JP6636443B2 - 出血性症候群の場合における失血を制御する及び/又は血小板の代用にすることが可能であるコラーゲンに基づいた注射用製剤 - Google Patents
出血性症候群の場合における失血を制御する及び/又は血小板の代用にすることが可能であるコラーゲンに基づいた注射用製剤 Download PDFInfo
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- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
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- 230000002885 thrombogenetic effect Effects 0.000 description 1
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 1
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- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
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Classifications
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
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- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
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- C—CHEMISTRY; METALLURGY
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- C07K2319/00—Fusion polypeptide
- C07K2319/20—Fusion polypeptide containing a tag with affinity for a non-protein ligand
- C07K2319/21—Fusion polypeptide containing a tag with affinity for a non-protein ligand containing a His-tag
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- Pharmacology & Pharmacy (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
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- General Chemical & Material Sciences (AREA)
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- Biochemistry (AREA)
- Toxicology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Hematology (AREA)
- Diabetes (AREA)
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- Medicinal Preparation (AREA)
Description
- 血流中で血小板を活性化させる能力を要する、大量失血、特に、非圧縮性のエピソード中;
- 特に全血又は血小板の輸血に基づいた手法の補完としての、医療センターから離れた輸血蘇生法中のアジュバントとして;
- 特に頭蓋内の手術又は出血用の解毒剤を含まない、現在市販されている新たな抗血小板薬(例えば、プラスグレル、チカグレロル)のための回復剤(reverting agent)として、
コラーゲンに由来する血小板活性化タンパク質又はペプチドを新たな注射用止血薬として静脈内投与することへの関心に関する。
- 長さ10μm未満の粒子又は原線維であって、かかる粒子又は原線維タンパク質若しくはペプチドは血小板の接着及び活性化、又はそれらの凝集を誘導する、粒子又は原線維;並びに
- 少なくとも1種の薬学的に許容されるビヒクル又は賦形剤
を含む注射用製剤に関する。
