CN110691614A - 粉末状止血剂递送用装置 - Google Patents
粉末状止血剂递送用装置 Download PDFInfo
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- CN110691614A CN110691614A CN201880014903.1A CN201880014903A CN110691614A CN 110691614 A CN110691614 A CN 110691614A CN 201880014903 A CN201880014903 A CN 201880014903A CN 110691614 A CN110691614 A CN 110691614A
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- hemostatic
- thrombin
- hemostatic agent
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Abstract
本公开提供了多层止血装置，其包括包含羧甲基纤维素的第一层；在第一层上提供的、包含粉末状止血剂的第二层；以及在第二层上提供的、包含纱布、氧化纤维素或胶原中至少一种的第三层，其中第一层和第三层包封第二层，并且止血剂包括下述物质之一：纤维蛋白原、凝血酶、纤维蛋白单体、或凝血酶与明胶的组合。
Description
技术领域
本公开整体上涉及多层止血装置。更具体地，本公开涉及包括粉末状止血剂和快速溶解/降解膜的多层止血装置。
背景技术
止血剂和密封剂目前用作包括手术期间的出血在内的止血的辅助手段。止血剂通常以固体织物，粉末或颗粒形式，或作为液体存在。可流动的止血剂提供与伤口的典型不规则表面的良好接触，从而可以实现良好的止血。然而，颗粒止血剂的可流动性质也使得它们在使用中相对难以处理。目前的粉末状止血剂通常采用塑料波纹管式涂敷器进行施用。用这种类型的递送系统可控和精确地施用粉末可以是具有挑战性的，例如，导致止血剂从伤口部位吹走，使得大部分止血剂可能被浪费。
发明内容
本公开的一个方面提供了多层止血装置，其包括包含羧甲基纤维素的第一层；在第一层上提供的、包含粉末状止血剂的第二层；以及在第二层上提供的、包含纱布、氧化纤维素或胶原中至少一种的第三层，其中第一层和第三层包封第二层，并且止血剂包括纤维蛋白原、凝血酶、纤维蛋白单体或凝血酶与明胶的组合中的一种。
通过阅读以下详细描述，更多的方面和优点对于本领域普通技术人员将是显而易见的。尽管方法和组合物可以有各种形式的实施方案，但是下文的描述包括具体实施方案，应理解本公开内容是示例性的，并不是要将本公开限制至本文描述的具体实施方案。
附图说明
为了进一步便于理解本发明，附上两幅附图。
图1显示了包括第一可溶/可降解层、第二粉末状止血剂层和第三可溶/可降解层的多层装置演示图，并且还显示在将装置施加到伤口上后使得第一层与伤口接触，第一层的溶解/降解允许止血剂与伤口直接接触以及随后第三层溶解/降解。
图2示出了包括第一可溶/可降解层、第二粉末状止血剂层和第三不可溶/不可降解层的多层装置演示图，并且还显示在将装置施加到伤口上后使得第一层与伤口接触，第一层的溶解/降解允许止血剂与伤口直接接触以及随后去除第三层。
发明详述
