JP2002060341A - Hemostatic agent - Google Patents

Hemostatic agent

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JP2002060341A
JP2002060341A JP2000249624A JP2000249624A JP2002060341A JP 2002060341 A JP2002060341 A JP 2002060341A JP 2000249624 A JP2000249624 A JP 2000249624A JP 2000249624 A JP2000249624 A JP 2000249624A JP 2002060341 A JP2002060341 A JP 2002060341A
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hemostatic agent
dna
hemostatic
protamine
nucleic acid
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JP2000249624A
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Japanese (ja)
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Haruo Ishiyama
Akira Mochizuki
明 望月
晴生 石山
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Terumo Corp
テルモ株式会社
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Abstract

PROBLEM TO BE SOLVED: To obtain a hemostatic agent not disturbing the healing of wound surfaces and exhibiting a rapid coagulation reaction capable of stopping bleeding of arterial blood, adhesive property to tissues and biodegradability. SOLUTION: This hemostatic agent comprises a calcium salt of a nucleic acid such as DNA, or the like, as a main component.

Description

【発明の詳細な説明】 DETAILED DESCRIPTION OF THE INVENTION

【0001】 [0001]

【従来の技術】医学の進歩に伴い外科手術伸展が著しい。 Significant surgery extension with the Background of the Invention medical advances. この中で、病変部の除去や構造の再構築、人工補綴物の導入といった構造構築に係わる手技において格段の進歩がある。 In this, reconstruction of removal and structure of the lesion, there is a great progress in the technique according to the structure construction such introduction of the prosthesis. 一方、これらの手術は血管にメスを入れる事が必須であるため、術後の止血を如何にするかが大きな課題である。 On the other hand, these procedures because it is essential to put the female in blood vessels, is a major issue or not to how the hemostasis of postoperative. このためにフィブリン糊、コラーゲン系止血剤、酸化セルロースといった各種止血剤が開発され、実際に使用されてはいるが、その止血力は弱く、動脈系からの出血には殆ど無力であり、医師等による長時間の圧迫止血が行われているのが現状である。 Fibrin glue For this, collagen-based hemostatic agents, various hemostatic agents have been developed such as oxidized cellulose, but is actually used, the hemostatic force is weak, a little powerless bleeding from arterial system, doctors, etc. the long-term pressure hemostasis due to have been carried out at present. 又、外科以外の分野においてもカテーテル技術の進歩により血管内治療や血管造影が頻繁に行われるようになっているが、カテーテル抜去後の血管、特に大口径の動脈からの出血に対し有効な手法がなく圧迫止血が行われているのが現状である。 Although endovascular or angiography is adapted to be frequently performed Advances in catheter technology in the field of non-surgical, effective technique to bleeding from the blood vessel after catheter removal, especially a large diameter artery at present, pressure hemostasis is being carried out without. 又、人工透析においては留置針を血管に穿刺した後透析治療を行うわけであるが、透析が終了し、留置針を抜去した後はやはり圧迫止血がなされている。 Although in the dialysis is not performing hemodialysis treatment after puncturing the indwelling needle into a blood vessel, the dialysis is completed and after removing the indwelling needle is also astriction is made. このように、現状では確実に止血できる有効な薬剤がないため、圧迫止血と言う原始的な方法に頼っているのが現実である。 Thus, since there is no effective drug that can reliably hemostasis at present, it is realistic that rely on primitive way to say astriction.

【0002】 [0002]

【発明が解決しようとする課題】現在、最も多量に使用されている止血剤としてはフィブリン糊があるが、これは血液由来のフィブリンを出血部でゲル化させ止血するものであり、高含水ゲル状態にあるため止血力は弱く、 [0005] Currently, as a hemostatic agent most heavily used is fibrin glue, which is intended to hemostasis is gelled fibrin from blood bleeding part, high water gel hemostatic force due to the state weak,
また、動脈からの止血に対してはほとんど効果が認められないのが現状である。 In addition, at present, it has little effect not observed with respect to hemostasis from the artery. 又、人由来のフィブリンを用いているため未知ウィルスによる感染の危険性が常につきまとうと言うリスクがある。 In addition, there is a risk that say the risk of infection by an unknown virus because of the use of fibrin derived from human is always beset with. コラーゲン或いはゼラチン系止血剤においては、これらのタンパク質が血小板を活性化する性質がある事を利用して止血効果を得ようと言うものであるが、出血量の多い部所への適応は困難であり、抗原性の問題もある。 In the collagen or gelatin-based hemostatic agents, but these proteins is intended to refer order to obtain a hemostatic effect by utilizing the fact that the property of activating the platelets, adaptation to high bleeding amount duty post is difficult Yes, there is also a antigenicity of the problem. 合成系高分子を利用した止血剤としてはシアノアクリレートやアクリル系のものが有る。 The hemostatic agent utilizing a synthetic polymer there is one cyanoacrylate and acrylic. これらは短期的には出血を止めることが出来るものの、本質的な止血にはなっておらず、逆に血管に出来た傷口の自然修復を阻害する。 These are but short term it is possible to stop the bleeding, not become essentially hemostasis, to inhibit the natural repair of the wound made to the vessel in reverse. このためポリマーの剥離後の再出血が起きるという問題を抱えている。 I have a problem that this for re-bleeding after detachment of the polymer occurs. 従って、優れた止血剤としては創傷面の治癒を妨げる事無く、又、 Therefore, the excellent hemostatic agent without interfering with the healing of the wound surface, and,
動脈血を止血できる素早い凝固反応、組織への粘着性、 Rapid coagulation reaction capable of hemostasis arterial blood, adhesion to tissue,
生分解性などがあわせて求められる。 Biodegradable, such as are required to meet.

