およびチオグリコール酸塩培地(Thioglycollate medium)が除去された培地(陰性対照群、negative control)、前記陰性対照群組成に植物性ペプトン候補群4種(Hy−PeaTM 7404、UltraPepTM Cotton、HyPepTM 7504、HyPepTM 4601N)が添加されたAPF培地(Animal Protein Free medium)を製造した(表1)。
実施例1−1および1−2の培地組成を有する10mLの滅菌された培地が入っている培養チューブ(culture tube)に20μLのクロストリジウム・ボツリヌス(疾病管理本部管理番号:4−029−CBB−IS−001)を接種して35℃で嫌気的条件で22〜30時間1次種培養(静置培養)をした。1次種培養で菌株の成長が確認されると、同じ培地組成を有する800mLの滅菌された培地が入っている1L培養ボトル(culture bottle)に8mLの1次種培養液を接種して35℃で嫌気的条件で8〜15時間2次種培養(静置培養)をした。
クロストリジウム・ボツリヌス菌株を培養してボツリヌス毒素を産生するために本培養を実施して、実施例1−1および1−2の組成で培地9.3Lを調製して、10L培養器に入れた後、培地滅菌を行った。嫌気的条件は、窒素を供給して作って、温度は35℃、撹はん速度は50rpmに設定して成長環境を維持させた。
実施例1で4種の植物性ペプトンを添加した培地で育ったクロストリジウム・ボツリヌス菌株の成長が、既存培地で培養する時より遅かったため、これの解決策を下記のように講じた。
1)嫌気性状態を作る役割をするチオグリコール酸塩(Thioglycollate)による影響を確認しようと既存培地にチオグリコール酸塩を除去して成長速度差を確認した。
2)窒素源(Nitrogen source)不足による成長速度低下である可能性があってペプトン濃度を2倍に増加させて培養した。
3)既存植物性ペプトンを含む培地にミネラル成分、アミノ酸、ビタミンを添加した培地とアラガン(Allergan)社の特許(US8,012,716)に出ているAPF培地におけるクロストリジウム・ボツリヌス菌株の成長の可否を比較した(表2)。
実施例2でAPF培地候補群(表2:2〜4 APF培地)中植物性ペプトンとミネラル、アミノ酸およびビタミンを含む培地で既存培地と似た成長速度でクロストリジウム・ボツリヌス菌株が育つことを確認したが、培地の滅菌処理後沈殿物ができる現象が現れてそれに対する原因を把握しようとした(表3)。
実施例3で確認された培地の滅菌処理による沈殿物形成に関与するミネラル成分を確認しようと様々な組み合わせでそれぞれ異なるミネラル成分を培地に添加した後、滅菌処理をした(表4)。
実施例4の植物性ペプトンとミネラルが含まれたAPF培地にビタミンとアミノ酸を追加で添加する場合、クロストリジウム・ボツリヌス菌株の培養が可能であるか否かを確認しようした。また、これとは別に植物性ペプトンとミネラルを排除してビタミン、アミノ酸および/または「BD RechargeTM without Glucose and L−Glutamine」(Cat No.670002,BD bioscience)(酵母抽出物をベースに製作されたブドウ糖とL−グルタミンが排除された培地性分)を含む場合、菌株の培養が可能であるか否かも確認した(表5)。
実施例5のAPF培地に植物性ペプトンの種類を互いに異なる組み合わせで添加する場合、クロストリジウム・ボツリヌス菌株の培養が可能であるか否かを確認しようとした。
実施例1〜7でクロストリジウム・ボツリヌス菌株培養用として利用されたAPF培地組成は、ブドウ糖(glucose)、塩化ナトリウム(NaCl)、植物性ペプトン4種、ミネラル成分3種、アミノ酸、ビタミンに確定して、これらの中成長に大きい影響を及ぼさない培地成分は除去して培地の種類を減少させようとした。したがって、アミノ酸とビタミンは、クロストリジウム・ボツリヌス菌株の成長に大きい影響を及ぼさないとの判断下で培地成分から除去した。また、ミネラル3種中2種を選別するために、表7のような培地組成で菌株を培養して菌株接種後24時間および48時間が過ぎた時点で、OD(540nm、600nm)を測定してその値を比較した。
表9および表10に示された通り、混合物設計に従って植物性ペプトンを組み合わせてクロストリジウム・ボツリヌス菌株の成長を確認した。
実施例1〜8で使用された培地組成中NaClの濃度は0.5g/Lで少量添加された。NaClの濃度によるクロストリジウム・ボツリヌス菌株の成長を調べようと培地のNaCl添加量を0〜1g/Lに調節した後、前記菌株を培養した。
実施例1〜9に基づいて組成された最終選別されたクロストリジウム・ボツリヌス菌株培養用培地(ブドウ糖10g/L、Hy−PeaTM 7404 5g/L、UltraPepTM Cotton 10g/L、HyPepTM 4601N 5g/L、K2HPO4 5.5g/L、Na2HPO4 3g/L)にクロストリジウム・ボツリヌス菌株を接種した後、菌株の成長パターンと毒素濃度を測定した。
実施例1〜10を介して確立されたAPF培地組成でも、既存培地比向上された菌株の成長率を示したが、菌株の成長率をさらに向上させながらもTSEなどの感染の恐れがない培地成分の添加を考慮し、その結果、TSE感染事例が報告されたことがない豚由来ペプトをAPF培地に添加して菌株の成長を調べることにした。
実施例1〜11に係る方法で植物性ペプトン及び豚由来ペプトンが添加された培地組成物を利用して、クロストリジウム・ボツリヌス菌株を培養して菌株の成長パターンを調べてみた(表15参照)。
Claims (12)
- 莢豌豆加水分解物、綿実加水分解物および小麦グルテン加水分解物で構成された群から選択される一つ以上の植物性ペプトンと豚由来ペプトンとを含むクロストリジウム・ボツリヌス菌株培養用培地組成物。
