JP2007055899A - Medicinal composition for treating or preventing disease based on blood coagulation failure comprising blood coagulation xth factor as main ingredient - Google Patents
Medicinal composition for treating or preventing disease based on blood coagulation failure comprising blood coagulation xth factor as main ingredient Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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Abstract
Description
本願発明は、医療用医薬品の分野に属し血液に由来する成分を主たる有効成分とする医薬品に関する。詳細には、血液凝固障害が、血小板を含む血液凝固因子欠損または異常による出血症状、傷害による出血症状、その中でも特に血液凝固因子に対するインヒビター（抗体）を有することにより止血障害を呈する血液凝固障害を伴う患者の止血管理に用いられる医薬品に関する。より詳細には、血液凝固第Ｘ因子（以下、ＦＸと称することがある）単独もしくはこれに活性化血液凝固第ＶＩＩ因子（以下、ＦＶＩＩａと称することがある）を組み合わせてなる組成物を主たる有効成分とする、血液凝固障害に伴う出血症状の予防・治療用医薬組成物に関する。 The present invention relates to a pharmaceutical that belongs to the field of ethical pharmaceuticals and has a blood-derived component as a main active ingredient. Specifically, blood coagulation disorders are caused by blood coagulation factor deficiency or abnormality including platelets, bleeding symptoms due to injury, and in particular, blood coagulation disorders exhibiting hemostasis disorder due to inhibitors (antibodies) against blood coagulation factors. The present invention relates to a medicinal product used for hemostasis management of accompanying patients. More specifically, a composition comprising a blood coagulation factor X (hereinafter sometimes referred to as FX) alone or a combination thereof with an activated blood coagulation factor VII (hereinafter sometimes referred to as FVIIa) is mainly effective. The present invention relates to a pharmaceutical composition for preventing / treating bleeding symptoms associated with blood coagulation disorders.
止血反応は、極めて重要な生体の防御機構の一つあり、一般的に、血管損傷部位への血小板の粘着・凝集による一次止血と、可溶性のフィブリノーゲンが不溶性のフィブリンへ転換されて血管損傷部位をふさぐ二次止血に大別される。二次止血の過程は各種の血液凝固因子及び補助因子による血液凝固カスケードとして知られる一連の連続的な反応に基づいており、内因系凝固と外因系凝固の二つの経路からなる（図１参照のこと）。従って、この血液凝固カスケード中の因子が欠損または正常に機能しないと、血液凝固が妨げられ、出血症状を呈することがある。その多くは遺伝的素因に基づく場合が多く、先天性凝固因子障害によって引き起こされる代表的な疾患として、血液凝固第ＶＩＩＩ因子（以下、第ＶＩＩＩ因子と称することがある）が欠損した血友病Ａ、血液凝固第ＩＸ因子（以下、第ＩＸ因子と称することがある）が欠損した血友病Ｂがよく知られている。 The hemostatic reaction is one of the vital defense mechanisms of the body. Generally, primary hemostasis by adhesion / aggregation of platelets to the site of vascular injury and the conversion of soluble fibrinogen to insoluble fibrin to reduce the site of vascular injury. It is roughly divided into secondary secondary hemostasis. The process of secondary hemostasis is based on a series of sequential reactions known as blood coagulation cascades with various blood coagulation factors and cofactors, and consists of two pathways: intrinsic coagulation and extrinsic coagulation (see Figure 1). thing). Therefore, if a factor in the blood coagulation cascade is deficient or does not function normally, blood coagulation may be hindered and bleeding symptoms may occur. Many of them are based on genetic predisposition, and hemophilia A lacking blood coagulation factor VIII (hereinafter sometimes referred to as factor VIII) is a typical disease caused by congenital coagulation factor disorders. Hemophilia B deficient in blood coagulation factor IX (hereinafter sometimes referred to as factor IX) is well known.