本公开提供了多层止血装置，其包括包含羧甲基纤维素的第一层；在第一层上提供的、包含粉末状止血剂的第二层；以及在第二层上提供的、包含纱布、氧化纤维素或胶原中至少一种的第三层，其中第一层和第三层包封第二层，并且止血剂包括纤维蛋白原、凝血酶、纤维蛋白单体或凝血酶与明胶的组合中的一种。有利地，本公开的多层止血装置允许以在手术部位处最大化利用粉末状止血剂的方式精确、可控地递送和施用可流动的粉末状止血剂至伤口部位，而没有由于不精确的递送或从递送位置吹走止血剂导致的浪费。
如本发明中所用的，“粉末状止血剂”是指可流动的固体颗粒材料。“粉末”和“颗粒”在本发明中可互换使用。
在实施方案中，将粉末状止血剂以重复图案提供于第一层上。在实施方案中，第一层和第三层的周边边缘是密封的。
在实施方案中，第一层在生理条件下是可溶的，使得第一层在与来自伤口的液体接触时会溶解。生理条件包括水性环境，其具有约20至约40℃的温度范围，约6至约8的pH，约0.8atm至约1.2atm的大气压以及相应的大气氧浓度。在实施方案中，第一层在生理条件下是可降解的，使得第一层在与来自伤口的液体接触时会降解。在实施方案中，第三层在生理条件下是可降解的，使得第三层在与来自伤口的液体接触时会降解。在实施方案中，第三层在生理条件下形成凝胶。在实施方案中，第三层在生理条件下是不可溶的和/或不可降解的，使得在与来自伤口的液体接触时以及在将装置施用于伤口并且第一层溶解和/或降解之后第三层不会溶解或降解，当将止血装置施用于伤口时第二层被置于伤口和第三层之间。
第一层
本发明的装置包括第一层，其为伤口接触层。第一层可包含在生理条件下可溶和/或可降解的材料，使得第一层在与来自伤口的液体(例如，血液和/或伤口渗出物)接触时会溶解和/或降解。在实施方案中，第一层在生理条件下可快速溶解和/或降解，并且与来自伤口的液体接触少于约90秒后，与来自伤口的液体接触少于约60秒后，或与来自伤口的液体接触少于约30秒后会溶解和/或降解。
在实施方案中，第一层包含羧甲基纤维素，并且可以作为针织的非织造织物，作为织造织物，或作为可溶/可降解的膜提供。用作羧甲基纤维素的补充或替代的其它材料包括但不限于聚乙烯醇和改性聚乙烯醇，聚丙烯酸酯，水溶性丙烯酸酯共聚物，聚乙烯吡咯烷酮，支链淀粉，明胶，羟丙基甲基纤维素(HPMC)，聚环氧乙烷，聚乙二醇，低粘度级羟丙基纤维素，多糖，水溶性天然聚合物，包括但不限于瓜尔胶，黄原胶，刺槐豆胶，角叉菜胶，以及淀粉，改性淀粉，包括但不限于乙氧基化淀粉和羟丙基化淀粉，前述物质的共聚物和任何前述物质的组合。
根据本发明的可溶/可降解薄膜可包括其他任选的添加剂成分，包括但不限于增塑剂、表面活性剂、成膜剂和其他功能成分，例如以适合其预期目的的量。
合适的增塑剂可包括甘油，二甘油，丙二醇，乙二醇，二甘醇，三甘醇，四甘醇，高达MW 400的聚乙二醇，邻苯二甲酸酯衍生物，包括但不限于邻苯二甲酸二甲酯、邻苯二甲酸二乙酯和二丁基酯，柠檬酸酯衍生物，包括但不限于柠檬酸三丁酯、柠檬酸三乙酯、柠檬酸乙酰酯、柠檬酸三醋酸甘油酯，以及蓖麻油。
在实施方案中，第一层在生理条件下是可溶的，使得第一层在与来自伤口的液体接触时会溶解。在实施方案中，第一层在生理条件下是可降解的，使得第一层在与来自伤口的液体接触时会降解。
第二层
本公开的装置包括了在第一层上提供的包含粉末状止血剂的第二层。第二粉末状止血剂层可以是均质层或异质层。在实施方案中，将粉末状止血剂以重复图案提供于第一层上，例如，粉末状止血剂可以以离散点的图案，以离散的列或行的图案，或以其他几何形状的重复图案沉积在第一层上。
如本发明中所用的，“止血剂”是指对出血伤口施加被动或主动模式的止血作用的材料。
