JP2015504925A - 非抗凝固性の硫酸化またはスルホン酸化合成ポリマー - Google Patents
非抗凝固性の硫酸化またはスルホン酸化合成ポリマー Download PDFInfo
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Abstract
Description
本出願は、2012年1月30日出願の米国仮特許出願第61/592,554号の利益を主張するものであり、その内容は、全ての目的のためにその全体が参照により本明細書に明確に組み込まれる。
血友病、例えば、血友病Aおよび血友病B、重度のフォンヴィレブランド疾患(svWD)、ならびに重度の第VII因子(FVII)欠乏症を含む血液凝固障害は、典型的には、因子置換(例えば、血友病AおよびsvWDには第VIII因子、血友病Bには第IX因子、ならびにFVII−欠乏には第VII因子(a)等)によって治療されている(Bishop,et al.(2004)Nat.Rev.Drug Discov.,3:684−694、Carcao,et al.(2004)Blood Rev.,18:101−113、Roberts,et al.(2004)Anesthesiology 100:722−730、およびLee(2004)Int.Anesthesiol.Clin.,42:59−76に総説される)。そのような治療が多くの場合効果的であるが、有用性を制限する特徴として、高額な費用、不便さ(すなわち、静脈内投与)、および中和抗体生成が挙げられる(Bishop,et al.(上記参照)、Carcao,et al.(上記参照)、Roberts,et al.(上記参照)、Lee(上記参照)、およびBohn,et al.(2004)Haemophilia 10 Suppl.,1:2−8)。様々な出血障害におけるFVIIaの利用が増えているが(Roberts,et al.(上記参照))、前述の制約および不利点がなく、幅広く適用される代替の単一化合物凝固促進療法が関心対象である。
本発明を説明する際、以下の用語が用いられ、以下に示されるように定義されるよう意図される。
本発明の様々な態様は、対象における血液凝固を亢進するための方法を含む。ある実施形態に従って方法を実践する際に、ある量の非抗凝固性の硫酸化またはスルホン酸化合成ポリマー(NASSP)が、対象における血液凝固を亢進するのに十分であるように対象に投与される。本発明の方法を実践するための組成物およびキットも提供される。
一態様において、本発明は、インビボまたはインビトロで哺乳類血液の凝固を亢進する能力を有する硫酸化またはスルホン酸化合成ポリマーを提供する。様々な実施形態において、この硫酸化またはスルホン酸化合成ポリマーは、凝固促進活性を有する。様々な態様において、本発明のポリマーの凝固促進活性は、標準の凝固アッセイ、例えば、トロンビン生成アッセイ(TGA)を用いて測定できる十分な規模である。
様々な実施形態において、本発明のNASSPは、薬学的製剤に組み込まれる。様々な実施形態において、NASSPの所望の作用および効力に応じて、1つ以上のNASSPが一緒に製剤化され得る。例えば、3つ以上のNASSPおよび4つ以上のNASSPを含む2つ以上のNASSPが一緒に製剤化され得る。2つ以上のNASSPが用いられるとき、組成物中の各NASSPの質量パーセントは、組成物の全質量の1%以上、例えば、2%以上、例えば、5%以上、例えば、10%以上、例えば、25%以上の範囲、および組成物の全質量の50%以上を含む範囲で変化し得る。
本発明は、非抗凝固性の硫酸化またはスルホン酸化合成ポリマー(NASSP)が出血障害を有する患者の治療において凝固促進剤として使用され得るという発見に基づく。止血を調節するための新規の手法は、凝固を促進するために硫酸化またはスルホン酸化合成ポリマー(すなわち、ヘパリン様)を利用する本発明者によって発見された。本明細書に記載の選択された硫酸化またはスルホン酸化合成ポリマーは、抗凝固活性を大きく欠くか、またはそれらが抗凝固活性を呈する濃度よりも著しく低い濃度で凝固促進活性を呈するため、「非抗凝固性の硫酸化またはスルホン酸化合成ポリマー」と表される。
一態様において、NASSPは、出血障害、具体的には、凝固因子の欠乏を伴う出血障害の治療時に止血を改善するか、または対象における抗凝固剤の作用を逆転させるために本発明の方法において用いられ得る。NASSPは、先天性凝固障害、後天性凝固障害、および外傷誘発性出血状態を含む出血障害を治療するために対象に投与され得る。NASSPで治療され得る出血障害の例には、血友病A、血友病B、フォンヴィレブランド疾患、特発性血小板減少症、1つ以上の凝固因子欠乏症(例えば、第XI因子、第XII因子、プレカリクレイン、およびHMWK)、臨床的に有意な出血を伴う1つ以上の因子欠乏症(例えば、第V因子、第VII因子、第VIII因子、第IX因子、第X因子、第XIII因子、第II因子(低プロトロンビン血症)、およびフォンヴィレブランド因子)、ビタミンK欠乏症、フィブリノゲン障害(無フィブリノゲン血症、低フィブリノゲン血症、および異常フィブリノゲン血症を含む)、α2−抗プラスミン欠乏症、ならびに肝疾患、腎疾患、血小板減少症、血小板機能異常症、血腫、内出血、関節血症、手術、外傷、低体温、月経、および妊娠等に起因する過剰な出血が含まれるが、これらに限定されない。