配列番号1:血小板の接着及び活性化を誘導することが可能である組換え型タンパク質のためのポリペプチドコーディング。
- 血小板の接着及び活性化を誘導するタンパク質又はペプチドを含む、10μm未満の長さを有する粒子又は原線維;及び
- 少なくとも1種の薬学的に許容されるビヒクル又は賦形剤
を含む注射用製剤に関する。
本発明の製剤の配合物に入っているタンパク質又はペプチドは、血小板の接着及び活性化、又は血小板の凝集をも誘導する能力を有する。これら2つ若しくは3つの活性は、同一のタンパク質又はペプチドの特性であることが理解されるべきである。これらのタンパク質又はペプチドは、10μm未満の長さを有する粒子又は原線維の形態である。
- 配列番号1のポリペプチド;
- GXYトリプレットの反復から形成される配列を有するポリペプチドであって、Gは、グリシンを指定し、X及びYは、n回くり返される任意のアミノ酸を指定し、nは2以上である、ポリペプチド
- 配列番号1の25〜184位までの配列を有するポリペプチド;又は
- その全長に沿って、配列番号1のポリペプチド、若しくは配列番号1の25〜184位までの配列を有するポリペプチドとの少なくとも70%の同一性を有するポリペプチド
の中から選ばれる少なくとも1種のポリペプチドを含む組換え型タンパク質の中から選ぶことができる。
- GX1X2GER(式中、X1及びX2は、独立に、A、R、N、D、Q、E、G、H、I、K、M、F、P、S、T、W、Y、V及びOの中から選ばれるアミノ酸を表す);
- (GPX3)n(nは4から10の間であり、X3は、P又はOを表す);並びに
- GPRGQX4GVMGFX5(X4及びX5は、独立にP又はOを表す)。
Pは、プロリンを表し、Oは、ヒドロキシプロリンを表す。
- GAPGER、
- KPGEPGPK、
- (GPP)n(nは、4から10の間である)、
- RGD。
(a)4GPOトリプレットの少なくとも1回の反復を有するペプチド配列;
(b)様々な血小板受容体への結合活性を有し、コラーゲンの天然配列中に存在するペプチド配列;及び
(c)配列(a)及び(b)の間のGXYトリプレットの反復から形成される結合配列(Gは、グリシンを指定し、X及びYは、任意のアミノ酸を指定する)
が含まれる。
- 配列番号1のポリペプチド;
- GXYトリプレットの反復から形成される配列を有するポリペプチドであって、Gは、グリシンを指定し、X及びYは、n回くり返される任意のアミノ酸を指定し、nは2以上である、ポリペプチド;
- 配列番号1の25〜184位までの配列を有するポリペプチド;又は
- その全長に沿って、配列番号1のポリペプチド、若しく配列番号1の25〜184位までの配列を有するポリペプチドとの少なくとも70%の同一性を有するポリペプチド
の中から選ぶことができる。
本発明による注射用製剤の配合物に入っているタンパク質は、長さ10μm未満の原線維の形態で構造化することができる。10μmを超える長さを有する線維が含まれ、長さ数マイクロメーターに達し得る原線維の形態は、血流への注射に適合しない。
本発明の製剤の配合物に入っている粒子には、血小板の接着及び活性化又はそれらの凝集を誘導するタンパク質又はペプチドが含まれる或いはそれらからなる。タンパク質及びペプチドは、前述した通りである。
- 配列番号1のポリペプチド;
- 配列番号1の25〜184位までの配列を有するポリペプチド;又は
- その全長に沿って、配列番号1のポリペプチド、若しくは配列番号1の25〜184位までの配列を有するポリペプチドとの少なくとも70%の同一性を有するポリペプチド
の中の少なくとも1種のポリペプチドを含む組換え型タンパク質を含む又はそれらからなる場合;
並びにDLSによって測定される通り、粒子が2μmを超える平均直径を示す場合、粒子は、血小板の接着、活性化及び凝集を誘導することが可能である。この効果は、平均直径が、2μmを下回る、例えば、0.02μmから1μmの間、0.05μmから0.5μmの間、又は0.1μmから0.3μmの間である分子でも見出される。
本発明による薬学的に許容されるビヒクル又は賦形剤、すなわち、個体への投与が、重大な有害作用を伴わないビヒクル又は賦形剤は、当業者によく知られている。
CHO-S細胞(Invitrogen社)の3週間の前培養を、トランスフェクション前に行う。細胞を、CO2 5%で37℃のインキュベーターにおいて撹拌しながら(80rpm)125mLの振とうフラスコ(shake flask)中で4mM L-グルタミン(Lonza社)及び1×proHT(Lonza社)を補充したCHO細胞(Power-CHO、EXCEL 302、proCHO4、proCHO5等)に特異的な培地で維持する。トランスフェクションの2日前、細胞を、培地の完全な変化により5×105個の生細胞/mLで播種し、125mLの振とうフラスコ中でCHO細胞に特異的な補充された培地12.5mLで培養する。
