JP2019517481A - 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 - Google Patents
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 Download PDFInfo
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- JP2019517481A JP2019517481A JP2018562171A JP2018562171A JP2019517481A JP 2019517481 A JP2019517481 A JP 2019517481A JP 2018562171 A JP2018562171 A JP 2018562171A JP 2018562171 A JP2018562171 A JP 2018562171A JP 2019517481 A JP2019517481 A JP 2019517481A
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- tryptophan
- botulinum neurotoxin
- neurotoxin
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Abstract
Description
・配列番号1のアミノ酸1〜448
・配列番号2のアミノ酸1〜440
・配列番号3のアミノ酸1〜441
・配列番号4のアミノ酸1〜445
・配列番号5のアミノ酸1〜422
・配列番号6のアミノ酸1〜439
・配列番号7のアミノ酸1〜441
のうち1つと少なくとも50%、好ましくは少なくとも60%、70%、80%、90%または95%の配列同一性を有し、小胞媒介性神経伝達物質放出に関与するSNAREタンパク質の1つを切断する能力を保持するアミノ酸配列を有していてもよい。
・配列番号1のアミノ酸449〜871
・配列番号2のアミノ酸441〜858
・配列番号3のアミノ酸442〜866
・配列番号4のアミノ酸446〜862
・配列番号5のアミノ酸423〜845
・配列番号6のアミノ酸440〜864
・配列番号7のアミノ酸442〜863
のうち1つと少なくとも50%、好ましくは少なくとも60%、70%、80%、90%または95%の配列同一性を有し、転移能力を保持するアミノ酸配列を有していてもよい。
・配列番号1のアミノ酸872〜1296
・配列番号2のアミノ酸859〜1291
・配列番号3のアミノ酸867〜1291
・配列番号4のアミノ酸863〜1276
・配列番号5のアミノ酸846〜1252
・配列番号6のアミノ酸865〜1274
・配列番号7のアミノ酸864〜1297
のうち1つと少なくとも50%、好ましくは少なくとも60%、70%、80%、90%または95%の配列同一性を有し、神経筋細胞に結合する能力を保持するアミノ酸配列を有していてもよい。
・配列番号1のアミノ酸1111〜1296
・配列番号2のアミノ酸1098〜1291
・配列番号3のアミノ酸1112〜1291
・配列番号4のアミノ酸1099〜1276
・配列番号5のアミノ酸1086〜1252
・配列番号6のアミノ酸1106〜1274
・配列番号7のアミノ酸1106〜1297
のうち1つと少なくとも50%、好ましくは少なくとも60%、70%、80%、90%または95%の配列同一性を有し、神経筋細胞に結合する能力を保持するアミノ酸配列を有していてもよい。
・1mLあたり4〜10000LD50単位のボツリヌス神経毒素、
・0.001〜15%v/vのポリソルベート、
・0.1〜5mg/mLのトリプトファン、
・10〜500mMのNaCl、
・1〜50mMのKCl、
・1〜100mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pH5.5〜8であり、5℃で6ヶ月間安定である。
・1mLあたり10〜2000LD50単位のボツリヌス神経毒素、
・0.005〜2%v/vのポリソルベート、
・0.1〜5mg/mLのトリプトファン、
・25〜300mMのNaCl、
・1〜10mMのKCl、
・2〜50mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pH6.0〜7.5であり、5℃で12ヶ月間安定である。
・1mLあたり10〜2000LD50単位のボツリヌス神経毒素、
・0.05〜0.2%v/vのポリソルベート80、
・0.1〜5mg/mLのトリプトファン、
・25〜300mMのNaCl、
・1〜10mMのKCl、
