CN1711111A - 带有凝血酶的生物可吸收合成非织造织物 - Google Patents

带有凝血酶的生物可吸收合成非织造织物 Download PDF

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CN1711111A
CN1711111A CNA2003801031524A CN200380103152A CN1711111A CN 1711111 A CN1711111 A CN 1711111A CN A2003801031524 A CNA2003801031524 A CN A2003801031524A CN 200380103152 A CN200380103152 A CN 200380103152A CN 1711111 A CN1711111 A CN 1711111A
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CN100356987C (zh
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内田隆德
新屋希子
嘉悦洋
今村隆幸
野崎周英
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Chemo Sero Therapeutic Research Institute Kaketsuken
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Abstract

本发明的目的在于提供一种安全并且有效的止血物并且涉及生物可吸收合成非织造织物以及含有该非织造织物的止血物，该非织造织物的特点在于凝血酶作为有效成分固定于其上。本发明的带有凝血酶的生物可吸收合成非织造织物可通过将生物可吸收合成非织造织物浸入含有凝血酶的溶液的步骤以及冻干所得非织造织物的步骤制备，并且通过使用该带有凝血酶的生物可吸收合成非织造织物可以实现快速且有效的止血。

Description

带有凝血酶的生物可吸收合成非织造织物
技术领域
本发明涉及生物可吸收合成非织造织物、该非织造织物的制造方法以及包含所述非织造织物的止血物，所述非织造织物的特点在于其中带有凝血酶作为有效成分。
背景技术
在医疗领域，止血处理非常重要。当活体中的血管被损坏后，各种凝血因子在该局部区域被激活并且纤维蛋白最终形成从而止血。在这个过程中，凝血酶是最重要的酶，其作用于纤维蛋白原从而将其转化成纤维蛋白。纤维蛋白原本身，虽然存在于血液中，但没有止血功能。要依靠凝血酶的作用才能发挥止血功能。也就是说，在活体的止血反应中凝血酶起最重要的作用。
发明内容
(本发明要解决的技术问题)
常规凝血酶制剂是液体或粉末形式的，因而当施用于流血区域时经常被冲走，导致凝血酶的止血效果不充分。为了消除这个缺点，已有各种关于在生物可吸收材料上带有凝血酶的片材的报道(例如WO90/13320和日本专利公告No.61/59737)。这些片材中的一种是将来自血液的凝血酶固定在由明胶制成的片材上得到的片材。但是如下面的实施例所示，该片材没有展示出充分的止血效果，并且由于制造困难以及实际使用时的问题，该片材距离实际使用还有很远的距离。存在其中牛明胶与牛凝血酶混在一起的凝胶形式的止血剂，但这类止血剂也是不利的，因为有感染例如BSE的危险并且使用时不便压缩。
另一类止血剂是其中凝血酶与其它凝血因子相结合的纤维蛋白粘合剂。纤维蛋白粘合剂，主要包括凝血酶和纤维蛋白原，是生物组织粘合剂，其通过凝血酶的作用利用纤维蛋白原向纤维蛋白的转变，并且广泛应用于临床领域中的粘合、止血和封合用途。但是，对在例如外科手术中的用途，通过溶解制备凝血酶溶液和纤维蛋白原溶液需要时间，因而对于使用特别是紧急情况非常不方便。
考虑到这些不方便，通过使用片材直接按压到流血区域而施用的纤维蛋白粘合剂也已经实际应用。但是，目前可用的片材类型的粘合剂并不理想，因为其包括作为基本材料的马胶原蛋白和得自牛的凝血酶，也就是得自非人动物种的材料，因而有可能引出抗异种蛋白的抗体以及人畜共患性感染如朊病毒病的危险。所以，目前可用的局部止血剂在操作和安全方面并不令人满意地方便。
为了解决上述问题，需要含有得自人并且没有感染性试剂的凝血因子的止血物，所述止血物是由严格挑选并设计为具备完全的止血效果并且对活体安全的材料制成的片材形式。
(解决问题的方法)
考虑到上述的各种问题，发明人进行了深入细致的研究并完成了关于局部止血物的本发明。因而，从各种生物可吸收材料中挑选以非织造织物形式加工的生物可吸收合成材料，本发明涉及带有凝血酶作为止血有效成分的生物可吸收合成非织造织物、制造该非织造织物的方法以及含有所述非织造织物的止血物。
(比现有技术更加有效的效果)
本发明的带有凝血酶的生物可吸收合成非织造织物具有如下所列的优异性质，因而是理想的局部止血物。
(1)具有优异的止血效果；
(2)在紧急情况下容易处理；
(3)安全性高；
(4)随时间推移被吸收；
(5)表现出优异的弹性和柔软性；
(6)能够对宽阔区域进行止血；
(7)引起轻微的或没有发炎反应。
因此，本发明提供了包含生物可吸收合成非织造织物的止血物，该止血物允许在各种不同领域手术中对需要组织封合的外科手术进行安全止血。
发明的最佳实施方式
本发明所使用的生物可吸收合成非织造织物可以是由生物可吸收合成纤维制成的任意的非织造织物。本发明的非织造织物优选具有适当的柔软性以确保其肯定能够覆盖任何损伤区域。例如，能够形成这样的非织造织物的合成纤维包括聚乙醇酸、聚乳酸或乙醇酸和乳酸的共聚物等等，这些合成纤维可在加工成非织造织物后使用。在这些非织造织物之中，由聚乙醇酸通过加工成非织造织物而制备的生物可吸收合成非织造织物是用于本发明目的最优选的材料。
本发明的非织造织物可以是任意形状，但考虑到对不同应用的通用性优选片状形式。