在实施方案中，粉末状止血剂选自纤维蛋白原，凝血酶，纤维蛋白单体，明胶和前述物质的混合物。粉末状止血剂可以是冻干的止血剂，例如冻干的凝血酶或冻干的纤维蛋白原。在实施方案中，粉末状止血剂选自纤维蛋白原，凝血酶，纤维蛋白单体，凝血酶与明胶的组合，以及前述物质的混合物。在实施方案中，粉末状止血剂包含纤维蛋白原。在实施方案中，粉末状止血剂为纤维蛋白原。在实施方案中，粉末状止血剂包含纤维蛋白单体。在实施方案中，粉末状止血剂为纤维蛋白单体。在实施方案中，粉末状止血剂包含凝血酶。在实施方案中，粉末状止血剂包含凝血酶和明胶。在实施方案中，粉末状止血剂为凝血酶。在实施方案中，粉末状止血剂为凝血酶与明胶的组合。
如本发明中所用的，“纤维蛋白单体”包括任何形式的纤维蛋白，例如纤维蛋白I，纤维蛋白II或des BB纤维蛋白，其中纤维蛋白是单体形式或寡聚体形式，其可以被溶解并且可以转化为纤维蛋白聚合物。纤维蛋白寡聚物能够在生理条件下溶解，而纤维蛋白聚合物在生理条件下不可溶。
用于补充或替代纤维蛋白原、凝血酶、纤维蛋白单体和明胶的其他粉末状/颗粒止血剂包括但不限于氧化纤维素，壳聚糖，藻酸盐，多糖，乙基纤维素珠和其他氧化纤维素珠，麦芽糖糊精，凝血因子浓缩物，重组因子Vila，alphanate FVIII浓缩物，bioclate FVm浓缩物，monoclate FVHI浓缩物，haemate P FVIII，von Willebrand因子浓缩物，helixateFVII浓缩物，kogenate FVII浓缩物，recombinate FVIII浓缩物，mononine FIX浓缩物，fibrogammin P FXIII浓缩物，以及前述物质的组合。
第三层
本发明的装置包括在第二层上提供的第三层，其中第一层和第三层包封第二层。在实施方案中，第三层在生理条件下可以是可溶的和/或可降解的，使得第三层在与来自伤口的液体接触时会溶解和/或降解。在实施方案中，第三层在生理条件下可以是不可溶的和不可降解的，使得第三层在与来自伤口的液体接触时不会溶解或降解，即使在伤口和第三层之间的接触持续长时间，例如，大于5分钟，15分钟，甚至1小时，也是如此。在实施方案中，第三层可以在生理条件下形成凝胶。
在实施方案中，第三层包含选自纱布、氧化纤维素、胶原和前述物质的混合物的材料。在实施方案中，第三层包含纱布。在实施方案中，第三层为纱布。在实施方案中，第三层包含氧化纤维素。在实施方案中，第三层为氧化纤维素。在实施方案中，第三层包含胶原。在实施方案中，第三层为胶原。任选地，氧化纤维素是氧化再生纤维素。
用于补充或替代纱布、氧化纤维素和胶原的合适的其他材料包括但不限于硅酮，角蛋白，明胶，几丁质，壳聚糖，聚乙烯吡咯烷酮，藻酸盐，交联聚乙烯，酒精，以及前述物质的组合。
第三层还可任选地包括pH调节剂。不受理论的束缚，据信当第二层包含凝血酶并且第三层包含氧化纤维素或氧化再生纤维素时，第三层的酸性pH可能导致纤维蛋白原在有机会与凝血酶反应形成凝块之前从伤口析出。因此，不受理论的束缚，可以在第三层中包含pH调节剂以为第三层提供中性pH以避免纤维蛋白原的析出。合适的pH调节剂包括但不限于苏打灰，硅酸钠，石灰，磷酸钠和缓冲剂组合物，例如乙酸盐缓冲液，柠檬酸盐缓冲液，磷酸盐缓冲液。pH调节剂可以以颗粒形式提供或者可以涂覆在第三层上，例如作为溶液。
本发明的装置可具有任何合适的形状，包括但不限于三角形，四边形，例如正方形或矩形，圆形，椭圆形，五边形，六边形和八边形。在实施例中，至少第一层和第三层具有类似的形状，使得第一层和第三层具有基本平行的周边边缘，以便于第一层和第三层之间的第二层的包封和密封。
在实施方案中，可以密封第一层和第三层的周边边缘。可以根据本领域已知的任何合适的方法密封第一层和第三层的周边边缘，包括但不限于溶剂密封和热密封。