粒子の形態の配列番号1のポリペプチドに基づいた製剤は、ウィルブランド因子を結合する能力を有する。ELISA技法による配列番号1のポリペプチドのウィルブランド因子結合活性の測定を、96-ウェルプレート(Nunc Maxisorp)において行う。これには、リン酸緩衝液又は任意の他の適切な緩衝液中に2μg/mLのポリペプチドを含有する100μLの体積の溶液を各ウェルに加え、22℃で18〜20時間インキュベートする。PBS-0.05% Tween 200μLで3回洗浄後、BSAのリン酸緩衝液1%溶液(Euromedex社、0.45μmでろ過した)200μLを、各ウェルに加え、室温(22℃)で2時間インキュベートする。PBS-0.05% Tween 200μLで3回洗浄後、100μLの様々な濃度(IU/dLで表される)の精製されたウィルブランド因子(Wilfactin 100IU/mL、LFB)及び/又はリン酸緩衝液若しくは任意の他の適切な緩衝液に希釈された患者の血漿を、室温(22℃)で1時間30分インキュベートする。更に3回洗浄した後、リン酸緩衝液又は任意の他の適切な緩衝液で1:8000に希釈された西洋ワサビペルオキシダーゼ(ウサギ抗ヒトVWF/HRP、DAKO)結合1次抗-vWF抗体を含有する溶液100μLを、22℃で1時間インキュベートし;次いで、4回の洗浄を前述した通り行う。次いで、テトラメチルベンジジン溶液(TMB、Sigma)125μLを、ペルオキシダーゼの基質として加え;プレートを暗所で最大10〜45分インキュベートする。反応を、2N HCL(Sigma)125μLを加えることによりクエンチする。直ぐに、450nmでの吸収度を、分光光度計(Wallacvictor 3)で測定する。精製されたvWF又は血漿をリン酸緩衝液若しくは任意の他の適切な緩衝液で置き換えることにより、ブランクを行う。
粒子の形態の配列番号1のポリペプチドに基づいた製剤は、血小板の活性化を誘導する能力を有する。この活性化は、フローサイトメトリーによるP-セレクチンの血小板表面の発現を測定することにより全血において決定することができる。休止血小板において、P-セレクチンは、αグレイン(alpha grain)と呼ばれる顆粒中に貯蔵されている。血小板が様々なアゴニストによって活性化される場合、P-セレクチンは、これらの顆粒から放出され、血小板表面で検出可能である。
粒子の形態の配列番号1のポリペプチドに基づいた製剤は、参照技法(Born、1962年)に従って、血栓-血小板凝集計(Soderel社、Florange、France)で検出されたヒト血小板においてプロアグレゲント活性を有する。多血小板血漿(PRP)を、アゴニスト(PRP 290μL中の10μL)と接触させて入れ、培地が澄んでいく(凝集体の形成と関連する)のを、実時間でモニターする(凝集曲線)。血小板凝集の非存在下で、シグナルは、平らのままである(培地は混濁したままである)。測定の終了時にその管を検査することにより凝集体の存在又は非存在を検証することが可能である。血小板凝集試験反応の評価を、37℃で撹拌を続けながら(1000rpm)行う。器具を以下のように標準化する:多血小板血漿による0%凝集(ゆっくりとした遠心分離によって得られ、濃度が300×109/Lに調整された製剤)及び乏血小板血漿(platelet-poor plasma)による100%凝集(急速な遠心分離によって得られた製剤)。血小板製剤の品質は、抗血小板治療の開発のために用いられる参照アゴニスト(5μM ADP及びコラーゲン1μg/mL)への応答を検証することにより評価される。40%を超える不可逆的な凝集を誘導することが可能である場合に対して、タンパク質は、プロアグレゲントと考えられる。
分子の高分子構造を異なる解像度及びスケールで可視化することができる様々な顕微鏡技法がある。図5は、コラーゲン型タンパク質の構造の観察を可能にする3つの顕微鏡技法(透過型顕微鏡、走査型電子顕微鏡及び原子間力顕微鏡)を用いて得られた画像を示す。