对于凝血酶，得自人血液的凝血酶和通过DNA重组技术得到的重组凝血酶都可使用。除了凝血酶，也可添加可药用的稳定剂和添加剂。这样的稳定剂和添加剂的例子包括例如白蛋白、聚乙二醇、精氨酸、透明质酸钠、甘油、甘露醇和氯化钙等。
本发明的带有凝血酶的生物可吸收合成非织造织物可用例如如下描述的方法制造。
将凝血酶溶于盐水或缓冲液中并任选进一步向其中加入作为稳定剂或添加剂的白蛋白、聚乙二醇、精氨酸、透明质酸、甘油、甘露醇或氯化钙等。然后将生物可吸收合成非织造织物浸入该溶液中，在-80℃冷冻2小时，冻干得到所需产品。
本发明带有凝血酶的生物可吸收非织造织物可以被按压到出血区域通过压力防止血液流出，并且除此之外，该片状止血物含有的凝血酶立刻和血液中的纤维蛋白原反应，使得纤维蛋白原转变为纤维蛋白，由此在此局部区域达到止血效果。所形成的纤维蛋白可以附着于周围的组织上。
由聚乙醇酸制成的生物可吸收非织造织物早已用于医疗目的，并且它的安全性已经由其被吸收进活体并被分解为水和二氧化碳所证明。
工业实用性
这样，本发明带有凝血酶的生物可吸收非织造织物可以容易并且迅速地施用于局部出血并且可以通过压力和血液凝固反应有效止血。除此之外，因为在所述生物可吸收非织造织物中使用的每一种材料对活体都是安全的，因此该生物可吸收非织造织物可不经考虑就用于临床情况。
通过下面的实施例更加详细地解释本发明，但本发明不限于实施例。
实施例1：重组凝血酶的制备
如日本专利申请No.2001/206919所述制备重组凝血酶。简单地说，培养导入了人前凝血酶(prethrombin)基因的动物细胞，然后从所得的培养基中纯化前凝血酶。另一方面，从导入了ecarin基因的动物细胞培养基中纯化ecarin。前凝血酶被所得到的ecarin激活从而得到可被纯化的凝血酶。
实施例2：带有凝血酶的片的制备
通过以下描述的方法制备本发明带有凝血酶的片。
向含有0.001-0.01％透明质酸钠(nacalai tesque；18237-41)或0.5-2％甘油(nacalai tesque；17018)的溶液中加入最终浓度为0.5-1.5％的甘露醇(nacalai tesque；21303)和40mM氯化钙，接着加入最终浓度为1000U/mL的重组凝血酶。将该溶液滴加到由聚乙醇酸制成的生物可吸收合成非织造织物(3cm×3cm；Neoveil，Gunze Limited，厚度0.15mm)中，滴加量为0.05mL/cm2。该片在-80℃冷冻2小时并冻干后，用作带有重组凝血酶的片状样品。类似地，制备带有得自血液的凝血酶的片，所用凝血酶得自人血液而不是重组凝血酶。
作为对照，使用了没有用凝血酶处理的生物可吸收合成非织造织物、如WO 90/13320实施例描述所制备的明胶制成的止血海绵以及市场上可买到的片状纤维蛋白粘合剂。
组1：带有得自血液的凝血酶的片
使用一种片，其中在聚乙醇酸制成的非织造织物中带有50U/cm2的得自人血液的凝血酶。
组2：带有重组凝血酶的片
使用一种片，其中在聚乙醇酸制成的非织造织物中带有50U/cm2的重组凝血酶。
组3：没有凝血酶的片
使用一种片，其中聚乙醇酸制成的非织造织物除了没有凝血酶外按组1的方法处理。
组4：带有固定凝血酶的止血海绵
使用一种止血海绵，该止血海绵由含有得自人血液的凝血酶的明胶制成，并按照如WO 90/13320(Spongostan，Johnson & JohnsonK.K.)实施例的描述制备。
组5：片状纤维蛋白粘合剂
使用一种其中纤维蛋白粘合剂的组分固定于胶原蛋白片(TachoComb，Torii Pharmaceutical Co.，Ltd.)上的片状纤维蛋白粘合剂，其中组分如纤维蛋白原和凝血酶通过冻干法固定于由马胶原蛋白制成的海绵片的一侧。
实施例3：在渗出性出血中检测止血性
使用兔子作为动物模型以评估止血性。将兔子剖腹并切除部分肝脏，对整个伤口区域向其流血区域施用如实施例2制备的各组止血物并按压一分钟。所用的评估如下所示。
(1)将用戊巴比妥麻醉的兔子实施剖腹术。
(2)静脉给药300U/kg肝素。
(3)将右叶、内侧左叶或外侧左叶的肝脏表面切除直径为1.5cm厚度为4mm的圆形。
(4)用纱布吸收从切除伤口流出的血液10秒钟并称重。形成切除伤口后流血量约为0.50g。
(5)尝试用上述各种止血物止血。每一次治疗的实施都没有驱血但有血液流出。
(6)用纱布吸收并称重5分钟的流血量，包括止血治疗需要的时间。5分钟后当观察到伤口表面流血时，重复进行止血治疗和流血的称重。
(7)止血治疗最多重复四次，通过止血所需的止血治疗次数和从止血治疗开始直到止血的流血的全部重量进行评估(表1)。
表1
  组   经过每次止血治疗能够止血的病例的数目  止血治疗后的总流血量/g
  第一次   第二次   第三次   第四次
  1     7     1     0     0     0.51±0.31
  2     7     1     0     0     0.34±0.15
  3     2     3     3     0     2.03±0.95
  4     0     2     4     2*     6.28±1.67
  5     0     4     1     3*     6.70±2.64
*：即使经过第四次止血治疗后，所观察到的不能止血的病例。
如表1所示，与对照止血片的止血效果相比，带有得自血液的凝血酶(组1)和重组凝血酶(组2)的本发明的止血片展示出了更加优异的止血效果。只有非织造织物而未经凝血酶处理(组3)，几乎没有观察到止血效果，但也比WO 90/13320描述的由明胶制成的带有固定凝血酶的止血海绵(组4)的止血效果高。这表明，在已知的生物可吸收材料中，用于本发明作为基质的生物可吸收非织造织物是最适合用于止血的材料。另外，还表明在该非织造织物中带有凝血酶可以更快速和更有效地止血。除此之外，由对比测试结果清晰可见，与本发明带有凝血酶的止血片相比，其中胶原蛋白用作基质的片状纤维蛋白粘合剂(组5)表现出差得多的止血效果。