ある実施形態において、NASSPは、血友病A、血友病B、およびフォンヴィレブランド疾患を含む先天性凝固障害を治療するために用いられる。他の実施形態では、NASSPは、第VIII因子、フォンヴィレブランド因子、第IX因子、第V因子、第XI因子、第XII因子および第XIII因子の欠乏、具体的には、血液凝固因子に対する阻害剤もしくは自己免疫に起因する障害、または凝固因子合成の減少をもたらす疾患もしくは状態に起因する止血障害を含む後天性凝固障害を治療するために用いられる。
例示の実施形態において、NASSPを用いて少なくとも1つの治療上有効な治療サイクルが対象に投与される。「治療上有効な治療サイクル」とは、投与されると、個体の出血障害の治療に対して正の治療応答をもたらす治療サイクルを指す。止血を改善するNASSPでの治療のサイクルが特に関心対象である。例えば、1つ以上の治療上有効な治療サイクルは、包括的な止血および凝固アッセイ(例えば、CAT、aPTT(以下で詳細に説明される))によって決定される凝固速度を1%以上、例えば、5%以上、例えば、10%以上、例えば、15%以上、例えば、20%以上、例えば、30%以上、例えば、40%以上、例えば、50%以上、例えば、75%以上、例えば、90%以上、例えば、95%以上増加させ得る(トロンビン生成を99%以上増加させることを含む)。他の例では、1つ以上の治療上有効な治療サイクルは、血栓形成を1.5倍以上、例えば、2倍以上、例えば、5倍以上、例えば、10倍以上、例えば、50倍以上増加させ得る(血栓形成を100倍以上増加させることを含む)。いくつかの実施形態において、本発明の方法によって治療される対象は、正の治療応答を呈する。本明細書で使用されるとき、「正の治療応答」とは、本発明に従って治療を受けた個体が、血液凝固時間の短縮および出血の減少、ならびに/または因子置換療法の必要性の減少等の改善を含む、出血障害の1つ以上の症状の改善を呈することを意味する。
a)生体試料をNASSPを含む組成物と合わせることと、
b)生体試料の凝固時間を測定することと、
c)生体試料の凝固時間をNASSPに曝露されていない対応する生体試料の凝固時間と比較することと、を含み、NASSPに曝露された生体試料の凝固時間の減少は、観察された場合、凝固を加速させるNASSPを示す。
本明細書に記載の実施例および実施形態が単に例示のためであり、これらを考慮して様々な修正および変更が当業者に提案され、本明細書の精神および範囲ならびに添付の特許請求の範囲に包含されるべきであることが理解される。本明細書で引用される全ての出版物、特許、および特許出願は、全ての目的のためにそれらの全体が参照により本明細書に組み込まれる。
(実施例1)
(実施例2)
活性化部分トロンボプラスチン時間アッセイ(aPTT)
(実施例3)
Caco−2細胞/インビボ試験
NASSPの経口生物学的利用能を向上させるための1つの戦略は、キトサン、ブロメライン、デオキシコリン(DOC)、またはカプリン酸ナトリウム等の密着結合調節透過亢進剤の適用である。この試験の目標は、透過亢進剤の存在下および不在下でのCaco−2細胞モデルにおける選択したNASSPのインビトロ吸収を決定することである。
半透性フィルター上で培養したヒト結腸腺癌(Caco−2)細胞は自発的分化して、融合性単層を形成する。この細胞層は、構造的にも機能的にも小腸上皮に似ている。Caco−2細胞を10%ウシ胎仔血清および1%L−グルタミンを補充したRPMI細胞増殖培地中のPETトランスウェル−24プレート中で培養した。37℃で95%空気および5%CO2の雰囲気下のインキュベーターに置いてから21日後に融合性単層を得る。透過亢進剤を有するかまたは有しない200μLの増殖培地中に溶解した選択したNASSPを頂端区画内の細胞上に1mg/mLの濃度で添加し、37℃でインキュベートする。培地試料(100μL)を2、4、6、および8時間時点で側底側(体積850μL)から、8時間前および8時間時点で頂端側から収集する。試料回収毎に、除去したアリコートを新鮮な増殖培地と交換する。細胞層が実験中に無傷のままであることを確実にするために、経上皮電気抵抗(TEER)を監視および記録する。各実験において、三重ウェルを試験し、実験を1〜3回行う。
4つまたは5つの亢進剤と組み合わせた合成NASSPの吸収をCaco−2細胞モデルにおいて試験する。細胞の側底側のNASPの量は時間とともに増加する。理論的に可能な最大濃度(μg/mL)は、試料採取に起因する希釈因子のため各時点でわずかに異なる。最大可能NASSPをμg/mLとして表す。8時間時点での吸収も%吸収で表す。吸収は、亢進剤の存在下で増加する。
(実施例4)