・2〜50mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pH6.0〜7.5であり、5℃で12ヶ月間安定である。
・ボツリヌス神経毒素A、
・0.2%v/vのポリソルベート80、
・1mg/mLのトリプトファン、
・140mMのNaCl、
・3mMのKCl、
・10mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約6.6である。
・ボツリヌス神経毒素A、
・0.04%v/vのポリソルベート80、
・1mg/mLのトリプトファン、
・140mMのNaCl、
・3mMのKCl、
・10mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約6.9である。
・ボツリヌス神経毒素B、
・0.25%v/vのポリソルベート20、
・4mg/mLのトリプトファン、
・140mMのNaCl、
・3mMのKCl、
・10mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約7.4である。
・ボツリヌス神経毒素A、
・0.01%v/vのポリソルベート80、
・0.25mg/mLのトリプトファン、
・255mMのNaCl、
・2mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約7.2である。
・ボツリヌス神経毒素A、
・0.01%v/vのポリソルベート80、
・0.25mg/mLのトリプトファン、
・255mMのNaCl、
・10mMのKCl、
・50mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約6.3である。
・ボツリヌス神経毒素A、
・1%v/vのポリソルベート80、
・0.25mg/mLのトリプトファン、
・255mMのNaCl、
・50mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約6.3である。
・ボツリヌス神経毒素A、
・1%v/vのポリソルベート80、
・3mg/mLのトリプトファン、
・255mMのNaCl、
・10mMのKCl、
・50mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約7.2である。
・ボツリヌス神経毒素A、
・0.1%v/vのポリソルベート80、
・1.625mg/mLのトリプトファン、
・140mMのNaCl、
・3mMのKCl、
・10mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約6.75である。
・ボツリヌス神経毒素A、
・0.01%v/vのポリソルベート80、
・1mg/mLのトリプトファン、
・140mMのNaCl、
・3mMのKCl、
・10mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約6.75である。
・ボツリヌス神経毒素A、
・0.1%v/vのポリソルベート80、
・1mg/mLのトリプトファン、
・140mMのNaCl、
・3mMのKCl、
・10mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約6.75である。
・ボツリヌス神経毒素A、
・1%v/vのポリソルベート80、
・1mg/mLのトリプトファン、
・140mMのNaCl、
・3mMのKCl、
・10mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約6.75である。
・ボツリヌス神経毒素B、
・15%v/vのポリソルベート20、
・1mg/mLのトリプトファン、
・140mMのNaCl、
・3mMのKCl、
・10mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約7.4である。
・ボツリヌス神経毒素B、
・15%v/vのポリソルベート20、
・4mg/mLのトリプトファン、
・140mMのNaCl、
・3mMのKCl、
・10mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約7.4である。
・ボツリヌス神経毒素B、
・0.25%v/vのポリソルベート20、
・4mg/mLのトリプトファン、
・140mMのNaCl、
・3mMのKCl、
・10mMのリン酸ナトリウム
を含むか、または本質的にそれらからなり、
pHが約7.4である。