【0003】 [0003]

【課題を解決するための手段】上記課題を考慮し、鋭意検討した結果、本発明者らは以下の発明に到達した。 Considering the above problems SUMMARY OF THE INVENTION, a result of intensive studies, the present inventors have reached the following invention. すなわち、核酸を基材としたヒドロゲル素材を用いる事で上記問題点を解決した止血剤を見出したのである。 That is, the found hemostatic agent which solves the above problems by the use of hydrogel materials in which the nucleic acid substrate. 具体的に、本発明は下記の1)−5)の内容により達成される。 Specifically, the present invention can be achieved by the content of 1) -5) below. 1)核酸のカルシウム塩を主成分とした止血剤。 1) hemostatic agent mainly composed of calcium salts of nucleic acids. 2)前記核酸がDNAである1)に記載の止血剤。 Hemostatic agent according to 2) wherein the nucleic acid is DNA 1). 3)前記核酸のカルシウム塩が核酸のカウンターカチオンの10−100当量%がカルシウムイオンである1) 3) 10-100 equivalent percent of the calcium salt of the nucleic acid is a nucleic acid counter cation is calcium ion 1)
または2)に記載の止血剤。 Hemostatic agent according to or 2). 4)前記止血剤が、更にタンパク質を含有する1)〜 4) The hemostatic agent further contains protein 1) -
3)のいずれかに記載の止血剤。 Hemostatic agent according to any one of 3). 5)前記タンパク質がプロタミン、コラーゲン、ゼラチンからなる群より選ばれる少なくとも1種である4)に記載の止血剤。 Hemostatic agent according to 5) the protein is at least one selected from the group consisting of protamine, collagen, gelatin 4).

【0004】 [0004]

【発明の実施の形態】以下に本発明の好適な実施の形態について詳細に説明する。 BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter the preferred embodiments of the present invention will be described in detail. 本発明に使用される核酸はD Nucleic acids used in the present invention is D
NA、RNA何れでも良く、各種動物由来のものが利用できる。 NA, RNA either good, those derived from various animals can be used. 分子量的には数万から数百万のものが利用可能であるが止血剤の調製方法、操作性、の観点から10万から200万程度の物が望ましい。 Process for the preparation of Although the molecular weight basis available those tens of thousands of millions hemostatic agent, operability, it is desirable to about 200 million to 100,000 in terms of. 核酸を得る動物主としては鮭の精子或いは精巣から抽出されるDNAがコスト面で好ましいが、これに限定されるものではない。 DNA extracted from sperm or testes salmon is preferred in terms of cost as animals mainly to obtain nucleic acid, but not limited thereto. 核酸は生体成分で有り、抗原性等の問題もなく生体適合性に優れた材料である。 Nucleic acids There a biological component, a material excellent in without problems biocompatible antigenicity and the like. また、生体内で分解されるため、合成高分子系の止血剤のように生体内に異物として残留してしまうこともない。 Moreover, because it is degraded in vivo, nor would remain as foreign matter in the body as synthetic polymer hemostatic agent.