Claims (9)

1.一种生物可吸收合成非织造织物，其带有凝血酶作为有效成分。
2.权利要求1的生物可吸收合成非织造织物，其中所述生物可吸收合成非织造织物由选自聚乙醇酸、聚乳酸以及乙醇酸和乳酸共聚物的材料制成。
3.权利要求2的生物可吸收合成非织造织物，其中所述材料是聚乙醇酸。
4.权利要求1-3中任一项的生物可吸收合成非织造织物，其中凝血酶是得自人血液的凝血酶或通过DNA重组技术制备的重组人凝血酶。
5.一种止血物，其使用权利要求1-4中任一项所述的生物可吸收合成非织造织物。
6.制备带有凝血酶的生物可吸收合成非织造织物的方法，该方法包括将生物可吸收合成非织造织物浸入含有凝血酶的溶液以及冻干所得非织造织物的步骤。
7.权利要求6的方法，其中所述生物可吸收合成非织造织物由选自聚乙醇酸、聚乳酸以及乙醇酸和乳酸共聚物的材料制成。
8.权利要求7的方法，其中所述材料是聚乙醇酸。
9.权利要求6-8中任一项的方法，其中凝血酶是得自人血液的凝血酶或通过DNA重组技术制备的重组人凝血酶。
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104027846A (zh) * 2014-06-20 2014-09-10 东华大学 一种非织造材料增强组织工程复合三维支架及其制备方法
CN102105141B (zh) * 2008-04-16 2015-06-24 一般财团法人化学及血清疗法研究所 保持有凝血酶的生物可吸收性片制剂的制造方法
CN110251468A (zh) * 2012-12-03 2019-09-20 奥姆里克斯生物药品有限公司 凝血酶溶液及其使用方法