・眼瞼痙攣、斜視(拘束型または筋性斜視を含む)、弱視、動揺視、保護性眼瞼下垂、角膜保護のための治療的眼瞼下垂、眼振、内斜視、複視、眼瞼内反、眼瞼後退、眼窩ミオパチー、眼球斜位、共同性眼位異常、非共同性眼位異常、原発性または二次性内斜視または外斜視、核間性眼筋麻痺、斜偏位、デュアン症候群および上眼瞼後退からなる群から選択される眼科障害、
・片側顔面痙攣、斜頸、小児または成人の痙縮(脳性麻痺、脳卒中後、多発性硬化症、外傷性脳損傷または脊髄損傷患者など)、特発性限局性ジストニア、筋硬直、書痙、手のジストニア、第VI神経麻痺、顎口腔ジストニア、頭部振戦、遅発性ジスキネジア、遅発性ジストニア、職業性痙攣(音楽家の痙攣を含む)、顔面神経麻痺、閉口痙攣、顔面痙攣、病的共同運動、振戦、原発性書字振戦、ミオクローヌス、全身強直性症候群、足のジストニア、顔面麻痺、painful−arm−and−moving−fingers症候群、チック障害、ジストニア性チック、トゥレット症候群、神経性筋強直症、顎の震え、外直筋麻痺、ジストニア性内反足、下顎ジストニア、ラビット症候群、小脳性振戦、第III神経麻痺、軟口蓋ミオクローヌス、アカシジア(akasthesia)、筋痙攣、第IV神経麻痺、すくみ足歩行、伸筋躯幹ジストニア、顔面神経麻痺後の病的共同運動、二次性ジストニア、パーキンソン病、ハンチントン舞踏病、てんかん、オフピリオドジストニア、頭部破傷風、ミオキミアおよび筋痙攣線維束性収縮症候群を含む運動障害、
・痙攣性発声障害、耳の障害、聴覚障害、イヤークリック、耳鳴り、めまい、メニエール病、蝸牛神経機能障害、吃音、輪状咽頭嚥下障害、歯ぎしり、慢性誤嚥の喉頭閉鎖、声帯肉芽腫、喉頭室ジストニア(ventricular dystonia)、仮声帯発声、変声障害、開口障害、いびき、声の震え、誤嚥、舌突出ジストニア、口蓋の震え、唇の過蓋咬合および喉頭ジストニア、ファーストバイト症候群を含む耳鼻咽喉科障害、
・アカラシア、裂肛、便秘、顎関節機能障害、オディ括約筋機能障害、オディ括約筋の持続性緊張亢進、腸管筋障害、恥骨直腸筋症候群、アニスムス、幽門痙攣、胆嚢機能不全、胃腸または食道の運動機能障害、びまん性食道痙攣および胃不全麻痺を含む胃腸障害、
・排尿筋括約筋協調不全、排尿筋反射亢進、(パーキンソン病、脊髄損傷、脳卒中または多発性硬化症患者などにおける)神経性膀胱機能障害、過活動膀胱、神経性排尿筋過活動、膀胱痙攣、尿失禁、尿閉、膀胱頚部肥大、排尿障害、間質性膀胱炎、膣痙、子宮内膜症、骨盤痛、前立腺肥大(良性前立腺肥大症)、前立腺痛、前立腺癌および持続勃起症を含む泌尿生殖器障害、
・皮膚細胞増殖性障害、皮膚創傷、乾癬、酒さ、にきび;フォックス・フォアダイス症候群またはヘイリー・ヘイリー病などの希少な遺伝性皮膚疾患;ケロイドおよび肥厚性瘢痕の減少;ポアサイズの減少;皮膚の炎症症状;皮膚の疼痛性炎症症状を含む皮膚科障害、
・背部痛(上部背痛、下部背痛)、筋筋膜痛、緊張型頭痛、線維筋痛症、有痛性症候群、筋肉痛、片頭痛、むち打ち症、関節痛、術後疼痛、筋けいれんに関連しない疼痛、および平滑筋障害に関連した疼痛を含む疼痛障害、
・膵炎、神経性炎症性障害(痛風、腱炎、滑液包炎、皮膚筋炎および強直性脊椎炎を含む)を含む炎症性障害、
・過度の腺分泌、多汗症(腋窩多汗症、手掌多汗症およびフレイ症候群を含む)、唾液分泌過多、流涎症、臭汗症、粘液分泌過多、流涙過多、ホロクリン腺機能不全、皮脂分泌過剰などの分泌障害、
・鼻炎(アレルギー性鼻炎を含む)、COPD、喘息および結核を含む呼吸器障害、
・筋肉肥大、咬筋肥大、末端肥大症、および筋肉痛を伴う神経性前脛骨筋肥大を含む肥大性障害、
・テニスひじ(またはひじの上顆炎)、関節の炎症、股関節炎、変形性関節症、肩の回転筋帽(rotator muscle cap)の病理、関節リウマチおよび手根管症候群を含む関節障害、
・2型糖尿病、高グルカゴン血症、高インスリン血症、低インスリン血症、高カルシウム血症、低カルシウム血症、甲状腺障害(グレーブス病、甲状腺炎、橋本甲状腺炎、甲状腺機能亢進症および甲状腺機能低下症を含む)、副甲状腺障害(副甲状腺機能亢進症および副甲状腺機能低下症を含む)、グッシング症候群および肥満などの内分泌障害、
・全身性エリテマトーデスなどの自己免疫疾患、
・傍神経節腫、前立腺癌および骨腫瘍などの増殖性疾患、
・スポーツ傷害、筋肉傷害、腱創傷および骨折を含む外傷性傷害、ならびに
・獣医学的用途(例えば、哺乳動物の不動化、ウマ疝痛、動物のアカラシア、または動物の筋痙攣)。