如图1和图2所示，本公开的装置可置于伤口上，以提供粉末状止血剂的精确递送和施用。有利地，在施用装置使得第一层与伤口接触之后，面向伤口的第一层容易溶解和/或降解，使得第二层的止血剂随后被置于伤口和第三层之间并与伤口接触。可以选择第三层，使得其在伤口止血已发生之前不会溶解或降解，或者其根本不会溶解或降解并会保持在原位直到伤口止血已发生和移除第三层。
因此，在实施方案中，第一层在生理条件下的溶解和/或降解速率大于第三层在生理条件下的降解和/或溶解速率。此外，在实施方案中，第三层在生理条件下是不可溶的和/或不可降解的，并且在将止血装置施用于伤口之后将第二层置于伤口和第三层之间。
可替选地，可以选择第三层以在施用于伤口，以及随后第一层溶解/降解，并将第二层的止血剂递送至伤口后容易地溶解和/或降解，使得第三层与伤口接触。
在实施方案中，当止血剂包含纤维蛋白原时，第三层包含胶原。
下表1中提供的组合各自是特别考虑的实施方案。在表1中提供的每种组合中，具体考虑了第一层、第二层和第三层可包括所列材料或可由所列材料组成。
| 表1 | 第一层 | 第二层 | 第三层 |
| 1 | 羧甲基纤维素 | 凝血酶和明胶 | 氧化纤维素 |
| 2 | 羧甲基纤维素 | 凝血酶和明胶 | 纱布 |
| 3 | 羧甲基纤维素 | 凝血酶和明胶 | 胶原 |
| 4 | 羧甲基纤维素 | 纤维蛋白原 | 氧化再生纤维素 |
| 5 | 羧甲基纤维素 | 凝血酶 | 氧化再生纤维素 |
| 6 | 羧甲基纤维素 | 纤维蛋白单体 | 氧化再生纤维素 |
因为本发明范围内的修改对于本领域普通技术人员来说是显而易见的，所以给出前面的描述仅是为了理解清楚，而不应该从中理解出不必要的限制。
本文中引用的所有专利、公布和参考文献通过引用的方式全部纳入本文。在本公开与所纳入的专利、公布和参考文献之间存在冲突的情况下，应当以本公开为准。
Claims (22)
1.一种多层止血装置，其包括：
包含羧甲基纤维素的第一层；
在所述第一层上提供的、包含粉末状止血剂的第二层；以及
在所述第二层上提供的、包含纱布、氧化纤维素或胶原中至少一种的第三层，其中所述第一层和所述第三层包封所述第二层，
其中所述止血剂包括以下的至少一种：纤维蛋白原，凝血酶，纤维蛋白单体，或凝血酶与明胶的组合。
2.根据权利要求1所述的多层止血装置，其中所述粉末状止血剂为固体颗粒。
3.根据权利要求1或2所述的多层止血装置，其中将所述粉末状止血剂以重复图案被提供于所述第一层上。
4.根据前述权利要求任一项所述的多层止血装置，其中所述第一层和所述第三层具有周边边缘，并且沿着所述周边边缘将所述第一层和所述第三层密封。
5.根据权利要求4所述的多层止血装置，其中所述第一层和所述第三层的周边边缘被热密封。
6.根据权利要求4所述的多层止血装置，其中所述第一层和所述第三层的周边边缘被溶剂密封。
7.根据前述权利要求任一项所述的多层止血装置，其中所述第一层在生理条件下可溶，使得所述第一层在与来自伤口的液体接触时会溶解。
8.根据前述权利要求任一项所述的多层止血装置，其中所述第一层在生理条件下的溶解速率大于所述第三层在生理条件下的降解速率。
9.根据前述权利要求任一项所述的多层止血装置，其中所述第三层在生理条件下形成凝胶。
10.根据前述权利要求任一项所述的多层止血装置，其中所述第三层在生理条件下是不可溶的和/或不可降解的，并且当将所述止血装置施用于伤口时所述第二层被置于所述伤口和所述第三层之间。
11.根据前述权利要求任一项所述的多层止血装置，其中所述氧化纤维素是氧化再生纤维素。
12.根据前述权利要求任一项所述的多层止血装置，其中所述第三层包含氧化纤维素，并且所述止血剂包含凝血酶与明胶的组合。
