JP7378425B2 - 肺サーファクタントおよびbpdの予防のためのステロイドを含む治療的組合せ - Google Patents
肺サーファクタントおよびbpdの予防のためのステロイドを含む治療的組合せ Download PDFInfo
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- JP7378425B2 JP7378425B2 JP2020560195A JP2020560195A JP7378425B2 JP 7378425 B2 JP7378425 B2 JP 7378425B2 JP 2020560195 A JP2020560195 A JP 2020560195A JP 2020560195 A JP2020560195 A JP 2020560195A JP 7378425 B2 JP7378425 B2 JP 7378425B2
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Description
SP-C33(leu)アセテート 1.5%;
Mini-B(leu)アセテート 0.2%;および
DPPC:POPGが50:50重量比である。
上記再構成された界面活性剤は、以下、CGF 5633として引用される。
ポラクタントアルファ(ブデソニドの存在下、2ml、1.0mg)の表面活性を、Calmia Medical, Inc., USA から市販されているキャピラリー界面活性計によって、ポラクタントアルファ単独と比較して評価した。
成分 数量
製薬用単位
ポラクタントアルファ 160 mg
微粉末ブデソニド 0.1 mg
ポリソルベート(Tween)20 2.0 mg
モノラウリン酸ソルビタン 0.4 mg
塩化ナトリウム 18 mg
注射用水qsfor 2.0 ml。
成分 数量
製薬用単位
ポラクタントアルファ 160 mg
微粉末ブデソニド 0.04 mg
ポリソルベート(Tween)20 2.0 mg
モノラウリン酸ソルビタン 0.4 mg。
成分 数量
製薬用単位
CHF 5633 160 mg
微粉末ブデソニド 0.04 mg
ポリソルベート(Tween)20 2.0 mg
モノラウリン酸ソルビタン 0.4 mg。
高酸素に曝露された気管支肺異形成症(BPD)早産ウサギモデルをこの実験に用いた。このモデルは、他の場所で詳細に説明されている(Richter J.ら(2014)、ウサギにおける早産後の高酸素誘発肺障害の機能評価、Am J Physiol Lung Cell Mol Physiol 306: L277-283; Jimenez J、ら(2016) 高酸素に暴露した早産ウサギの気管支肺異形成症モデルにおける進行性の血管機能的および構造的損傷、Int J Mol Sci 17:E1776;およびSalaets Tら(2015)、高酸素曝露7日後の早産ウサギ肺のトランスクリプトーム解析、PLoS One 10:e0136569参照)。簡潔に言うと、早産のウサギは、妊娠28日(初期嚢状肺発達期)で帝王切開により出産した(満期=31日)。分娩直後、仔をインキュベーター(32℃)に入れ、5~6匹/群の3群に無作為に分けた(下記参照)。早産のウサギを4日間高酸素状態(酸素95%)に保ち、経口胃管を介して調乳とともに1日2回給餌し、予防的抗生物質およびビタミンKを投与した。3日目に、各動物にサーファクタント単独100mg/kg体重(第1群)、またはサーファクタント100mg/kg+ブデソニド0.05mg/kg体重(第2群)、または界面活性剤100mg/kg+ブデソニド0.25mg/kg体重(第3群)を単回気管内注射した。0.25mg/kgの用量はYehら、2008において最適であると報告されている。
本検討の目的は、子羊モデルを用いて、ポラクタントアルファ中の低用量ブデソニドが全身作用が少なく、炎症の生理学および指標の改善に同等に有効であるという仮説を検証することであった。
雌ヒツジは、係合され約50日目に妊娠確認した。雌ヒツジは、手術による胎児の娩出前に操縦されなかった。ヒツジはケタミン静注で鎮静し、脊椎麻酔を行った。胎児の頭頸部を露出させ、胎児にケタミン10mg/kgを筋注投与したところ、補足的鎮静および気管上の皮膚へのリドカイン浸透として胎児体重が推定された。4.5mmの気管内チューブを気管内に固定し、続いて50mlシリンジでETチューブを通して胎児肺液を吸引し、穏やかに吸引した。肺における界面活性剤/ブデソニドの均一な分布を補助するために、子羊を送達し、表層的に乾燥させ、秤量し、最初の身体位置決め期間を伴う機械的換気に置いた。
新生子羊を2つの処置に無作為に割り付けた:
キュロサーフ200mg/kg(2.5ml/kg)+ブデソニド0.1mg/kg(0.5ml/kg)
キュロサーフ200mg/kg(2.5ml/kg)+ブデソニド0.04mg/kg(0.5ml/kg)
比較のために、キュロサーフ200mg/kg+ブデソニド0.25mg/kgを使用した。
平均気道圧(MAP)および40cmH2O(V40/kg)での体積を図2に報告し、圧力-体積曲線からのV40/Kgの外挿を公知の方法に従って行った。
Claims (11)
- 早産新生児における気管支肺異形成症(BPD)の予防に使用するための組成物であって、
(a)前記早産新生児の200mg/kg体重の投与量のポラクタントアルファと
(b)早産新生児の0.1mg/kg体重の投与量のブデソニド
との組み合わせであり、
前記早産新生児の生後1~4日の間に、1度または2度投与される組成物。 - 薬学的に許容される担体を含む水性懸濁液の形態である、請求項1に記載の組成物。
- 早産新生児における気管支肺異形成症(BPD)の予防に使用するためのキットであって、前記早産新生児の生後1~4日の間に、1度または2度使用されるキットであり、
(a)早産新生児の200mg/kg体重の用量のポラクタントアルファ、および第1の単位剤形中の薬学的に許容される担体または希釈剤、
(b)早産新生児の0.1mg/kg体重の用量のブデソニド、および第2の単位剤形中の薬学的に許容される担体または希釈剤、および
(c)前記第1および第2の剤形を収容するための容器、
を含む、キット。 - 早産新生児における気管支肺異形成症(BPD)の予防のための組成物であって、
200mg/kg体重の用量のポラクタントアルファと、0.1mg/kg体重の用量のブデソニドを含み、
早産新生児の生後1~4日の間に、1度または2度投与される組成物。 - 前記早産新生児が非侵入的換気処置下に維持される、請求項4に記載の組成物。
- 前記非侵入的換気処置が鼻CPAPである、請求項5に記載の組成物。
- ポラクタントアルファとブデソニドが同時に投与される、請求項4~6のいずれか1項に記載の組成物。
- ポラクタントアルファおよびブデソニドが連続的に投与される、請求項4~6のいずれか1項に記載の組成物。
- ポラクタントアルファおよびブデソニドが別々に投与される、請求項4~6のいずれか1項に記載の組成物。
- ポラクタントアルファおよびブデソニドが、吸入または気管内経路によって投与される、請求項4~6のいずれか1項に記載の組成物。
- 前記ポラクタントアルファおよびブデソニドが、薬学的に許容される担体を含む水性懸濁液の形態で投与される、請求項10に記載の組成物。
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US62/751,830 | 2018-10-29 | ||
PCT/EP2019/059742 WO2019206731A1 (en) | 2018-04-23 | 2019-04-16 | A therapeutic combination comprising a pulmonary surfactant and a steroid for the prophylaxis of bpd |
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