これら血友病患者の治療には、欠損因子の補充を目的として第ＶＩＩＩ因子あるいは第ＩＸ因子を含む濃縮製剤が開発され、止血管理に使用されており、これを補充療法という。通常、血友病患者の血漿中の第ＶＩＩＩ因子活性、第ＩＸ因子活性を５〜２０％のレベルになるように補充する。しかし、その結果、第ＶＩＩＩ因子あるいは第ＩＸ因子に対する抗体（これは、通常インヒビターと呼ばれる）が患者の約２〜２４％に発生することが知られており（非特許文献１参照, 非特許文献２参照, 非特許文献３参照, 非特許文献４参照）、これは補充療法における最も深刻な副作用の一つである。インヒビターが発生すると、従来の補充療法は効果がなくなり、患者の止血管理は困難をきわめる。また、血友病のような遺伝的な素因がない場合でも、自然発生的または自己免疫疾患的にインヒビターが発現することが多数報告されている（非特許文献５参照）。 For the treatment of these hemophilia patients, concentrated preparations containing factor VIII or factor IX have been developed for the purpose of supplementing the deficient factors and are used for hemostasis management, which is referred to as replacement therapy. Usually, the factor VIII activity and the factor IX activity in the plasma of hemophilia patients are supplemented to a level of 5 to 20%. However, as a result, it is known that an antibody against factor VIII or factor IX (which is usually called an inhibitor) occurs in about 2 to 24% of patients (see Non-patent Document 1, Non-patent Document). 2, see Non-Patent Document 3, see Non-Patent Document 4), which is one of the most serious side effects in replacement therapy. When inhibitors occur, conventional replacement therapy becomes ineffective and patient hemostasis management becomes difficult. In addition, even if there is no genetic predisposition such as hemophilia, it has been reported that inhibitors are expressed spontaneously or autoimmune diseases (see Non-Patent Document 5).
現在インヒビターを有する患者の治療には主に以下の方法が用いられている。
（ａ）中和療法：インヒビターを凌駕するような高投与量の濃縮製剤を投与することでインヒビターを中和し、さらに止血に必要な因子の補充を行なう。
（ｂ）バイパス療法：第ＶＩＩＩ因子や第ＩＸ因子は共に内因系凝固に関与する因子であるので、内因系を介さない、即ちバイパスする外因系凝固により止血する。外因系凝固能を高めるため、ＡＰＣＣと呼ばれる活性化プロトロンビン複合体濃縮製剤やＦＶＩＩａ製剤の投与が行なわれている。
（ｃ）免疫寛容療法：大量の濃縮製剤を連日投与することにより、インヒビター産生能を免疫学的に疲弊させて、抗体の消失を図る。
Currently, the following methods are mainly used to treat patients with inhibitors.
(A) Neutralization therapy: The inhibitor is neutralized by administering a high-dose concentrated preparation that surpasses the inhibitor, and further supplemented with factors necessary for hemostasis.
(B) Bypass therapy: Since both factor VIII and factor IX are factors involved in intrinsic coagulation, hemostasis is stopped by exogenous coagulation that bypasses the intrinsic system, that is, bypasses. In order to enhance the extrinsic system coagulation ability, an activated prothrombin complex concentrate preparation or FVIIa preparation called APCC has been administered.
(C) Immune tolerance therapy: A large amount of concentrated preparation is administered every day to immunologically exhaust the inhibitor producing ability and to eliminate the antibody.
しかしながら、前記方法は各々幾つかの欠点をかかえている。即ち、（ａ）中和療法はインヒビター価の低い患者に対しては有効であるが、ハイリスポンダーと呼ばれる高いインヒビター価を有する患者に対しては無効である。（ｂ）バイパス療法におけるＡＰＣＣは心筋梗塞（非特許文献６参照やＤＩＣ（非特許文献７参照）の副作用が報告されており安全性に問題がある。一方、その安全性の高さからインヒビター患者の止血管理で最も汎用されているＦＶＩＩａ製剤は、ＦＶＩＩａの生体半減期が短いため頻回投与が必要であり（非特許文献８参照、経済的な面も含め患者に多大な負担を負わせることになっている。また、その有効性も充分とは言えない。（ｃ）免疫寛容療法は限られた患者においてのみ有効であり、且つ患者の経済的負担が大きい。このように、現状ではインヒビター患者に対する種々の止血管理方法は充分なものとはいえず、より安全で、効果が高く、止血管理が容易な製剤が切望されている。 However, each of the above methods has some drawbacks. That is, (a) neutralization therapy is effective for patients with low inhibitor titers, but is ineffective for patients with high inhibitor titers called high-responders. (B) APCC in bypass therapy has a side effect of myocardial infarction (see non-patent document 6 and DIC (see non-patent document 7)) and has a problem in safety. The most widely used FVIIa preparation for hemostasis management of FVIIa requires frequent administration due to the short biological half-life of FVIIa (see Non-Patent Document 8, which imposes a great burden on patients including economical aspects). (C) Immunotolerance therapy is effective only in a limited number of patients and has a large financial burden on the patient. Various hemostasis management methods for patients are not satisfactory, and preparations that are safer, more effective, and easier to manage hemostasis are desired.