- 前記植物性ペプトンの含有量は、0.1〜10w/v%であることを特徴とする請求項1に記載のクロストリジウム・ボツリヌス菌株培養用培地組成物。
- 前記莢豌豆加水分解物、綿実加水分解物および小麦グルテン加水分解物を全て含む場合、莢豌豆加水分解物、綿実加水分解物および小麦グルテン加水分解物の含有量比は、重量を基準に1:0.24〜43.62:0.01〜50.57であることを特徴とする請求項1に記載のクロストリジウム・ボツリヌス菌株培養用培地組成物。
- 前記豚由来ペプトンの含有量は、0.2〜10w/v%であることを特徴とする請求項1に記載のクロストリジウム・ボツリヌス菌株培養用培地組成物。
- 前記豚由来ペプトンは、500Da以下のペプチドを約54.91〜60.69重量%含有する加水分解物および/または500Da以下のペプチドを約38.48〜42.53重量%含有する加水分解物であることを特徴とする請求項1に記載のクロストリジウム・ボツリヌス菌株培養用培地組成物。
- 前記豚由来ペプトンが500Da以下のペプチドを約54.91〜60.69重量%含有する加水分解物および500Da以下のペプチドを約38.48〜42.53重量%含有する加水分解物を全て含む場合、豚由来ペプトンの含量の範囲は、重量基準で下記の式(1)を利用して計算する方法を使用することを特徴とする請求項5に記載のクロストリジウム・ボツリヌス菌株培養用培地組成物:
[数1]
B≧−0.625*A+12.5、B≦−1.019*A+53・・・(1)
A:500Da以下のペプチドを約54.91〜60.69重量%含有する加水分解物の含量(0〜5.2w/v%);
B:500Da以下のペプチドを約38.48〜42.53重量%含有する加水分解物の含量(0〜5.3w/v%)。 - 前記植物性ペプトンおよび豚由来ペプトンは、酵素処理されたことを特徴とする請求項1に記載のクロストリジウム・ボツリヌス菌株培養用培地組成物。
- 前記クロストリジウム・ボツリヌス菌株培養用培地組成物は、炭素源とK2HPO4(Dipotassium phosphate)、Na2HPO4(Disodium phosphate)およびKH2PO4(Dipotassium phosphate)で構成された群から選択される一つ以上のミネラルとをさらに含むことを特徴とする請求項1に記載のクロストリジウム・ボツリヌス菌株培養用培地組成物。
- 前記ミネラルの含有量は、0.05〜3.5w/v%であることを特徴とする請求項8に記載のクロストリジウム・ボツリヌス菌株培養用培地組成物。
- 下記段階を含むボツリヌス毒素の製造方法:
(a)請求項1〜9のいずれか一項に記載の培地組成物を利用してクロストリジウム・ボツリヌスを培養してボツリヌス毒素を生成させる段階;及び
(b)前記生成されたボツリヌス毒素を回収する段階。 - 前記培養は、嫌気条件で行うことを特徴とする請求項10に記載のボツリヌス毒素の製造方法。
- 前記毒素は、ボツリヌス毒素A、B、C、D、E、F及びGで構成された群から選択されることを特徴とする請求項10に記載のボツリヌス毒素の製造方法。
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KR101775682B1 (ko) * | 2015-11-30 | 2017-09-06 | 주식회사 대웅 | 보툴리눔 독소의 제조방법 |
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JP2009525283A (ja) * | 2006-01-30 | 2009-07-09 | オーキシリウム インターナショナル ホールディングス,インコーポレイテッド | コラーゲン媒介疾患を処置するための組成物および方法 |
JP2011520463A (ja) * | 2008-05-19 | 2011-07-21 | メディ‐トクス インコーポレイテッド | 植物由来成分を含有する培地及び可撓性密閉容器を利用してボツリヌス菌毒素を生産する方法 |
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EP3289071A1 (en) | 2018-03-07 |
RU2017120815A3 (ja) | 2018-12-14 |
WO2016175567A1 (en) | 2016-11-03 |
US20170260515A1 (en) | 2017-09-14 |
RU2017120815A (ru) | 2018-12-14 |
KR101723168B1 (ko) | 2017-04-05 |
TW201638330A (zh) | 2016-11-01 |
AR104418A1 (es) | 2017-07-19 |
BR112017012893A2 (pt) | 2018-01-30 |
US10308923B2 (en) | 2019-06-04 |
EP3289071A4 (en) | 2018-10-31 |
AU2016253790B2 (en) | 2018-11-29 |
CN107002026A (zh) | 2017-08-01 |
CA2968050A1 (en) | 2016-11-03 |
TWI592486B (zh) | 2017-07-21 |
AU2016253790A1 (en) | 2017-05-25 |
JP2020022436A (ja) | 2020-02-13 |
MX2017008198A (es) | 2017-09-13 |
RU2679836C2 (ru) | 2019-02-13 |
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