15ng/mLの高純度BoNT/Aと、15%v/vのポリソルベート20と、チロシン(Tyr)、トリプトファン(Trp)およびシステイン(Cys)から選択したアミノ酸、またはメチオニン(Met)、チロシン(Tyr)、トリプトファン(Trp)およびシステイン(Cys)の混合物(Sigma Aldrich)と、リン酸緩衝生理食塩水(Calbiochem製PBS)(140mM NaCl、10mMリン酸ナトリウムおよび3mM KCl、25℃でpH7.4)とを含む液体ボツリヌス毒素調製物を調製し、0.22μmPVDF(ポリフッ化ビニリデン)フィルターを使用して濾過し、2mLシリコーン処理ガラスシリンジに40℃で6日間保管し、その後、各調製物について力価試験を実施した。
350ng/mLの高純度BoNT/Bと、15%v/vのポリソルベート20と、チロシン(Tyr)、トリプトファン(Trp)およびシステイン(Cys)から選択したアミノ酸、またはメチオニン(Met)、チロシン(Tyr)、トリプトファン(Trp)およびシステイン(Cys)の混合物と、pH7.4のリン酸緩衝生理食塩水(PBS)とを含む液体ボツリヌス毒素調製物を調製し、0.22μmフィルターを使用して濾過し、2mLシリコーン処理ガラスシリンジに40℃で2週間保管し、その後、上述したように各調製物について力価試験を実施した。
高純度BoNT/AまたはBoNT/Bと、様々な濃度のポリソルベート20(PS20)およびトリプトファンと、pH7.4のリン酸緩衝生理食塩水(PBS)とを含む液体ボツリヌス毒素調製物を調製し、0.22μmフィルターを使用して濾過し、2mLシリコーン処理ガラスシリンジに保管した。後肢麻痺力価試験を上述したように各調製物について実施した。
精製による溶出緩衝液(5):0.2%(v:v)ポリソルベート20を含む50mM酢酸ナトリウム(pH4.5)、および400mM塩化ナトリウム。
*25℃の8mg/mL Trp0.25%ポリソルベート20の2種類のBoNT/A希釈液の混同がおそらく生じた。
100ng/mLの高純度BoNT/Bと、ポリソルベート20と、様々なアミノ酸供給業者から入手したトリプトファンと、pH7.4のPBS(Calbiochem)、pH7の12nMリン酸緩衝液(Apoteket)、およびpH5.5の20mM酢酸ナトリウム(NaAc)(Fluka製NaAcおよびMerck製酢酸)から選択した緩衝液とを含む液体ボツリヌス毒素調製物を調製し、0.22μmフィルターを使用して濾過し、2mLシリコーン処理ガラスシリンジに保管した。後肢麻痺力価試験を上述したように各調製物について実施した。
15ng/mLの高純度BoNT/Aと、ポリソルベート20(PS20)またはポリソルベート80(PS80)またはHSAと、トリプトファンと、PBSとを含む液体ボツリヌス毒素調製物を調製し、0.22μmフィルターを使用して濾過し、2mLシリコーン処理ガラスシリンジに保管した。後肢麻痺力価試験を上述したように各調製物について実施した。
10ng/mLの高純度BoNT/Aと、0.25%のPS80と、1mg/mLのトリプトファンと、PBSとを含む液体ボツリヌス毒素調製物を上述したように調製した。HClを添加してpHを6.6および7.0に調整した。各調製物を40℃で5週間保管した。
0.3ng/mLの高純度BoNT/Aと、PS20およびPS80から選択したポリソルベートと、1mg/mLのトリプトファンと、12mMのPBS(pH7.4)とを含む液体ボツリヌス毒素調製物を上述したように調製した。1.2M HClを添加して各調製物のpHをpH6.6または6.9に調整した。
様々な濃度のポリソルベート80、トリプトファン、リン酸ナトリウム、塩化ナトリウム、塩化カリウムおよび様々なpHを用いて、高純度A型ボツリヌス神経毒素を含む各種製剤を19種類調製した。各製剤は、500U/mLの目標名目力価を有していた。各製剤を脱気し、0.2μmフィルターで濾過し、バイアルに充填した。バイアル内の保護雰囲気として窒素ガスを使用した。充填は嫌気性チャンバ内で行った。2mLガラスバイアルに窒素雰囲気中で各製剤を1mLアリコートとして充填し、FluroTec(R)栓で蓋をし、アルミニウムフリップオフシールで密封し、直立で保管した。
0.1%(v/v)PS60、1mg/mLのL−トリプトファン、10mMのリン酸ナトリウム、140mMの塩化ナトリウム、3mMの塩化カリウム、および注射用水を用いて、高純度A型ボツリヌス神経毒素を含む製剤を調製した。HClでpHを6.75に調整した。製剤は、100U/mLの目標名目力価を有していた。製剤を脱気し、0.2μmフィルターで濾過し、窒素雰囲気の嫌気性チャンバ中の2mLバイアルに1mLの充填量で無菌充填した。バイアル内の保護雰囲気として窒素ガスを使用した。バイアルは、FluroTec(R)栓で蓋をしてアルミニウムフリップオフシールで密封した。
Claims (18)
- タンパク質性神経毒素と、界面活性剤と、トリプトファンおよびチロシンから選択されるアミノ酸と、ナトリウムイオン、塩化物イオンおよびリン酸イオンを含む緩衝液とを含む液体組成物であって、