なお、従来技術として、特開平７−１４５０７２〜１４５０７５（特許文献１〜４参照）により開示されている「血液凝固因子阻害因子処理のための水性組成物」は従来のＡＰＣＣ製剤における活性化の程度を規定しているだけであり、その本質を極めていない。また、特開平９−１１０７１５（特許文献５参照）により示されている「血液凝固疾患を治療するための医薬組成物とその製造法」も、従来のＡＰＣＣ中のＦＶＩＩａ含量を増加させることにより治療効果を期待している点に特徴を有するが、単独で治療効果が確認されているＦＶＩＩａをＡＰＣＣに加えただけであり、同様になお課題を残すものである。また、平成１１年特許願第３６８１２２号（特許文献６参照）により示されている「血液凝固異常に基づく疾患の治療・予防用医薬組成物」は、ＦＸとＦＶＩＩaの混合製剤が上記の血液凝固異常に基づく疾患の治療・予防に有効とする点に特徴を有するが、ＦＸを主成分とするＦＸ単独製剤に言及したものではない。 As a conventional technique, “Aqueous composition for blood coagulation factor inhibitory factor treatment” disclosed in Japanese Patent Application Laid-Open No. 7-145072 to 145075 (see Patent Documents 1 to 4) is a degree of activation in a conventional APCC preparation. Is stipulated, and its essence is not extremely important. In addition, the “pharmaceutical composition for treating blood coagulation disease and its production method” disclosed in JP-A-9-110715 (see Patent Document 5) is also treated by increasing the FVIIa content in conventional APCC. Although it is characterized in that it is expected to be effective, only FVIIa, which has been confirmed to have a therapeutic effect alone, has been added to APCC, and it still has problems. In addition, the “pharmaceutical composition for treatment / prevention of diseases based on abnormal blood coagulation” shown in Japanese Patent Application No. 368122 (refer to Patent Document 6) has a mixed preparation of FX and FVIIa as described above. Although it is characterized in that it is effective in the treatment and prevention of diseases based on abnormalities, it does not refer to an FX single preparation mainly comprising FX.
上記問題点を鑑み、本願発明者らは血液凝固障害に伴う出血症状に対する予防・治療剤を開発するべく鋭意研究した結果、驚くべきことに、ＦＸを主成分とする医薬組成物が血液凝固障害を原因とする止血障害の予防・治療剤として非常に有効であることを初めて見出し、さらにＦＸを主成分とする本願発明の医薬組成物に微量のＦＶＩＩaを添加した医薬組成物は、ＦＸを主成分とする医薬組成物の効果を増幅することを見出し、この知見に基づいて本願発明を完成するに至った。本願発明は従来の公知技術とは異なる新しい技術と新規な知見に基づくものである。 In view of the above-mentioned problems, the present inventors have intensively studied to develop a preventive / therapeutic agent for bleeding symptoms associated with blood coagulation disorders. As a result, surprisingly, a pharmaceutical composition mainly comprising FX is a blood coagulation disorder. The pharmaceutical composition of the present invention, which was found for the first time as a prophylactic / therapeutic agent for hemostasis disorders caused by cerebral hemorrhage, and further added a small amount of FVIIa to the pharmaceutical composition of the present invention mainly comprising FX, is mainly composed of FX. It has been found that the effect of the pharmaceutical composition as a component is amplified, and the present invention has been completed based on this finding. The present invention is based on new technologies and new knowledge different from conventional known technologies.
