JP6530772B2 - アンチセンス組成物およびその作製および使用 - Google Patents
アンチセンス組成物およびその作製および使用 Download PDFInfo
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- JP6530772B2 JP6530772B2 JP2017018231A JP2017018231A JP6530772B2 JP 6530772 B2 JP6530772 B2 JP 6530772B2 JP 2017018231 A JP2017018231 A JP 2017018231A JP 2017018231 A JP2017018231 A JP 2017018231A JP 6530772 B2 JP6530772 B2 JP 6530772B2
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Description
本願は、2008年11月12日に出願された欧州特許出願0845727.8、および2009年2月1日に出願された米国仮特許出願61/152,297への優先権を主張し、これらの出願の両方は、その全体が参考として援用される。
医薬療法には、コルチコステロイド類、抗生物質、免疫抑制薬、および抗TNFα剤が含まれる。現在の治療薬の治療的失敗および重大な副作用により、かわりの選択肢が必要である。
本発明は、例えば以下の項目を提供する。
(項目1)
アンチセンスオリゴヌクレオチドの経口投与用の医薬錠剤製剤
であって、
配列番号1により表されるアンチセンスオリゴヌクレオチドまたはその薬学的に許容可能な塩と薬学的に許容可能な充填剤とを含む顆粒内相と;
崩壊剤を含む顆粒外相と
を含む、医薬錠剤製剤。
(項目2)
配列番号1のヌクレオチド間結合が、O,O−結合ホスホロチオエートである、項目1に記載の医薬錠剤製剤。
(項目3)
前記アンチセンスオリゴヌクレオチドが、配列番号1のナトリウム塩である、項目1または2に記載の医薬製剤。
(項目4)
前記顆粒内相が、崩壊剤をさらに含む、項目1〜4のいずれか一つに記載の医薬錠剤製剤。
(項目5)
前記顆粒外相が、滑沢剤をさらに含む、項目1〜4のいずれか一つに記載の医薬錠剤製剤。
(項目6)
前記充填剤が、マンニトールである、項目1〜5のいずれか一つに記載の医薬錠剤製剤。
(項目7)
前記崩壊剤が、デンプングリコール酸ナトリウムである、項目1〜6のいずれか一つに記載の医薬錠剤製剤。
(項目8)
前記滑沢剤が、デンプングリコール酸ナトリウムである、項目1〜7のいずれか一つに記載の医薬錠剤製剤。
(項目9)
前記顆粒内相が、微結晶性セルロース、デンプングリコール酸ナトリウム、ヒドロキシプロピルメチルセルロース、およびその混合物より選択される成分をさらに含む、項目1〜8のいずれか一つに記載の医薬錠剤製剤。
(項目10)
前記顆粒外相が、微結晶性セルロースおよびステアリン酸マグネシウム、ならびにその混合物より選択される成分をさらに含む、項目1〜9のいずれか一つに記載の医薬錠剤製剤。
(項目11)
腸溶コーティングをさらに含む、項目1〜10のいずれか一つに記載の医薬錠剤製剤。(項目12)
前記腸溶コーティングが、前記錠剤の約12重量%〜約16重量%である、項目11に記載の錠剤。
(項目13)
前記腸溶コーティングが、エチルアクリレート‐メタクリル酸コポリマーを含む、項目11または12に記載の錠剤。
(項目14)
患者に経口投与されると、前記患者における前記オリゴヌクレオチドの実質的に最小限の血漿中濃度を生じる、項目1〜13のいずれか一つに記載の医薬錠剤製剤。
(項目15)
患者に経口投与されると、前記アンチセンスオリゴヌクレオチドの終末回腸および/または右結腸への実質的送達を生じる、項目1〜14のいずれか一つに記載の錠剤。
(項目16)
経口使用用の薬学的に許容可能な錠剤であって、
約0.5重量%〜約10重量%の配列番号1により表されるアンチセンスオリゴヌクレオチドまたはその薬学的に許容可能な塩と;
約30重量%〜約50重量%のマンニトールと;
約10重量%〜約30重量%の微結晶性セルロースと
を含む、薬学的に許容可能な錠剤。
(項目17)
約35mg〜約500mgの配列番号1により表されるアンチセンスオリゴヌクレオチドまたはその薬学的に許容可能な塩を含む、経口剤形。
(項目18)
経口使用用の薬学的に許容可能な錠剤であって、
約5重量%〜約10重量%の配列番号1により表されるアンチセンスオリゴヌクレオチドまたはその薬学的に許容可能な塩と;
約40重量%のマンニトールと、
約8重量%の微結晶性セルロースと、
約5重量%のヒドロプロピルメチルセルロースと、