粒子の形態の配列番号1のポリペプチド又は原線維のI型コラーゲンに基づいた製剤は、フローサイトメトリーによって測定されたP-セレクチンの血小板表面の発現により示される通り、全血の血小板の活性化を誘導するex vivoにおける能力を有する。これらの製剤が、血流に注射した後この同じ活性化を実際、誘導することができることが評価するために、血液サンプルを、I型コラーゲン400μg/kg若しくは配列番号1のポリペプチド2mg/kgの投与の15分後又は塞栓症(窒息)の第1の徴候の際に、マウスからクエン酸塩管(BD Vacutainer、BD Biosciences社)に採取する。血液50μLをガラス管に入れ、次いで、リン酸緩衝液250μLで安定させる。次いで、血球計算用の管において、先に論じた反応混合物20μLを、FITC(FITCマウス抗ヒトCD62P、BD Biosciences社)結合1次抗-CD62P抗体、又はFITC(FITCマウスIgG1 κアイソタイプ対照、BD Biosciences社)結合アイソタイプ対照抗体のいずれかを含有する溶液20μLに加え、暗所で室温において10分間インキュベートする。次いで、リン酸緩衝液2mLを各管に加える。直ぐに、520nmにおける平均蛍光強度(MFI)を、フローサイトメーター(LSRII、BD Biosciences社)を用いて測定する。
本発明は、血小板の活性化に依存した機序による、出血の治療のための、コラーゲンに由来するタンパク質又はペプチドの使用を記載している。出血の状況とは無関係に、粒子の形態の、コラーゲンに由来するこれらのタンパク質又はペプチドの注射によって誘導されるin vivo血小板活性化が、血栓症のリスクを伴うか否か決定するために、コラーゲン及びエピネフリンの投与によりマウスにおいて誘導される肺塞栓症のモデルが用いた。本目的は、本発明のコラーゲンに由来するタンパク質又はペプチドによって誘導される血小板活性化が、注射後に血栓症を誘導することによりそれ自体有害となることはないと示すことである。この投与の潜在的血栓効果を特徴付けるために、動物が肺塞栓症により死亡するのにかかった時間を測定することからなる、本モデルにおいて古典的に用いられる観察基準に加えて、同位体画像(SPECT)によって可視化することができる放射性トレーサーを観察基準として用いた。静脈内注射後、テクネチウム-99mで標識されたヒトアルブミンの巨大凝集体は、血流中で循環し、肺又はいくつかの静脈のシンチグラフを撮ることを可能にする。血栓病巣が存在する場合、このトレーサーの正常な肺の分布は変更され、同位体画像は、肺においてトレーサーの減少又は非存在を示すことになる。
上記で示した結果から、粒子の形態の配列番号1のポリペプチドは、マウスの血流に投与された後血小板活性化を誘導することが実際可能であるということ、及び原線維のI型コラーゲンと違い、この活性化は、血栓形成効果がないことが確認される。本発明のコラーゲンに由来するタンパク質又はペプチドの血流への注射によって、血小板活性化に依存した機序によって失血の停止を誘導することが実際可能になることを評価するために、マウスにおける尾からの誘導された失血のモデルにおいて、配列番号1のポリペプチドの投与による、血液の喪失に対する効果を評価した。
(参考文献)
Claims (4)
- 出血の治療におけるその使用のための注射用製剤であって、
- 血小板の接着及び活性化を誘導するタンパク質又はペプチドを含む、10μm未満の長さを有する粒子;並びに
- 少なくとも1種の薬学的に許容されるビヒクル又は賦形剤
を含み、
前記粒子が、自己組織化によって得られ、
前記粒子が、0.05μmから6μmの範囲の平均直径を有し、
前記タンパク質が、コラーゲン、又は配列が、
- 配列番号1のポリペプチド;
- 配列番号1の25〜184位の配列を有するポリペプチド;若しくは
- その全長に沿って、配列番号1のポリペプチド、若しくは配列番号1の25〜184位の配列を有するポリペプチドとの少なくとも70%の同一性を有するポリペプチド
の中から選ばれる少なくとも1種のポリペプチドを含む組換え型タンパク質
の中から選ばれ、
前記ペプチドが、
- 配列番号1のポリペプチド;
- 配列番号1の25〜184位の配列を有するポリペプチド;又は
- その全長に沿って、配列番号1のポリペプチド、若しくは配列番号1の25〜184位の配列を有するポリペプチドとの少なくとも70%の同一性を有するポリペプチド
の中から選ばれる、
注射用製剤。 - 前記粒子が、コラーゲン又は組換え型タンパク質の中から選ばれるペプチド又はタンパク質からなる、請求項1に記載の使用のための注射用製剤。
- 前記粒子が、1μmから6μmの範囲の平均直径を有する、請求項1又は2に記載の使用のための注射用製剤。
- 前記コラーゲン又は前記タンパク質が、ペグ化又はパス化されている、請求項1から3のいずれか一項に記載の使用のための注射用製剤。
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