JP6235176B2 - 非タンパク質安定化クロストリジウム毒素医薬組成物 - Google Patents
非タンパク質安定化クロストリジウム毒素医薬組成物 Download PDFInfo
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- JP6235176B2 JP6235176B2 JP2017010322A JP2017010322A JP6235176B2 JP 6235176 B2 JP6235176 B2 JP 6235176B2 JP 2017010322 A JP2017010322 A JP 2017010322A JP 2017010322 A JP2017010322 A JP 2017010322A JP 6235176 B2 JP6235176 B2 JP 6235176B2
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Description
医薬組成物中に存在するボツリヌス毒素を安定化するために、例えばアルブミンおよびゼラチンなどといった種々の賦形剤が使用されている。アルブミンは豊富に存在する小さな血漿タンパク質である。ヒト血清アルブミンは約69キロダルトン(kD)の分子量を持ち、医薬組成物に非活性成分として使用されてきた。その場合、ヒト血清アルブミンは、医薬組成物中に存在する一定のタンパク質活性成分のバルク担体および安定剤として役立つことができる。
クロストリジウム属には127を越える種があり、形態学および機能に従って分類されている。嫌気性グラム陽性細菌であるボツリヌス菌(Clostridium botulinum)は、ボツリヌス中毒として知ら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共に土壌中に見出され、該細菌は、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。
(1)頸部ジストニーを処置するための筋肉内注射(多数の筋肉)あたり約75単位〜125単位のBOTOX(登録商標)(Allergan, Inc. (アーバイン、カリフォルニア)から商品名BOTOX(登録商標)で入手可能);
(2)眉間のしわを処置するための筋肉内注射あたり約5単位〜10単位のBOTOX(登録商標)(5単位が鼻根筋に筋肉内注射され、10単位がそれぞれの皺眉筋に筋肉内注射される);
(3)恥骨直腸筋の括約筋内注射による便秘を処置するための約30単位〜80単位のBOTOX(登録商標);
(4)上瞼の外側瞼板前部眼輪筋および下瞼の外側瞼板前部眼輪筋に注射することによって眼瞼痙攣を処置するために筋肉あたり約1単位〜5単位の筋肉内注射されるBOTOX(登録商標);
(6)卒中後の上肢痙性を処置するために、下記のように5つの異なる上肢屈筋にBOTOX(登録商標)が筋肉内注射される:
(a)深指屈筋:7.5U〜30U
(b)浅指屈筋:7.5U〜30U
(c)尺側手根屈筋:10U〜40U
(d)橈側手根屈筋:15U〜60U
(e)上腕二頭筋:50U〜200U。5つの示された筋肉のそれぞれには同じ処置時に注射されるので、患者には、それぞれの処置毎に筋肉内注射によって90U〜360Uの上肢屈筋BOTOX(登録商標)が投与される。
(7)偏頭痛を治療するために、25UのBOTOX(登録商標)を頭蓋周囲に注射する(眉間、前頭および側頭筋に対称的に注射する):該注射は、偏頭痛頻度、最大重症度、付随嘔吐および急性薬剤使用の減少(25U注射後の3ヶ月間にわたる)によって評価した場合に、ビヒクルと比較して、偏頭痛の予防療法として有意な利益を与える。
本発明はこの必要性を満たし、非タンパク質賦形剤で安定化したボツリヌス毒素医薬組成物を提供する。
本明細書で使用する場合、下記の単語または用語は下記の定義を持つ。
「約」とは、そのように修飾された事項、パラメータまたは用語が、明記した事項、パラメータまたは用語の値の上下に±10%の範囲を包含することを意味する。
「基本的に含まない」(または「から基本的になる」)とは、その物質が痕跡量しか検出され得ないことを意味する。
