CN110201216B - 一种用于贯穿伤快速止血材料及其制备方法 - Google Patents

一种用于贯穿伤快速止血材料及其制备方法 Download PDF

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CN110201216B
CN110201216B CN201910669653.1A CN201910669653A CN110201216B CN 110201216 B CN110201216 B CN 110201216B CN 201910669653 A CN201910669653 A CN 201910669653A CN 110201216 B CN110201216 B CN 110201216B
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张蓉
周敏
李国兵
黄景彬
唐勤
赖文静
张倩
刘吴毅
盛芳芳
胡长鹏
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Second Affiliated Hospital Army Medical University
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Abstract

本发明公开了一种用于贯穿伤快速止血材料，为Cur‑CMC/PVA，由姜黄素、羧基壳聚糖和聚乙烯醇反应制成，该止血材料，进一步包含一种或多种药物，所述药物选自缩血管药物、促凝剂、抗生素和镇痛药，该止血材料不但具有高吸血膨胀性、快速止血、镇痛、抗感染等作用，还可通过颜色将本止血材料与组织有效区分，方便后期手术与组织分离。

Description

一种用于贯穿伤快速止血材料及其制备方法
技术领域
本发明属于医用材料领域，具体涉及一种易于手术分离的贯穿伤快速止血材料及其制备方法。
背景技术
战场士兵牺牲的主要原因是贯穿伤及其导致的失血过多。战场贯穿伤多集中在防弹衣等防护设备无法有效防护的四肢、腋窝及臀部等部位。研究表明，伤者在受伤10分钟内获得快速止血抢救是决定其存活的关键因素，因此开发一种可于战场条件下使用的贯穿伤快速止血材料具有重大意义。由于战场环境紧急混乱，军医或卫生兵无法有效顾及到每个伤者并进行紧急救援。现有贯穿伤止血治疗主要采用压迫止血、灼烧止血、油脂和纱布填充止血等方法，其中填充止血法最为常用，然而油脂和纱布本身止血效率低，且战场环境恶劣，纱布不能有效保持无菌状态，致使后续治疗及恢复更加困难。此外，目前市售的止血材料使用后呈现出与伤口附近组织相近的颜色，导致在后期的伤口清理手术过程中，医护人员很难将组织和止血材料分开，从而给后期手术带来不便。因此，研发出新的可达到战场使用条件的止血材料迫在眉睫。
姜黄素(Curcumin,本文简称为“Cur”)是从姜科、天南星科植物根茎中提取的一种多酚，具有抗菌、抗炎、降血脂、抗氧化、抗癌等作用。且姜黄素对还原剂的稳定性较高，着色性强，一经着色便不易褪色。本发明人发现采用姜黄素与羧甲基壳聚糖(本文简称“CMC”)通过化学键连接，得到鲜黄色的姜黄素改性羧甲基壳聚糖(Cur-CMC)，再与聚乙烯醇(PVA)甲醛缩醛化形成交联，交联反应形成泡沫过程中加入一定比例缩血管药物去甲肾上腺素、促凝剂酚磺乙胺、抗生素莫匹罗星(抗革兰阳性菌)和多粘菌素(抗革兰阴性菌)、镇痛药吗啡，制备一种具有高吸血膨胀性的多功能止血材料，该止血材料具有高吸血膨胀性、快速止血、镇痛、抗感染等作用；且材料为鲜黄色，与血液结合凝固后呈现橘色，将止血材料与组织有效区分，具有方便后期手术与组织分离等优点。为此完成本发明。
发明内容
本发明目的在于提供一种易于手术分离的贯穿伤快速止血材料，为Cur-CMC/PVA，主要由姜黄素、羧基壳聚糖和聚乙烯醇反应制成。
上述本发明的贯穿伤快速止血材料，其中间体Cur-CMC的制备的反应路线如下：
Figure BDA0002141251020000021
上述本发明的止血材料，进一步包含一种或多种药物，所述药物选自缩血管药物、促凝剂、抗生素和镇痛药，所述缩血管药物为去甲肾上腺素，所述促凝剂为酚磺乙胺，所述抗生素为莫匹罗星或/和多粘菌素，所述镇痛药为吗啡或芬太尼。
本发明另一目的在于提供了一种制备贯穿伤料快速止血材料的方法，包括以下步骤：
1)羧甲基壳聚糖溶于水/DMSO混合溶剂中，加入二环己基碳二亚胺和二甲氨基吡啶，搅拌1～2h；
2)然后滴加含有姜黄素的DMSO溶液反应，反应结束后，将反应产物在DMSO介质中透析1-2天，再以去离子水为介质透析2～3天，然后冻干得到Cur-CMC；