凝固改善パラメータにおける全血TEG FVIII阻害モルモットモデルにおけるエクスビボでのNASSPの有効性を試験すること。
雄ダンキンハートリーモルモットに、ヤギ抗ヒトFVIII阻害剤血漿を42BU/kg(1.9mL/kg)の用量で試料採取の45分前に静脈内注入する。40分後、NASSPを0.05、0.15、0.45、または1.35mg/kg(N=5/群)でこの動物に静脈内投与する。300U/kg FEIBA(Baxter,BioScience,Austria)を正の対照とし、生理食塩水をビヒクル対照とする。注入直後、大静脈を穿刺し、血液を全血TEG分析のためにクエン酸の存在下(1:9比)で回収する。トロンボエラストグラフィー(TEG)止血分析装置5000(Haemonetics Corp,USA)を用いて37℃で測定を行う。全ての血液試料をTEGキュベット中の20μLの0.2M CaCl2溶液を37℃で事前に加温し、340μLの血液を添加し、混合し、その後、TEG記録を直ちに開始することによって調製する。測定を少なくとも120分間続けた。凝固時間(R時間)、血栓強固速度(角度)、および最大血栓硬度(MA)のTEGパラメータを記録する。主要エンドポイントR時間をプロットし、異なる投与群の中央値を互いに比較する。
aNASSPを用いたCATアッセイからのインビトロ結果に基づいて、0.05、0.15、0.45、または1.35mg/kgのNASSPを静脈内投与した後にFVIII阻害モルモット(n=5)における凝固促進作用を試験するために投与量パターンを利用する。この動物は、0.15および0.45mg/kgのNASSPを投与したときにわずかに低下した中央R時間(凝固時間)を示す。
(実施例5)
経口投与後のCDラットにおけるNASSPの薬物動態特性を試験すること。この試験は、透過亢進剤がNASSPのインビボ経口生物学的利用能を向上させるかの疑問にも対処する。
一晩断食させた後、雄CDラットに、NASSPの2つの液体製剤を50mg/kgおよび5mL/kgの用量で経口強制飼養する。これらの物質を亢進剤を有しない生理食塩水溶液または0.8重量%のDOCもしくは3重量%のキトサン+0.5mg/mLブロメラインを有する生理食塩水溶液中で調製する。NASSPの投与を受けた各群は、6匹のラットから成った。各製剤について、さらなる3匹のラットを媒体対照とした。血液試料を投与前、ならびに投与の15分、30分、1時間、5時間、および7時間後に、クエン酸の存在下(1:9比)で収集する。乏血小板血漿を3000rpmで10分間の2つの遠心分離ステップによって調製する。
生理食塩水中50mg/kgのNASSPを経口投与したラットは、NASSPの検出可能な血漿レベルを示す。
(実施例6)
静脈内投与後のCDラットにおけるNASSPの薬物動態特性を試験すること。
雄CDラットにNASSPを5mg/kgの用量で静脈内投与する。これらの物質を生理食塩水溶液中で調製し、5mL/kgで注入する。各群は、3匹のラットから成った。血液試料を投与前、ならびに投与の5分、30分、1時間、3時間、6時間、および10時間後に、クエン酸の存在下(1:9比)で収集する。乏血小板血漿を3000rpmでの2つの遠心分離ステップによって調製する。血漿試料を液体クロマトグラフィー質量分析によってNASSPについて分析する。
Claims (22)
- 治療上有効な量の非抗凝固性の非糖類スルホン酸化/硫酸化合成ポリマー(NASSP)と、薬学的に許容される賦形剤と、を含む、薬学的組成物。
- 血液凝固の亢進を必要とする対象を治療するための方法で用いる単位投与量製剤であって、非抗凝固性の非糖類スルホン酸化/硫酸化ポリマーを含む治療上有効な量の組成物を前記対象に投与することを含み、前記単位投与量製剤が、治療上有効な量の請求項1〜3のいずれかに記載のポリマーを含む、単位投与量製剤。
- 約0.5mg〜約1000mgの前記非抗凝固性の非糖類スルホン酸化/硫酸化ポリマーを含む、請求項4に記載の単位投与量製剤。
- 前記ポリマーが、約0.01mg/kg〜約100mg/kgの投与量を提供するのに十分な量である、請求項4または5に記載の単位投与量製剤。
- 前記ポリマーが、前記単位投与量製剤が投与される対象における血液凝固を亢進するのに十分な量で前記製剤中に存在する、請求項4〜6のいずれかに記載の単位投与量製剤。
- 前記単位投与量製剤が経口単位投与量製剤である、請求項4〜7のいずれかに記載の単位投与量製剤。
- 血液凝固の亢進を必要とする対象を治療するための方法であって、非抗凝固性の非糖類スルホン酸化/硫酸化ポリマーを含む治療上有効な量の組成物を前記対象に投与することを含む、方法。
- 前記ポリマーが約0.01mg/kg〜約100mg/kgの投与量で前記対象に投与される、請求項9に記載の方法。
- 前記ポリマーが単位投与量製剤として投与される、請求項9または10に記載の方法。
- 前記ポリマーが経口投与される、請求項9〜11のいずれかに記載の方法。