【0005】本発明において核酸の対陽イオン(カウンターカチオン)は10−100当量%の範囲でカルシウムイオンであることが望ましい。 [0005] counter cation of the nucleic acid in the present invention (counter cation) is preferably a calcium ion in the range of 10-100 equivalent%. すなわち、核酸の全アニオンのうちの10−100当量%がカルシウムのカチオンによって中和されている。 In other words, 10-100 equivalent percent of the total anion of nucleic acids have been neutralized by the cation of calcium. カルシウムイオンを用いる理由はカルシウムイオンによる血液凝固の促進効果を合わせて使用できるためである。 The reason for using a calcium ion is because it can be used together promoting effect of the blood coagulation by calcium ions. 医療現場において、患者に対し手術時、或いはカテーテル施行時にはヘパリンを抗凝固のために投与するが、手術終了後には、不要な出血を減らすために抗ヘパリン薬が投与される。 In the medical field, the time of surgery to the patient, or at the time of catheter enforcement will be administered for anticoagulant heparin, after the end of the operation, the anti-heparin agent is administered in order to reduce unnecessary bleeding. その具体的例としてプロタミンがある。 There are protamine as a concrete example. プロタミンは生理活性タンパク質であり、すでに医薬品として使用されており例えばヘパリン過量投与時の中和、血液透析・人工心肺などの血液体外循環後のヘパリン作用の中和に使用されている。 Protamine is a bioactive protein, it has been used previously neutralized during and as heparin overdose is used as a medicament to neutralize heparin action after extracorporeal blood circulation such as hemodialysis, cardiopulmonary bypass. プロタミンはサケ科などの魚類の精巣より得られる分子量2,000〜12,000の蛋白質で、塩基性アミノ酸のアルギニンの含量が多く、強塩基性の蛋白質で、酸性高分子化合物のヘパリンと結合して、ヘパリンの抗凝血作用を阻止するといわれている。 Protamine is a protein having a molecular weight of 2,000 to 12,000 obtained from testes of fish such as salmon, in many content of arginine basic amino acid, strongly basic protein, binds to heparin acidic polymer compound, heparin It is said that to prevent the anti-clotting effect.

【0006】本発明において使用される核酸はその化学構造から分かるように燐酸基を側鎖に多量に有した一種のポリアニオンである。 [0006] The nucleic acids used in the present invention is a kind of polyanion that a large amount had a side chain phosphate groups, as can be seen from the chemical structure. このため生理活性を有するタンパク質、或いはポリペプチドのうち塩基性アミノ基を多量に含有するプロタミンのようなタンパク質、或いはポリペプチドは、核酸塩基のリン酸基とイオン相互作用をするため複合体を形成すると予想される。 Therefore protein having physiological activity, or proteins such as protamine to high content of basic amino groups of the polypeptide or polypeptides, form a complex to a phosphate group and ionic interactions nucleobases Then it is expected. このため、本発明の用途である止血剤、特にヘパリン加血液の止血に対してはプロタミンとの複合化が好適である。 Therefore, application in a hemostatic agent of the present invention, it is preferable complexation with protamine particularly for hemostasis of heparinized blood. 又、止血に当たっては血小板系も大きな働きをしており、この系を利用することも重要である。 In addition, platelet system when hemostasis are also a big role, it is also important to take advantage of this system. すなわち血小板を活性化するタンパク質、ポリペプチドを添加する事が重要である。 That protein which activates platelets, it is important to add the polypeptide. 中でも、コラーゲン及び/或いはゼラチンを利用することが望ましい。 Among them, it is desirable to utilize collagen and / or gelatin. 更にコラーゲンの中でも抗原性を軽減したアテロコラーゲン又は低分子量ゼラチンが望ましい。 Furthermore atelocollagen or low molecular weight gelatin with reduced antigenicity among collagen is desirable. これらのタンパク質、及び/又はポリペプチドの添加量は核酸に対し0−90wt%の範囲であることが望ましい。 The addition amount of these proteins, and / or polypeptide is preferably in the range of 0-90Wt% to nucleic acids. 90%を超えると核酸のメリットであるいわゆるDDS担体としての機能が減少する。 More than 90%, the function as a so-called DDS carrier is a merit of the nucleic acid decreases.

【0007】本発明の止血剤の剤形及び使用方法としては粉末として局所へ振り掛ける方法、フィルムとし出血部位へ貼付する方法、液状とし出血部位へ散布或いは塗布する方法が使用できる。 [0007] Dosage forms and methods of use of the hemostatic agent of the present invention is a method of sprinkling topical as a powder, a method of sticking to the bleeding site as a film, a method of spraying or applying to the bleeding site and the liquid can be used.