13.根据权利要求1至10中任一项所述的多层止血装置，其中所述第三层包括纱布，并且所述止血剂包括凝血酶与明胶的组合。
14.根据权利要求1至10中任一项所述的多层止血装置，其中所述第三层包含胶原，并且所述止血剂包括凝血酶与明胶的组合。
15.根据权利要求1至11中任一项所述的多层止血装置，其中所述第三层包含氧化再生纤维素，并且所述止血剂包含纤维蛋白原。
16.根据权利要求1至11中任一项所述的多层止血装置，其中所述第三层包含氧化再生纤维素，并且所述止血剂包含凝血酶。
17.根据权利要求1至11中任一项所述的多层止血装置，其中所述第三层包含氧化再生纤维素，并且所述止血剂包含纤维蛋白单体。
18.根据权利要求12、13或14中任一项所述的多层止血装置，其中所述止血剂为凝血酶与明胶的组合。
19.根据权利要求15所述的多层止血装置，其中所述止血剂为纤维蛋白原。
20.根据权利要求16所述的多层止血装置，其中所述止血剂为凝血酶。
21.根据权利要求17所述的多层止血装置，其中所述止血剂为纤维蛋白单体。
22.根据权利要求1至10中任一项所述的多层止血装置，其中所述第一层包含以下的至少一种：羧甲基纤维素，聚乙烯醇和改性聚乙烯醇，聚丙烯酸酯，水溶性丙烯酸酯共聚物，聚乙烯吡咯烷酮，支链淀粉，明胶，羟丙基甲基纤维素(HPMC)，聚环氧乙烷，聚乙二醇，低粘度级羟丙基纤维素，多糖，水溶性天然聚合物，包括但不限于瓜尔胶，黄原胶，刺槐豆胶，角叉菜胶，以及淀粉，改性淀粉，包括但不限于乙氧基化淀粉和羟丙基化淀粉，前述物质的共聚物和任何前述物质的组合；
所述第二层包含以下的至少一种：纤维蛋白原，凝血酶，纤维蛋白单体，明胶，氧化纤维素，壳聚糖，藻酸盐，多糖，乙基纤维素珠和其他氧化纤维素珠，麦芽糖糊精，凝血因子浓缩物，重组因子Vila，alphanate FVIII浓缩物，bioclate FVm浓缩物，monoclate FVHI浓缩物，haemate P FVIII，von Willebrand因子浓缩物，helixate FVII浓缩物，kogenate FVII浓缩物，recombinate FVIII浓缩物，mononine FIX浓缩物，fibrogammin P FXIII浓缩物，以及前述物质的组合；并且
所述第三层包含以下的至少一种：纱布，氧化纤维素，胶原，硅酮，角蛋白，明胶，甲壳质，壳聚糖，聚乙烯吡咯烷酮，藻酸盐，交联聚乙烯醇，以及前述物质的组合。
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| KR102494734B1 (ko) * | 2022-02-21 | 2023-02-06 | 대가파우더시스템 주식회사 | 체내 흡수성 하이드로겔 지혈제 |
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| MX2019010663A (es) | 2019-12-02 |
| SG11201908061SA (en) | 2019-09-27 |
| WO2018165275A1 (en) | 2018-09-13 |
| EP3592395A1 (en) | 2020-01-15 |
| BR112019017884A2 (pt) | 2020-05-12 |
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| JP2020509799A (ja) | 2020-04-02 |
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