特に、本願発明によってもたらされる組成物の優れた点として、（１）ＡＰＣＣ製剤の副作用を引き起こしている原因物質としての可能性の高いＦＩＩ、ＦＩＩａ、ＦＩＸ、ＦＩＸａ及びリン脂質等を実質的に含まないため安全性が極めて高い。また、（２）ＦＸの生体内半減期が３０時間と報告されており（非特許文献９参照）、ＦＶＩＩａ製剤の欠点であった頻回投与の必要がなくなり、止血効果の持続性が高いことが予想される。即ち、安全で、効果が高く、止血管理が容易な、待ち望まれていた医薬組成物と言うことができる。また、ＦＩＩ及びＦＩＸ等をほとんど含まないという点で従来のＡＰＣＣ製剤と異なり、ＦＸを含む点でＦＶＩＩａ製剤とも異なる。本願発明は、ＦＸをＦＶＩＩaと混合せずに単独投与することを発明の骨子としているが、ＦＸに極微量のＦＶＩＩaを含むことも本願発明に含まれる。特許文献６により示されている「血液凝固異常に基づく疾患の治療・予防用医薬組成物」に記載されている、ＦＸとＦＶＩＩaの混合製剤はＦＸ単独製剤を意味しておらず、本願発明とはその技術思想を異にする製剤である。 In particular, as an excellent point of the composition brought about by the present invention, it substantially includes (1) FII, FIIa, FIX, FIXa, phospholipid and the like which are highly likely as causative substances causing side effects of the APCC preparation. There is no safety because it is not. In addition, (2) the in vivo half-life of FX has been reported to be 30 hours (see Non-Patent Document 9), eliminating the need for frequent administration, which was a drawback of the FVIIa preparation, and having a high hemostatic effect. Is expected. In other words, it can be said to be a pharmaceutical composition that is safe, highly effective, and easy to manage hemostasis. Moreover, it differs from the conventional APCC formulation in that it contains almost no FII, FIX, etc., and it differs from the FVIIa formulation in that it contains FX. In the present invention, the main point of the invention is to administer FX alone without mixing it with FVIIa, but it is also included in the present invention that a very small amount of FVIIa is contained in FX. The mixed preparation of FX and FVIIa described in "Pharmaceutical composition for treatment / prevention of diseases based on abnormal blood coagulation" shown in Patent Document 6 does not mean an FX single preparation. Is a preparation with different technical ideas.
血液凝固障害を原因とする止血障害に対する予防と止血に用いられているＦＶＩＩａ製剤は、その短い生体内半減期（2.7時間）のため、頻回投与を前提として使用されているが、本願発明のＦＸ単独製剤を用いればＦＸの生体内半減期が３０時間と長いため、極めて少ない投与回数で止血が完了できることが予想される。また、このＦＸに極微量のＦＶＩＩａを加えれば投与時には一過性により強い止血効果が得られる。 The FVIIa preparation used for prevention and hemostasis of hemostasis disorder caused by blood coagulation disorder is used on the premise of frequent administration because of its short in vivo half-life (2.7 hours). If the FX single preparation is used, the in vivo half-life of FX is as long as 30 hours. Therefore, it is expected that hemostasis can be completed with a very small number of administrations. Further, if a very small amount of FVIIa is added to this FX, a stronger hemostatic effect can be obtained transiently at the time of administration.
本願発明の医薬組成物の主たる成分の前駆体であるＦＸは４４８残基のアミノ酸からなる分子量約５９,０００のビタミンＫ依存性凝固因子であり、血漿中には５〜１０μｇ／ｍｌ含まれる。ＦＸは、カルシウムイオン存在下でＦＶＩＩａ／組織因子複合体により活性化されるか（外因系凝固経路）、あるいは、活性化血液凝固第ＶＩＩＩ因子、カルシウムイオン及びリン脂質存在下で活性化血液凝固第ＩＸ因子により活性化されて（内因系凝固経路）、活性化血液凝固第Ｘ因子（以下、ＦＸａと称することがある）となり、酵素活性を発揮するようになる。ＦＸａは活性化血液凝固第Ｖ因子、カルシウムイオン及びリン脂質存在下で、プロトロンビンをトロンビンに活性化し、その結果フィブリン形成を引き起こす。 FX, which is a precursor of the main component of the pharmaceutical composition of the present invention, is a vitamin K-dependent clotting factor having a molecular weight of about 59,000 consisting of 448 amino acid residues, and is contained in plasma at 5 to 10 μg / ml. FX is activated by the FVIIa / tissue factor complex in the presence of calcium ions (exogenous clotting pathway) or activated blood clotting in the presence of activated blood coagulation factor VIII, calcium ions and phospholipids. When activated by factor IX (endogenous coagulation pathway), it becomes activated blood coagulation factor X (hereinafter sometimes referred to as FXa) and exhibits enzyme activity. FXa activates prothrombin to thrombin in the presence of activated blood coagulation factor V, calcium ions and phospholipids, resulting in fibrin formation.