約2重量%のデンプングリコール酸ナトリウムと
を含む顆粒内相と;
約17重量%の微結晶性セルロースと、
約2重量%のデンプングリコール酸ナトリウムと、
約0.4重量%のステアリン酸マグネシウムと
を含む顆粒外相と;
約13重量%のAcyrlEZE(登録商標)を含む、該錠剤上の腸溶コーティングと
を含む、薬学的に許容可能な錠剤。
(項目19)
約40mgの前記アンチセンスオリゴヌクレオチドを有する、項目18に記載の錠剤。(項目20)
クローン病を治療する方法であって、項目1〜19のいずれか一つに記載の医薬製剤、錠剤または経口剤形を、クローン病の治療が必要な患者に経口投与する工程を含む、方法。
(項目21)
潰瘍性大腸炎を治療する方法であって、項目1〜19のいずれか一つに記載の医薬製剤、錠剤または経口剤形を、潰瘍性大腸炎の治療が必要な患者に経口投与する工程を含む、方法。
(項目22)
慢性炎症性腸疾患を治療する方法であって、項目1〜19のいずれか一つに記載の医薬製剤、錠剤または経口剤形を、慢性炎症性腸疾患の治療が必要な患者に経口投与する工程を含む、方法。
(項目23)
前記医薬製剤、錠剤または経口剤形を経口投与すると、前記医薬製剤、錠剤または経口剤形が、前記患者の前記終末回腸および/または右結腸に実質的に送達される、項目20〜22のいずれか一つに記載の方法。
各顆粒内成分を適当な容器に分配することにより、湿式顆粒を調製した。全ての顆粒内材料を、710μm篩を通してスクリーニングし、フードプロセッサボウルで約5分間ブレンドした。水顆粒化流体(water granulating fluid)を、シリンジを使用してゆっくり加えた。湿式塊を、2.00mmのハンドスクリーンに通し、オーブンで、40℃で90分間まで乾燥させた。乾燥後、顆粒を1.00mmのハンドスクリーンを通してスクリーニングした。乳鉢および乳棒を用いて、粗い顆粒の大きさを減少させた。Turbulaブレンダを10分間42rpmで用いて、ステアリン酸マグネシウムを除く顆粒外(extra−granular)賦形剤と顆粒をブレンドした。ステアリン酸マグネシウムをブレンドに加え、42rpmで2分間さらにブレンドした。Manesty F3シングルパンチ圧縮機で製剤を圧縮した。AS1錠剤の全体的製造プロセス工程系統図を、図2に見ることができる。
粒径分布、密度、Carr指数および安息角につき、製剤を評価した。粒径分析により、3.5mg用量強度の製剤は粒径がより大きい(335μm)ことが示されたが、35mgおよび250mg用量強度の製剤には通常の粒径分布が見られた。図3は、組成が表1に示される3.5mg用量強度の粒径分布を表す。図4は、組成が表1に示される35mg用量強度の粒径分布を表す。最後に、図5は、組成が表1に示される250mg用量強度での粒径分布を表す。表2は、三つの用量強度についての粉末の特性付けの結果を提示する。
実施例3‐腸溶コーティング
Acryl‐EZE(登録商標)コーティングのための20%コーティング溶液を調製した。必要量の水およびAcryl‐EZE(登録商標)を適当な容器に分配した。混合しながら、Acryl‐EZE(登録商標)をゆっくり渦中に加えた。分散物を45分間撹拌し、500μmの篩に通した。10%または16%の重量増加が得られるまで、吹付けを続けた。
AS1の40mgの錠剤(table)のためのバッチ処方が、以下に表される:
る。
表4に示すように、200mg用量強度のAS1錠剤を、概して実施例1の手順に従って製造した。すべての製剤の錠剤重量は、500mgであった。
この分析試験手順は、HPLCによるAS1腸溶コート錠の溶解分析を記載する。遅延放出固体剤形のためのPh.Eur.Procedureにしたがって方法Aを使用して溶解を行う。使用した装置は、Ph.Eur./USP装置2(パドル)であった。
上のバッチ1に記載の錠剤を用いて、16%のAcryl‐EZE(登録商標)コーティングを有する錠剤を作り、コーティングパンへの錠剤の重量増加が出発値の16%となるまで最終コーティングを行う。図7は、溶解プロフィルを表す。
本研究の目的は、経口投与または静脈内投与による単回用量を投与したときの、有意識非拘束のカニクイザルの心臓血管系、呼吸系、および中枢神経系に対するAS1の潜在的影響を確認することであった。この研究における静脈内投与は、全身曝露に伴う潜在的影響を調査することが含まれた。静脈内用量の製剤をバルク粉末として、経口投与ではゼラチンカプセルに含まれる腸溶錠として、投与した。3.6〜3.8歳で体重3.4〜3.9kgの四匹の実験で使用したことのある雄カニクイザルを、単一の群に割り当てた。
12日目に、すべての動物にゆっくり注射して静脈内に対照の投薬(リン酸塩緩衝食塩水)を行った後、14日目および19日目にAS1の静脈内投薬を行った。