【0008】 [0008]

【実施例】以下に実施例を挙げて、本発明を更に具体的に説明する。 EXAMPLES The following examples further illustrate the present invention. 実験例1(DNA-Caフィルム) 鮭DNA−Na塩粉末(精巣由来、和光純薬製)500mgを水、40m Experimental Example 1 (DNA-Ca Film) Salmon DNA-Na salt powder (testis, manufactured by Wako Pure Chemical Industries, Ltd.) and 500mg of water, 40 m
lに溶解し、透明粘稠な溶液を得た。 It was dissolved in l, to obtain a transparent viscous solution. これをシャーレ上に流延、室温風乾する事で、透明なDNA-Naフィルムを得た。 Casting it on a petri dish, By room air-dried to give a clear DNA-Na film. 該フィルムのNaイオンの60mol%に相当する塩化カルシウムを溶解したメタノール/水(25:75 wt/wt)混合液40g中に該フィルムを24時間浸漬する事で、イオン交換させDNA−Ca塩フィルムを調製した。 By the film is immersed for 24 hours in methanol / water (25:75 wt / wt) mixture of 40g was dissolved calcium chloride corresponding to 60 mol% of Na ion of the film, DNA-Ca salt film was ion-exchanged It was prepared.

【0009】実験例2(DNA-Na/プロタミン複合体フィルム) 鮭DNA−Na塩粉末(精巣由来、和光純薬製)500mgを水、40m [0009] Experimental Example 2 (DNA-Na / protamine complex film) Salmon DNA-Na salt powder (testis, manufactured by Wako Pure Chemical Industries, Ltd.) and 500mg of water, 40 m
lに溶解し、透明粘稠な溶液を得た。 It was dissolved in l, to obtain a transparent viscous solution. この溶液にプロタミン水溶液10ml(プロタミン10mg/ml含有)を加える事で一部不溶性ゲルが析出した複合体懸濁液を形成した。 This solution partially insoluble gel by adding an aqueous protamine solution 10 ml (protamine 10mg / ml containing) form a complex suspension precipitated in. この懸濁液をシャーレ上に流延し、風乾する事でDNA−Na/プロタミン複合体フィルムを調製した。 The suspension was cast on a Petri dish, was prepared DNA-Na / protamine complex film by air drying.

【0010】実験例3(DNA-Ca/プロタミン複合体フィルム) 鮭DNA−Na塩粉末(精巣由来、和光純薬製)500mgを水、40m [0010] Experiment 3 (DNA-Ca / protamine complex film) Salmon DNA-Na salt powder (testis, manufactured by Wako Pure Chemical Industries, Ltd.) and 500mg of water, 40 m
lに溶解し、透明粘稠な溶液を得た。 It was dissolved in l, to obtain a transparent viscous solution. これをシャーレ上に流延、室温風乾する事で、透明なDNA-Naフィルムを得た。 Casting it on a petri dish, By room air-dried to give a clear DNA-Na film. 該フィルムのNaイオンの60mol%に相当する塩化カルシウムを溶解したメタノール/水(25:75 wt/wt)混合液40g中にプロタミン水溶液10ml(プロタミン10mg/ml含有)を加え、該フィルムをこのカルシウム/プロタミン混合溶液に24時間浸漬する事で、DNA−Ca/プロタミン複合体フィルムを調製した。 Protamine solution 10ml (the protamine 10mg / ml contained) was added to methanol / water (25:75 wt / wt) mixture of 40g was dissolved calcium chloride corresponding to 60 mol% of Na ion of the film, the calcium the film / protamine mixed solution by immersion for 24 hours, to prepare a DNA-Ca / protamine complex film.

【0011】実施例1−3、比較例1 上記実験例1−3で得られたサンプルを用い以下の血液凝固性の評価を行った。 [0011] Example 1-3 were evaluated for the following coagulant using a sample obtained in Comparative Example 1 Experimental Example 1-3. ヘパリン化動脈血(ヘパリン Heparinized arterial blood (heparin
2.4U/mL)を、室温、無風状態で25mm dishに入れたサンプル上に1mL滴下し、30秒ごとにサンプルを傾け、 The 2.4 U / mL), at room temperature, and 1mL dropped onto the sample placed in a 25 mm dish in still air, tilting the sample every 30 seconds,
血液の流動性を観察した。 It was observed blood fluidity. 比較例のヘパリン化動脈血のみでは25分経過後も変化は認められなかったが、各サンプルとも5分経過後には血液塊が生じ、流動性が低下した。 Although only heparinized arterial blood of the comparative example was not observed change after 25 minutes, after lapse of 5 minutes in each sample resulting blood mass, the fluidity decreases. サンプルは半溶解状態になりながら血液塊を生じ、 Sample results in a blood mass while becoming a semi-dissolved state,
実験例2で得られたフィルムでは5-10分で凝固が確認された。 Clotting 5-10 minutes it has been confirmed in the film obtained in Example 2. 実験例1のフィルムでは15分後に凝固が確認された。 Coagulation after 15 minutes was confirmed with a film of Experimental Example 1. これらの結果から、本発明品は凝固化能が確認された。 From these results, the present invention product solidification ability was confirmed.