また、本願発明の補助的成分たるＦＶＩＩは４０６残基のアミノ酸からなる分子量約５０,０００を有するビタミンＫ依存性凝固因子であり、血漿中には約０.５μｇ／ｍｌ含まれる。ＦＶＩＩは分子内のＡｒｇ１５２−Ｉｌｅ１５３結合が加水分解されることにより酵素活性を持つ二本鎖のＦＶＩＩａとなる。ＦＶＩＩａは組織因子とともにカルシウムイオン存在下でＦＩＸ及びＦＸを活性化する。従って、外因系凝固経路において非常に重要な位置を占めている物質とみなすことができる。 Further, FVII as an auxiliary component of the present invention is a vitamin K-dependent coagulation factor having a molecular weight of about 50,000 consisting of 406 amino acids, and is contained in plasma at about 0.5 μg / ml. FVII becomes double-stranded FVIIa having enzymatic activity by hydrolyzing the Arg152-Ile153 bond in the molecule. FVIIa activates FIX and FX in the presence of calcium ions together with tissue factor. Therefore, it can be regarded as a substance that occupies a very important position in the extrinsic coagulation pathway.
本願発明に使用されるＦＸ及びＦＶＩＩaを製造する方法は特に限定されることなく、例えばヒト血液より分離する方法あるいは遺伝子組換え技術により作製する方法などによって製造することができる。また、遺伝子組換え技術により作製されたＦＸとＦＶＩＩaは本質的な生物活性が血漿由来ＦＸとＦＶＩＩaと同様であれば、本来のアミノ酸配列を別のアミノ酸配列に置換した改変体も本願発明に使用できる。 The method for producing FX and FVIIa used in the present invention is not particularly limited, and can be produced by, for example, a method of separating from human blood or a method of producing by gene recombination technology. If the essential biological activity of FX and FVIIa produced by gene recombination technology is the same as that of plasma-derived FX and FVIIa, a modified product in which the original amino acid sequence is replaced with another amino acid sequence is also used in the present invention. it can.
血液由来のＦＸの製法としては、例えば、新鮮凍結ヒト血漿を冷融解・遠心処理してクリオプレシピテートを除いた脱クリオ血漿から、陰イオン交換クロマトグラフィーにより粗精製後、抗ＦＸモノクローナル抗体固定化カラムを用いてのアフィニティークロマトグラフィーによってＦＸを精製する方法がある。前記と同様、得られるＦＸはその安全性を確保するために、ＦＩＩ、ＦＩＩａ、ＦＩＸ及びＦＩＸａを可能な限り伴わない方が好ましい。また、血液由来のＦＶＩＩａの製法としては、例えば、特開平３−１５５７９７（特許文献７参照）、特開平１０−０５９８６６（特許文献８参照）及び特開平１０−０５９８６７（特許文献１０参照）に示される方法がある。また、新鮮凍結ヒト血漿を冷融解・遠心処理してクリオプレシピテートを除いた脱クリオ血漿から、陰イオン交換クロマトグラフィーにより粗精製後、抗ＦＶＩＩモノクローナル抗体固定化カラムを用いてのアフィニティークロマトグラフィーによってＦＶＩＩを精製した後、他の血漿蛋白質、例えば活性化血液凝固第ＸＩＩ因子、ＦＸａなどによりＦＶＩＩａに活性化する方法がある。得られるＦＶＩＩａは、その安全性を確保するために、ＦＩＩ、ＦＩＩａ、ＦＩＸ及びＦＩＸａを可能な限り伴わない方が好ましい。 As a method for producing FX derived from blood, for example, freshly frozen human plasma is subjected to cold thawing and centrifugation to remove cryoprecipitate, and after crude purification by anion exchange chromatography, anti-FX monoclonal antibody fixation There is a method of purifying FX by affinity chromatography using an activated column. As described above, it is preferable that the obtained FX is not accompanied by FII, FIIa, FIX and FIXa as much as possible in order to ensure the safety. Examples of methods for producing blood-derived FVIIa include those disclosed in JP-A-3-155977 (see Patent Document 7), JP-A-10-059866 (see Patent Document 8) and JP-A-10-059867 (see Patent Document 10). There is a way. In addition, after cryopreservation of fresh frozen human plasma by cryo-thawing and centrifugation to remove cryoprecipitate, crude purification by anion exchange chromatography followed by affinity chromatography using an anti-FVII monoclonal antibody-immobilized column There is a method in which FVII is purified by, and then activated to FVIIa by other plasma proteins such as activated blood coagulation factor XII, FXa and the like. The obtained FVIIa is preferably free from FII, FIIa, FIX and FIXa as much as possible in order to ensure its safety.