pH5.5〜8であり、
動物由来タンパク質を含まず、かつ
経時的に安定である液体組成物。 - 上記界面活性剤が非イオン性界面活性剤である、請求項1に記載の液体組成物。
- 上記非イオン性界面活性剤がポリソルベート、好ましくはポリソルベート20、ポリソルベート60またはポリソルベート80である、請求項2に記載の液体組成物。
- 上記アミノ酸がトリプトファン、好ましくはL−トリプトファンである、請求項1〜3のいずれか一項に記載の液体組成物。
- 上記緩衝液がカリウムイオンをさらに含む、請求項1〜4のいずれか一項に記載の液体組成物。
- pHが6.0〜7.5である請求項1〜5のいずれか一項に記載の液体組成物。
- 5℃で2、3、6、12、18、24または36ヶ月にわたって起こる細胞外タンパク質分解活性の損失が30%以下である、請求項1〜6のいずれか一項に記載の液体組成物。
- 上記タンパク質性神経毒素が、複合体の天然ボツリヌス神経毒素、高純度天然ボツリヌス神経毒素、および組換えボツリヌス神経毒素から選択されるボツリヌス神経毒素である、請求項1〜7のいずれか一項に記載の液体組成物。
- 上記ボツリヌス神経毒素が、ボツリヌス神経毒素A、B、C、D、E、FまたはG、修飾ボツリヌス神経毒素、およびキメラボツリヌス神経毒素から選択される組換えボツリヌス神経毒素である、請求項8に記載の液体組成物。
- 1mLあたり4〜10000LD50単位のボツリヌス神経毒素、
0.001〜15%v/vのポリソルベート、
0.1〜5mg/mLのトリプトファン、
10〜500mMのNaCl、
1〜50mMのKCl、
1〜100mMのリン酸ナトリウム
を含み、
pH5.5〜8であり、かつ5℃で6ヶ月間安定である請求項1〜9のいずれか一項に記載の液体組成物。 - 1mLあたり10〜2000LD50単位のボツリヌス神経毒素、
0.05〜0.2%v/vのポリソルベート80、
0.1〜5mg/mLのトリプトファン、
25〜300mMのNaCl、
1〜10mMのKCl、
2〜50mMのリン酸ナトリウム
を含み、
pH6.0〜7.5であり、かつ5℃で12ヶ月間安定である請求項10に記載の液体組成物。 - 治療に使用するための請求項1〜11のいずれか一項に記載の液体組成物。
- 筋障害、神経筋障害、神経障害、眼科障害、疼痛障害、心理的障害、関節障害、炎症性障害、内分泌障害または泌尿器障害を治療または予防するのに使用するための請求項12に記載の液体組成物。
- 美容医療における、例えば、皮膚のしわ、特にしかめ面ラインなどの顔のしわ、目の輪郭のしわ、眉間しわ線、への字口、首のしわ(プラティスマバンド)、顎のしわ(オトガイ筋、橙皮状皮膚、割れ顎)、額のしわ、「引っかき傷のある皮膚」のしわ、鼻のリフト治療または睡眠線を治療または予防するための請求項1〜11のいずれか一項に記載の液体組成物の使用。
- 動物由来タンパク質を含まない液体組成物においてタンパク質性神経毒素を分解から保護するための、トリプトファンおよびチロシンから選択されるアミノ酸の使用。
- 上記アミノ酸がトリプトファンである、請求項15に記載の使用。
- 上記タンパク質性神経毒素がボツリヌス神経毒素である、請求項15または16に記載の使用。
- 上記アミノ酸が、界面活性剤、ならびにナトリウムイオン、塩化物イオンおよびリン酸イオンを含む緩衝液と併用され、かつ上記液体組成物のpHが5.5〜8である、請求項15に記載の使用。
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JP2003522154A (ja) * | 2000-02-08 | 2003-07-22 | アラーガン、インコーポレイテッド | ボツリヌス毒素医薬組成物 |
WO2001064241A1 (fr) * | 2000-02-29 | 2001-09-07 | Chugai Seiyaku Kabushiki Kaisha | Preparations stabilisees a long terme |
WO2006013370A1 (en) * | 2004-08-04 | 2006-02-09 | Ipsen Limited | Pharmaceutical composition containing botulinum neurotoxin a2 |
JP2010532784A (ja) * | 2007-07-10 | 2010-10-14 | メディ‐トックス、インク. | 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 |
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