【0012】実施例4−6、比較例2 実験例1−3で得られたフィルムを用い、動物を用い以下に示す方法で止血効果を評価した。 [0012] Examples 4-6, using the film obtained in Comparative Example 2 Experimental Example 1-3 was evaluated hemostatic effect by the following methods using animals. 露出したウサギ大腿動脈(ヘパリン200U/BWiv)を23Gの注射針で穿刺し、 Exposed rabbit femoral artery (heparin 200U / BWiv) punctured by the injection needle of 23G,
直ちに各サンプルにて出血部位に押し当て、止血性を観察した。 Pressed against the bleeding site in each sample immediately, to observe the hemostatic properties. 比較例2としてただ単なる圧迫止血のみでは止血までにおよそ10分間を要したが、各サンプルを用いた場合は3分で止血が完了した。 And Comparative Example 2 just only just astriction took between approximately 10 minutes to hemostasis, but hemostasis is completed in 3 minutes in the case of using each sample. 本実施例より、本発明品は拍動下動脈の出血孔への適用によって圧迫止血法を優位に凌駕する止血性が示された。 From this embodiment, the present invention products hemostatic be predominantly surpass compression hemostasis by application to bleeding hole pulsatile artery was shown.

【0013】 [0013]

【発明の効果】以上に詳述したように本発明は、核酸のカルシウム塩を主成分とした止血剤であるため、人由来の材料に起因する未知ウィルスによる感染の危険性がなく、出血量の多い部所への適応が可能で、抗原性の問題もない止血剤が提供できる。 The present invention as described in detail above, according to the present invention are the hemostatic agent mainly composed of calcium salts of nucleic acids, there is no risk of infection by unknown viruses due to the material of human origin, blood loss possible adaptation to the high duty post and can be provided also without hemostats antigenicity problem. また本発明によれば、血管に出来た傷口の自然修復を促進し、傷口からの再出血が起き難い止血剤が提供できる。 According to the invention, promote the natural repair of the wound made in the blood vessel, rebleeding occurred hardly hemostatic agent from the wound can be provided. 即ち、本発明によれば、 That is, according to the present invention,
創傷面の治癒を妨げる事無く、又、動脈血を止血できる素早い凝固反応、組織への粘着性、生分解性をあわせ持つ止血剤を提供することができる。 Without interfering with the healing of the wound surface, also rapid coagulation reaction capable of hemostasis arterial blood, adhesion to tissues, it is possible to provide a hemostatic agent having both biodegradability.

フロントページの続き (51)Int.Cl. 7識別記号 FI テーマコート゛(参考) A61P 7/04 A61K 37/08 // C07H 21/00 37/12 Of the front page Continued (51) Int.Cl. 7 identification mark FI theme Court Bu (Reference) A61P 7/04 A61K 37/08 // C07H 21/00 37/12

Claims (5)

    【特許請求の範囲】 [The claims]
  1. 【請求項1】核酸のカルシウム塩を主成分とした止血剤。 1. A hemostatic agent as a main component of calcium salt of acid.
  2. 【請求項2】前記核酸がDNAである請求項1記載の止血剤。 2. A hemostatic agent according to claim 1, wherein said nucleic acid is DNA.
  3. 【請求項3】前記核酸のカルシウム塩が核酸のカウンターカチオンの10−100当量%がカルシウムイオンである請求項1または2に記載の止血剤。 3. A hemostatic agent according to claim 1 or 2 10-100 equivalent percent of a calcium ion counter cation of the calcium salt of the nucleic acid.
  4. 【請求項4】前記止血剤が、更にタンパク質を含有する請求項1〜3のいずれかに記載の止血剤。 Wherein said hemostatic agent, hemostatic agent according to claim 1, further containing protein.
  5. 【請求項5】前記タンパク質がプロタミン、コラーゲン、ゼラチンからなる群より選ばれる少なくとも1種である請求項4記載の止血剤。 5. A hemostatic agent according to claim 4, wherein at least one said protein is selected from the group consisting of protamine, collagen, gelatin.
JP2000249624A 2000-08-21 2000-08-21 Hemostatic agent Pending JP2002060341A (en)

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US10035815B2 (en) 2004-07-02 2018-07-31 Geron Corporation Synthesis of protected 3′-amino nucleoside monomers
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