上述の方法で調製されたＦＸまたはＦＶＩＩａの活性を最大限に維持するために、それぞれ好適な安定化剤と共に凍結乾燥して保存することができるし、ＦＸ溶液またはＦＶＩＩａ溶液をそれぞれ凍結し保存することも可能である。さらには、ＦＸまたはＦＶＩＩａを好適な安定化剤と共に好適な濃度で混合し、凍結乾燥して保存することができるし、混合溶液を凍結し保存することも可能である。本願発明では、かかる有効成分としてＦＸを単独で含む組成物、またはＦＸとＦＶＩＩａを含む組成物と、公知の適当な賦形剤を組み合わせ、公知の方法で血液凝固障害を原因とする止血障害に対する予防・治療用製剤とすることができる。当該製剤の投与対象は、血液凝固障害によって引き起こされる止血障害のある患者であれば特に限定されることはない。 In order to maintain the activity of FX or FVIIa prepared as described above to the maximum, it can be lyophilized and stored with a suitable stabilizer, respectively, or the FX solution or FVIIa solution can be frozen and stored respectively. It is also possible. Furthermore, FX or FVIIa can be mixed with a suitable stabilizer at a suitable concentration, lyophilized and stored, or the mixed solution can be frozen and stored. In the present invention, a composition containing FX alone as such an active ingredient, or a composition containing FX and FVIIa and a known appropriate excipient are combined and used for a hemostatic disorder caused by a blood coagulation disorder by a known method. It can be used as a preparation for prevention and treatment. The administration target of the preparation is not particularly limited as long as it is a patient with a hemostasis disorder caused by a blood coagulation disorder.
ＦＸの有効投与量は、例えば投与対象者の年齢、症状及び重症度などにより変動するが、１６０μｇ／体重（ｋｇ）以上の投与量であり、また、 ＦＸ １６０μｇ／体重（ｋｇ）以上の投与量に５μｇ／体重（ｋｇ）未満の投与量のＦＶＩＩaを組み合わせることもできる。投与方法は単回投与（Ｂｏｌｕｓ）あるいは点滴の静脈内投与が最適である。本願発明の予防・治療用製剤は、ＦＸを主成分とすることを好適な実施態様とするが、ＦＸに投与量５μｇ／体重（ｋｇ）未満のＦＶＩＩaをＦＸとＦＶＩＩaの投与間隔が充分短ければ、個別に投与することも可能であり、同様に本願発明の効果を発揮する。
The effective dose of FX varies depending on, for example, the age, symptoms, and severity of the subject of administration, but is a dose of 160 μg / body weight (kg) or more, and a dose of
本願発明は、 ヒト血液より分離する方法あるいは遺伝子組換え技術により作製する方法などによって製造されたＦＸとＦＶＩＩaを基に、薬剤本態として１０μｇ／ｍｌ以上のＦＸ、または同量のＦＸに０．３１２５μｇ／ｍｌ以下の濃度のＦＶＩＩａを混合した組成に好適な安定剤を添加した血液凝固異常に基づく疾患の治療・予防用薬剤である。 The present invention is based on FX and FVIIa produced by a method of separating from human blood or a method of gene recombination, etc. Based on FX and FVIIa as a drug, at least 10 μg / ml FX, or 0.3125 μg in the same amount of FX. It is a drug for treatment / prevention of diseases based on abnormal blood coagulation to which a suitable stabilizer is added to a composition mixed with FVIIa at a concentration of / ml or less.