- 前記対象が、慢性または急性出血障害、血液因子欠乏に起因する先天性凝固障害、および後天性凝固障害からなる群から選択される出血障害を有する、請求項9〜12のいずれかに記載の方法。
- 前記血液因子欠乏が、第V因子、第VII因子、第VIII因子、第IX因子、第XI因子、第XII因子、第XIII因子、およびフォンヴィレブランド因子からなる群から選択される1つ以上の因子の欠乏である、請求項17に記載の方法。
- 前記ポリマーが、手術または他の侵襲的手技の前に前記対象に投与される、請求項9〜12のいずれかに記載の方法。
- 凝固促進剤、内因性凝固経路の活性化剤、外因性凝固経路の活性化剤、非抗凝固性の硫酸化/スルホン酸化多糖類(NASP)、および前記非抗凝固性の非糖類スルホン酸化/硫酸化ポリマーとは異なる構造を有する第2の非抗凝固性の非糖類スルホン酸化/硫酸化ポリマーからなる群から選択される作用物質を投与することをさらに含む、請求項7〜15のいずれかに記載の方法。
- 前記作用物質が、組織因子、第II因子、第V因子、第Va因子、第VII因子、第VIIa因子、第VIII因子、第VIIIa因子、第X因子、第X因子、第Xa因子、第IXa因子、第XI因子、第XIa因子、第XII因子、第XIIa因子、第XIII因子、プレカリクレイン、HMWK、およびフォンヴィレブランド因子からなる群から選択される、請求項16に記載の方法。
- 前記抗凝固剤が、ヘパリン、クマリン誘導体(ワルファリンまたはジクマロール等)、組織因子経路阻害剤(TFPI)、抗トロンビンIII、ループス抗凝固剤、線虫抗凝固ペプチド(NAPc2)、活性部位遮断第VIIa因子(第VIIai因子)、第IXa因子阻害剤、第Xa因子阻害剤(フォンダパリヌクス、イドラパリヌクス、DX−9065a、およびラザキサバン(DPC906)を含む)、第Va因子および第VIIIa因子阻害剤(活性化タンパク質C(APC)および可溶性トロンボモジュリンを含む)、トロンビン阻害剤(ヒルジン、ビバリルジン、アルガトロバン、およびキシメラガトランを含む)、ならびに凝固因子に結合する抗体からなる群から選択される、請求項16に記載の方法。
- 前記抗凝固剤が、第V因子、第VII因子、第VIII因子、第IX因子、第X因子、第XIII因子、第II因子、第XI因子、第XII因子、フォンヴィレブランド因子、プレカリクレイン、およびHMWKからなる群から選択される凝固因子に結合する抗体である、請求項16に記載の方法。
- 対象における組織因子経路阻害剤(TFPI)活性を阻害する方法であって、前記TFPIを阻害するのに十分な量の非抗凝固性の非糖類スルホン酸化/硫酸化ポリマーを含む組成物を前記対象に投与することを含む、方法。
- 生体試料におけるTFPI活性を阻害する方法であって、前記生体試料を前記TFPI活性を阻害するのに十分な量の非抗凝固性の非糖類スルホン酸化/硫酸化ポリマーと合わせることを含む、方法。
- 生体試料における非抗凝固性の非糖類スルホン酸化/硫酸化ポリマーによる血液凝固の加速度を測定する方法であって、a)前記生体試料を前記ポリマーを含む組成物と合わせることと、b)前記生体試料の凝固時間を測定することと、c)前記生体試料の凝固時間を前記ポリマーに曝露されていない対応する生体試料の凝固時間と比較することと、を含み、前記ポリマーに曝露された前記生体試料の凝固時間の減少が、前記凝固を加速させるポリマーを示す、方法。
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JP7410515B2 (ja) | 2020-05-19 | 2024-01-10 | 日油株式会社 | Aptt測定試薬用添加剤、aptt測定試薬、aptt測定用試薬キットおよびaptt測定法 |
Citations (5)
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GB355574A (en) * | 1929-11-04 | 1931-08-27 | Hoffmann La Roche | Process for the preparation of substances arresting blood-coagulation |
JPS6036505A (ja) * | 1983-06-29 | 1985-02-25 | コミツサリア タ レネルギー アトミーク | 重合体製品およびその製造方法 |
JPH0779774A (ja) * | 1993-06-30 | 1995-03-28 | Chemo Sero Therapeut Res Inst | 組織因子凝固系インヒビターの調製法 |
JP2008500367A (ja) * | 2004-05-27 | 2008-01-10 | アビジェン, インコーポレイテッド | 硫酸化多糖を用いて出血性疾患を処置するための方法 |
JP2012500780A (ja) * | 2008-08-22 | 2012-01-12 | バクスター・ヘルスケヤー・ソシエテ・アノニム | 出血性障害を処置するための方法 |