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003280730B2 (en) 2002-11-14 2010-04-29 Juridical Foundation The Chemo-Sero-Therapeutic Research Institute Thrombin-carrying bioabsorbable synthetic nonwoven fabric
DK2052746T3 (en) * 2004-10-20 2014-12-08 Ethicon Inc Absorbable hemostatic patch
US9358318B2 (en) * 2004-10-20 2016-06-07 Ethicon, Inc. Method of making a reinforced absorbable multilayered hemostatic wound dressing
JP2006345745A (ja) * 2005-06-15 2006-12-28 Juntendo 肝癌非ヒト動物モデルの作製方法
NZ601913A (en) * 2008-01-15 2014-02-28 Abbott Gmbh & Co Kg Powdered protein compositions and methods of making same
EP2851095B1 (en) 2012-05-14 2021-07-14 Teijin Limited Sheet molding and hemostatic material
KR101866571B1 (ko) * 2012-06-29 2018-06-11 코오롱인더스트리 주식회사 생분해성 부직포 웹, 그 제조방법, 및 이를 이용한 혈액 필터
US11826028B2 (en) 2020-06-10 2023-11-28 Ethicon, Inc. Two component sealing systems including synthetic matrices and biosynthetic adhesives for sealing resected surfaces of organs to control bleeding, fluid leaks and air leaks

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54104687A (en) * 1978-02-01 1979-08-17 Unitika Ltd Novel injury protecting material
US4265233A (en) * 1978-04-12 1981-05-05 Unitika Ltd. Material for wound healing
JPS5844057A (ja) * 1981-08-28 1983-03-14 ユニチカ株式会社 創傷部治療用材料
NZ205863A (en) * 1982-10-18 1985-09-13 Johnson & Johnson Prod Inc Absorbable haemostatic material containing lactide and glycolide homopolymers and copolymers
JPS6395041A (ja) * 1986-10-09 1988-04-26 グンゼ株式会社 医療用プレジェットの製造法
DK223389D0 (da) * 1989-05-05 1989-05-05 Ferrosan As Saarsvamp
GB9503750D0 (en) 1995-02-24 1995-04-12 Common Services Agency Thrombin preparation
JP3795100B2 (ja) * 1995-05-08 2006-07-12 株式会社伊垣医療設計 医療用縫合材
JP3526487B2 (ja) * 1995-05-08 2004-05-17 株式会社伊垣医療設計 医療用縫合材
JPH11309151A (ja) * 1998-04-30 1999-11-09 Nippon Waisuredarii Kk 手術用縫合デバイス
US6056970A (en) * 1998-05-07 2000-05-02 Genzyme Corporation Compositions comprising hemostatic compounds and bioabsorbable polymers
JP4480270B2 (ja) * 1998-05-19 2010-06-16 ジ・アメリカン・ナショナル・レッド・クロス 止血サンドウィッチ包帯
AU2003280730B2 (en) 2002-11-14 2010-04-29 Juridical Foundation The Chemo-Sero-Therapeutic Research Institute Thrombin-carrying bioabsorbable synthetic nonwoven fabric
AU2004206150B2 (en) * 2003-01-20 2009-10-29 Km Biologics Co., Ltd. Hemostatic materials

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102105141B (zh) * 2008-04-16 2015-06-24 一般财团法人化学及血清疗法研究所 保持有凝血酶的生物可吸收性片制剂的制造方法
CN110251468A (zh) * 2012-12-03 2019-09-20 奥姆里克斯生物药品有限公司 凝血酶溶液及其使用方法
US11993797B2 (en) 2012-12-03 2024-05-28 Omrix Biopharmaceuticals Ltd. Thrombin solution and methods of use thereof
CN104027846A (zh) * 2014-06-20 2014-09-10 东华大学 一种非织造材料增强组织工程复合三维支架及其制备方法

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