以下に実施例を挙げて本願発明を具体的に説明するが、本願発明はこれらの例に何ら限定されるものではない。 EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
（本願発明組成物のＡＰＴＴ測定による評価）
活性化部分トロンボプラスチン時間（以下、ＡＰＴＴと称することがある）は、ＡＰＴＴ試薬を用いて測定される内因系スクリーニング検査法である。具体的には、被検血漿にＡＰＴＴ試薬とカルシウムイオンを添加しフィブリンが形成されるまでの内因性凝固の酵素反応を総合的に測定するもので、特に、血友病ＡまたはＢに代表される内因系凝固因子の量的ないし質的異常、または内因系凝固因子に対するインヒビターの存在などによりＡＰＴＴは延長する。正常値は３０〜４０秒であり、その延長の度合は量的ないし質的異常を示している内因系凝固因子の凝固活性に依存し、一般に重篤な臨床症状を示す血友病（インヒビターも含む）では極度に延長する。齋藤らが報告したＦＶＩＩａ製剤の臨床評価結果によると、インヒビターを有する血友病患者１２人のＡＰＴＴは１２２.０±１８.７秒（平均±ＳＤ）に延長していたが、遺伝子組換えＦＶＩＩａ投与２０分後には８２.９±２１.６秒に低下した（非特許文献１０参照）。また、ｉｎ ｖｉｔｒｏにおいてもＦＶＩＩＩまたはＦＩＸ等の各種欠乏血漿にＦＶＩＩａを添加すると、ＡＰＴＴが有意に短縮することが報告されている（非特許文献１１参照）。
(Evaluation by APTT measurement of the present invention composition)
The activated partial thromboplastin time (hereinafter sometimes referred to as APTT) is an intrinsic screening test method that is measured using an APTT reagent. Specifically, the enzyme reaction of endogenous coagulation until APFT reagent and calcium ions are added to the test plasma to form fibrin is comprehensively measured. In particular, it is represented by hemophilia A or B. The APTT is prolonged due to the quantitative or qualitative abnormality of the intrinsic clotting factor or the presence of an inhibitor against the intrinsic clotting factor. The normal value is 30 to 40 seconds, and the degree of extension depends on the clotting activity of endogenous clotting factors showing quantitative or qualitative abnormalities. (Including) extend extremely. According to the clinical evaluation results of the FVIIa formulation reported by Saito et al., The APTT of 12 hemophilia patients with inhibitors was extended to 122.0 ± 18.7 seconds (mean ± SD), but the recombinant FVIIa It decreased to 82.9 ± 21.6
本実験は上記事実に基づき、血友病患者様血漿として第ＶＩＩＩ因子（ＦＶＩＩＩ）欠乏血漿または第ＩＸ因子（ＦＩＸ）欠乏血漿（いずれも、デイドベーリングマールブルグ社製）を用い、ＦＸによるＡＰＴＴの短縮効果を評価した。ＡＰＴＴ試薬としては、Ａｃｔｉｎ（商品名）（デイドベーリングマールブルグ社製）を使用した。評価したＦＸ等の濃度は、ＦＸ：終濃度０〜１６０μｇ／ｍｌ血漿（正常ヒト血漿中の濃度：約１０μｇ／ｍｌ血漿）、ＦＶＩＩａ：終濃度０〜０．１２５μｇ／ｍｌ血漿、結果を図２と図３に示す。図２と図３は、ＦＸを各々の各欠乏血漿に添加した場合のＡＰＴＴへの濃度依存的な影響を表したものである。ＦＶＩＩＩ欠乏血漿の場合、ＦＸの添加は約１００μｇ／ｍｌ血漿濃度まで濃度依存的にＡＰＴＴを短縮させた。ＦＩＸ欠乏血漿の場合、ＦＸの添加は約１６０μｇ／ｍｌ血漿濃度まで濃度依存的にＡＰＴＴを短縮させた。 Based on the above fact, this experiment uses factor VIII (FVIII) -deficient plasma or factor IX (FIX) -deficient plasma (both made by Dade Behring Marburg) as hemophilia patient-like plasma, and shortens APTT by FX. The effect was evaluated. Actin (trade name) (manufactured by Dade Behring Marburg) was used as the APTT reagent. The concentrations of FX and the like evaluated were as follows: FX: final concentration of 0 to 160 μg / ml plasma (concentration in normal human plasma: about 10 μg / ml plasma), FVIIa: final concentration of 0 to 0.125 μg / ml plasma, and the results are shown in FIG. And shown in FIG. FIGS. 2 and 3 show the concentration-dependent effects on APTT when FX is added to each deficient plasma. In the case of FVIII-deficient plasma, the addition of FX shortened the APTT in a concentration-dependent manner up to about 100 μg / ml plasma concentration. In the case of FIX-deficient plasma, the addition of FX shortened APTT in a concentration-dependent manner to about 160 μg / ml plasma concentration.