本研究の目的は、1日1回28日間マウスに経口投与し28日の回復期間を続けたときの、AS1の潜在毒性およびトキシコキネティクスを評価することであった。小さな被覆ビーズの形態の胃保護コーティングを含む製剤としてAS1製剤を調製した。AS1を不活性ビード上へ重ねてから、ヒト使用に適した経口製剤を模倣するためにこれをEudragit(登録商標)S100で被覆した。異なる用量レベルを投与された三群を用いた(30mg/kg/日(低);100mg/kg/日;300mg/kg/日)。
TNBS誘発性結腸炎モデルにおける腸炎症の経過に対するAS1の治療効果を試験するために、マウスをTNBSの直腸内投与の一日後に、単回用量のAS1またはSmad7センスオリゴヌクレオチドで治療した。125または250μg/マウスの単回用量により、体重減少が改善され、結腸炎の組織学的徴候の重症度が顕著に減少した。
本発明の特定の実施形態が記載されているが、上記の明細書は例示的であり限定的でない。本発明の多くの変化形が、本明細書を参照した当業者に明らかとなる。本発明の完全な範囲は、本特許請求の範囲をその等価物の完全な範囲とともに、本明細書をそのような変化形とともに参照することにより、決定されなければならない。
Claims (25)
- 複数の錠剤を含む経口剤形であって、
配列番号1のヌクレオチド配列を含むオリゴヌクレオチドまたはその薬学的に許容可能な塩および
エチルアクリレート‐メタクリル酸コポリマーを含む胃保護コーティング
の両方をそれぞれの錠剤が含む、経口剤形。 - 前記オリゴヌクレオチドが、配列番号1のナトリウム塩である、請求項1に記載の経口剤形。
- 配列番号1のヌクレオチド間結合の少なくとも1つが、O,O‐結合ホスホロチオエートである、請求項1に記載の経口剤形。
- 配列番号1の全てのヌクレオチド間結合が、O,O‐結合ホスホロチオエートである、請求項1に記載の経口剤形。
- 薬学的に許容可能な充填剤をさらに含む、請求項1に記載の経口剤形。
- 前記薬学的に許容可能な充填剤が、マンニトールである、請求項5に記載の経口剤形。
- 前記胃保護コーティングが、各錠剤の約8重量%〜12重量%である、請求項1に記載の経口剤形。
- 前記胃保護コーティングが、各錠剤の約8重量%〜約15重量%である、請求項1に記載の経口剤形。
- 前記胃保護コーティングが、各錠剤の約12重量%〜約16重量%である、請求項1に記載の経口剤形。
- 前記胃保護コーティングが、各錠剤の約10重量%〜約12重量%である、請求項1に記載の経口剤形。
- 約35mgの前記オリゴヌクレオチドを有する、請求項1に記載の経口剤形。
- 約40mgの前記オリゴヌクレオチドを有する、請求項1に記載の経口剤形。
- 約50mgの前記オリゴヌクレオチドを有する、請求項1に記載の経口剤形。
- 約70mgの前記オリゴヌクレオチドを有する、請求項1に記載の経口剤形。
- 約100mgの前記オリゴヌクレオチドを有する、請求項1に記載の経口剤形。
- 約150mgの前記オリゴヌクレオチドを有する、請求項1に記載の経口剤形。
- 前記複数の錠剤が、カプセルに含まれる、請求項1に記載の経口剤形。
- 患者に経口投与されると、前記患者における前記オリゴヌクレオチドまたはその薬学的に許容可能な塩の実質的に最小限の血漿中濃度を生じる、請求項1に記載の経口剤形。
- 前記オリゴヌクレオチドまたはその薬学的に許容可能な塩の終末回腸および/または右結腸への実質的送達に適した、請求項1に記載の経口剤形。
- 炎症性腸疾患を治療するための請求項1〜19のいずれか一項に記載の経口剤形であって、前記経口剤形が、炎症性腸疾患の治療が必要な患者に経口投与されることを特徴とする、経口剤形。
- 前記炎症性腸疾患が、クローン病または潰瘍性大腸炎である、請求項20に記載の経口剤形。
- クローン病を治療するための請求項1〜19のいずれか一項に記載の経口剤形であって、前記経口剤形が、クローン病の治療が必要な患者に経口投与されることを特徴とする、経口剤形。
- 潰瘍性大腸炎を治療するための請求項1〜19のいずれか一項に記載の経口剤形であって、前記経口剤形が、潰瘍性大腸炎の治療が必要な患者に経口投与されることを特徴とする、経口剤形。
- 慢性炎症性腸疾患を治療するための請求項1〜19のいずれか一項に記載の経口剤形であって、前記経口剤形が、慢性炎症性腸疾患の治療が必要な患者に経口投与されることを特徴とする、経口剤形。
- 前記経口剤形を経口投与すると、前記経口剤形が、前記患者の前記終末回腸および/または右結腸に実質的に送達される、請求項20〜24のいずれか一つに記載の経口剤形。
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