Family Cites Families (1)
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JPH04208165A (ja) * | 1990-11-30 | 1992-07-29 | Toray Ind Inc | 抗血液凝固性材およびその製造方法 |
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- 2013-01-30 US US13/754,727 patent/US20130202550A1/en not_active Abandoned
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- 2013-01-30 WO PCT/US2013/023919 patent/WO2013116383A1/en active Application Filing
- 2013-01-30 EP EP19179032.8A patent/EP3607955A1/en not_active Withdrawn
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2017
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2019
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Patent Citations (5)
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GB355574A (en) * | 1929-11-04 | 1931-08-27 | Hoffmann La Roche | Process for the preparation of substances arresting blood-coagulation |
JPS6036505A (ja) * | 1983-06-29 | 1985-02-25 | コミツサリア タ レネルギー アトミーク | 重合体製品およびその製造方法 |
JPH0779774A (ja) * | 1993-06-30 | 1995-03-28 | Chemo Sero Therapeut Res Inst | 組織因子凝固系インヒビターの調製法 |
JP2008500367A (ja) * | 2004-05-27 | 2008-01-10 | アビジェン, インコーポレイテッド | 硫酸化多糖を用いて出血性疾患を処置するための方法 |
JP2012500780A (ja) * | 2008-08-22 | 2012-01-12 | バクスター・ヘルスケヤー・ソシエテ・アノニム | 出血性障害を処置するための方法 |
Non-Patent Citations (2)
Title |
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BIOMATERIALS, vol. 6, JPN6016043026, September 1985 (1985-09-01), pages 297 - 302, ISSN: 0003532628 * |
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH, vol. 25, JPN6016043027, 1991, pages 1347 - 1361, ISSN: 0003532629 * |
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JP7410515B2 (ja) | 2020-05-19 | 2024-01-10 | 日油株式会社 | Aptt測定試薬用添加剤、aptt測定試薬、aptt測定用試薬キットおよびaptt測定法 |
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EP2809330A1 (en) | 2014-12-10 |
US20170281671A1 (en) | 2017-10-05 |
ES2744595T3 (es) | 2020-02-25 |
AU2013215167A1 (en) | 2014-08-21 |
AU2013215167B2 (en) | 2017-12-21 |
US20190381092A1 (en) | 2019-12-19 |
US20130202550A1 (en) | 2013-08-08 |
JP6138829B2 (ja) | 2017-05-31 |
EP3607955A1 (en) | 2020-02-12 |
WO2013116383A1 (en) | 2013-08-08 |
EP2809330B1 (en) | 2019-06-12 |
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