図４と図５は、各欠乏血漿にＦＸを加え、さらにＦＶＩＩａ加えた場合のＡＰＴＴを示している。 ＦＸとＦＶＩＩａの血漿中の終濃度は、０〜１６０μｇ／ｍｌ、０〜０．１２５μｇ／ｍｌに設定した。ＦＸに少量のＦＶＩＩaを加えることによりＡＰＴＴの短縮効果は高まり、ＦＶＩＩaを０．１２５μｇ／ｍｌ加えることにより、ＦＶＩＩＩ欠乏血漿、ＦＩＸ欠乏血漿ともに各因子を１０％補充した場合のＡＰＴＴに近づいた。 4 and 5 show the APTT when FX is added to each deficient plasma and FVIIa is further added. The final concentrations of FX and FVIIa in plasma were set to 0 to 160 μg / ml and 0 to 0.125 μg / ml. The effect of shortening APTT was increased by adding a small amount of FVIIa to FX, and by adding 0.125 μg / ml of FVIIa, APTT was approached when 10% of each factor was supplemented for both FVIII-deficient plasma and FIX-deficient plasma.
Claims (8)
The pharmaceutical composition according to any one of claims 6 to 7, wherein FX is 160 µg / body weight (kg) or more, and FVIIa is 5 µg / body weight (kg) or less as a dose necessary for hemostasis.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003366353A JP2007055899A (en) | 2003-10-27 | 2003-10-27 | Medicinal composition for treating or preventing disease based on blood coagulation failure comprising blood coagulation xth factor as main ingredient |
| PCT/JP2004/015804 WO2005039628A1 (en) | 2003-10-27 | 2004-10-25 | Medicinal composition for treating/preventing diseases based on blood coagulation failure comprising blood coagulation factor x as the main ingredient |
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| JP2003366353A JP2007055899A (en) | 2003-10-27 | 2003-10-27 | Medicinal composition for treating or preventing disease based on blood coagulation failure comprising blood coagulation xth factor as main ingredient |
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| JP2007055899A true JP2007055899A (en) | 2007-03-08 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009028573A1 (en) | 2007-08-27 | 2009-03-05 | National University Corporation Nagoya University | Use of ribavirin in blood coagulation disorder |
| JP2017526669A (en) * | 2014-08-12 | 2017-09-14 | バクスアルタ インコーポレイテッド | Activation of factor X |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3165600D1 (en) * | 1980-01-28 | 1984-09-27 | Baxter Travenol Lab | Prothrombin-containing therapeutic compositions and methods of producing enzymatically active blood clotting factors from prothrombin-containing blood fractions |
| JP4676585B2 (en) * | 1999-12-24 | 2011-04-27 | 一般財団法人化学及血清療法研究所 | Pharmaceutical composition for treatment / prevention of diseases based on abnormal blood coagulation |
-
2003
- 2003-10-27 JP JP2003366353A patent/JP2007055899A/en not_active Withdrawn
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2004
- 2004-10-25 WO PCT/JP2004/015804 patent/WO2005039628A1/en not_active Ceased
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009028573A1 (en) | 2007-08-27 | 2009-03-05 | National University Corporation Nagoya University | Use of ribavirin in blood coagulation disorder |
| JP2017526669A (en) * | 2014-08-12 | 2017-09-14 | バクスアルタ インコーポレイテッド | Activation of factor X |
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| WO2005039628A1 (en) | 2005-05-06 |
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