「治療用製剤」とは、例えば末梢筋の活動亢進(すなわち痙縮)を特徴とする障害または疾患などといった障害または疾患を処置し、それによってその障害または疾患を軽減するために使用することができる製剤を意味する。
本明細書に開示する医薬組成物は、復元時または注射時に約5〜7.3のpHを持つことができる。
本発明は、クロストリジウム毒素の一次安定剤として非タンパク質賦形剤を用いて、安定化されたクロストリジウム毒素の医薬組成物を製造することができるという知見に基づく。
本発明者は、クロストリジウム毒素医薬組成物中のアルブミンまたはゼラチンなどといったタンパク質賦形剤の適当な代替物として、非タンパク質化合物を使用しうることを見出した。
以下の実施例は、本発明の具体的実施形態を説明するものであって、本発明の範囲を限定しようとするものではない。
N-Zアミンおよび酵母エキスを含有する培地で生育したボツリヌス菌(Clostridium botulinum)Hall株の培養物から、A型ボツリヌス毒素複合体を得た。一連の酸沈殿により、培養溶液から、活性高分子量毒素タンパク質および会合したヘマグルチニンタンパク質からなる結晶性複合体へと、A型ボツリヌス毒素複合体を精製した。次に、食塩水とアルブミンとを含有する溶液に、その結晶性複合体を再溶解し、滅菌濾過(0.2ミクロン)してから、真空乾燥した。真空乾燥組成物を、注射に先立って、滅菌非保存剤処理食塩水で復元した。真空乾燥組成物の各バイアルは、約100単位(U)のA型ボツリヌス菌毒素複合体、0.5ミリグラムのヒト血清アルブミンおよび0.9ミリグラムの塩化ナトリウムを、滅菌真空乾燥状態で含有し、保存剤は含まない。この医薬組成物は、注射前に食塩水で復元されるように、100単位バイアルに入れて、BOTOX(登録商標)という商標で市販されている。
一つ以上の異なる非タンパク質安定化賦形剤を使って複数のボツリヌス毒素製剤を製造する実験を行った。異なる非タンパク質賦形剤または異なる複数の非タンパク質賦形剤を使って各製剤を製造したこと、あるいはボツリヌス毒素製剤中に存在する非タンパク質賦形剤の量または複数の非タンパク質賦形剤の量が異なる製剤を製造したことを除いて、これらの製剤は全て、同じ方法で配合し、凍結乾燥し、復元し、力価を評価し、各製剤には同じタイプのボツリヌス毒素を使用した。
この実施例で行った実験(ここでは製剤を上述のように製造した)の結果を表1〜6に示す。
1.ポリビニルピロリドン(例えばKollidon 17)である特定濃度の単一非タンパク質賦形剤を使って製造したボツリヌス毒素製剤は、回収力価を示さないことがある(表1の第1〜4行参照)。
(a)ボツリヌス毒素医薬組成物中に存在するボツリヌス毒素は、二つ以上の一般的非タンパク質賦形剤を使ってその組成物を製造することにより、安定化されうる(良好な復元力価によって示されうる)。
48歳の男性が頚部ジストニアなどの痙性筋状態という診断を受ける。ラクトースおよびPVPを含有する組成のA型ボツリヌス毒素医薬組成物、約10-3U/kg〜約35U/kgを、その患者に筋肉内注射する。1〜7日以内に痙性筋状態は軽減し、症状の軽減は少なくとも約2ヶ月〜約6ヶ月は持続する。
1.アルブミンなどの血液製剤を一切含まず、したがってプリオンなどの血液製剤感染因子を一切含まない医薬組成物を製造することができる。
2.本医薬組成物は、現在入手することができる医薬組成物で達成されるものと同等またはそれを上回る安定性および高い毒素力価回収率を持つ。
3.筋肉内投与または静脈内投与によって評価される、低下した毒性。
4.低下した抗原性。
したがって、本願請求項の特質および範囲は、上述した好ましい実施形態の説明に限定されるべきではない。
Claims (2)
- (a)タンパク質賦形剤によって安定化されていないボツリヌス毒素、
(b)約5〜50mgの量で存在するポロキサマー、
(c)スクロースおよびトレハロースからなる群から選択される二糖、および
(d)メチオニン
を含む凍結乾燥または真空乾燥医薬組成物。 - 二糖がトレハロースである、請求項1に記載の医薬組成物。
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