3)将Cur-CMC溶于醋酸溶液中，配制成质量分数为0.5～0.8wt.％的Cur-CMC溶液，将聚乙烯醇溶于沸水中，配置成质量分数约为0.3～0.6％的聚乙烯醇溶液，将Cur-CMC溶液与聚乙烯醇溶液等体积混合均匀，得Cur-CMC/PVA共混溶液；
4)另取PVA以9～12％的质量分数溶于沸水中，降温，加入适量表面活性剂OP-10和甲醛溶液混合得到PVA溶液，再加入适量的碳酸氢钠溶液，搅拌20～30min，再加入浓盐酸，搅拌至溶液体积发泡，继续搅拌至泡沫稳定，得到发泡液；
5)将步骤4)的发泡液与步骤3)的Cur-CMC/PVA共混溶液混合搅拌均匀，加入碳酸氢钠，其中，碳酸氢钠与Cur-CMC/PVA共混液的质量体积比为1:1～1：3，优选1：2；泡沫体注入模具，50～60℃恒温4～65h，蒸馏水洗至中性，冷冻干燥即得Cur-CMC/PVA止血材料。
上述本发明的方法，步骤2)中，姜黄素与羧甲基壳聚糖的质量比为1：10，步骤3)中，醋酸溶液的浓度为0.25％。步骤4)中所述降温是指降至50℃左右，所述甲醛溶液，其浓度为37％，所述适量碳酸氢钠，其与PVA溶液的质量比为1:5。步骤5)中，碳酸氢钠与Cur-CMC/PVA共混液的质量体积比为1:2。
上述本发明的方法，进一步包括在步骤5)中，在步骤4)的发泡液与步骤3)的Cur-CMC/PVA共混溶液混合后，加入一种或多种药物，所述药物选自缩血管药物、促凝剂、抗生素和镇痛药，混合均匀，即制得含有药物的Cur-CMC/PVA止血材料。
技术效果
本发明的贯穿伤快速止血材料的优点：
1、本发明采用姜黄素与羧甲基壳聚糖通过化学键连接，得到鲜黄色的姜黄素改性羧甲基壳聚糖，再与聚乙烯醇甲醛缩醛化形成交联，交联反应形成泡沫过程中加入缩血管药物去甲肾上腺素、促凝剂酚磺乙胺、抗生素莫匹罗星(抗革兰阳性菌)和多粘菌素(抗革兰阴性菌)、镇痛药吗啡，制备一种具有高吸血膨胀性的多功能止血材料。通过将止血材料填充至贯穿伤口内，材料迅速吸血膨胀，可快速起到压迫止血的效果，同时材料中负载的药物可起到缩血管、促凝、抗感染、镇痛等多种功效，从而达到快速止血的作用。
2、战场贯穿伤快速止血后，常需要手术将止血材料与伤口组织分离开，传统的纱布填充止血后呈红色(暗红色)，与伤口组织颜色相近，手术分离不便。本发明创新性的通过化学反应引入了鲜黄色的姜黄素，其具有稳定性较高，着色性强，同时具有抗菌、抗炎、抗氧化等作用，本发明引入姜黄素后，制备的材料呈鲜黄色，与红色血液凝固后可呈橘黄色，可明显与组织区别，且姜黄素与羧甲基壳聚糖之间通过化学键连接，止血过程中不会发生姜黄素游离，所产生的颜色稳定，便于后期手术与组织分离。
具体实施方式
以下实施例用于进一步帮助理解本发明的精神实质，但不以任何方式限制本发明的范围。
实施例1易于分离贯穿伤快速止血材料(Cur-CMC/PVA)制备
制备工艺如下：
1.制备姜黄素改性羧甲基壳聚糖：称取质量分数为1.0～1.2wt.％的羧甲基壳聚糖(CMC)溶于H2O/DMSO(V/V,1/1)中，加入2.0wt.％的二环己基碳二亚胺(DCC)和1.0wt.％二甲氨基吡啶(DMAP)，搅拌1～2h；缓慢滴加姜黄素的DMSO溶液10ml，CMC与姜黄素的质量比为10：1，在60～65℃下搅拌反应6h；反应完全后，以DMSO为介质透析1-2天，再以去离子水为介质透析3天，样品冻干备用，记为Cur-CMC。
2.制备高吸血膨胀性的多功能止血材料：将Cur-CMC溶于0.25％的醋酸溶液中，配置为质量分数为0.5～0.8wt.％的Cur-CMC溶液；PVA溶于沸水中，配置成质量分数约为0.3～0.6％的聚乙烯醇溶液(PVA溶液)；将以上的Cur-CMC溶液与PVA溶液等体积混合均匀，得Cur-CMC/PVA共混溶液；另取20gPVA溶于沸水中，质量分数为9～12％，降温至50℃左右得到PVA溶液，加入1ml的表面活性剂OP-10、20ml浓度为37％的甲醛溶液，另加入4g碳酸氢钠，搅拌20～30min，再加入20ml浓盐酸，继续高速搅拌至溶液最大发泡体积，并持续搅拌30min使泡沫稳定；向稳定泡沫中加入8mlCur-CMC/PVA共混液、缩血管药物去甲肾上腺素、促凝剂酚磺乙胺搅拌均匀，碳酸氢钠与Cur-CMC/PVA共混液的质量体积比为1:2；泡沫体注入模具，50～60℃恒温5h，蒸馏水洗至中性冷冻干燥即得黄色的Cur-CMC/PVA止血材料；紫外灭菌30min，常温保存。
实施例2 Cur-CMC/PVA-Drug多功能止血材料的制备
其它反应条件和工艺步骤都与实施例1相同，只需在Cur-CMC/PVA材料制备过程中，即在向PVA溶液中加入Cur-CMC/PVA共混液时加入缩血管药物去甲肾上腺素、促凝剂酚磺乙胺、抗生素莫匹罗星、多粘菌素和镇痛药吗啡即可。
前期试验将Cur-CMC/PVA切成一定体积的长方体，在不锈钢磨具中压成薄片状，将薄片放入水中使其充分吸水，测定材料的吸水膨胀率，结果显示，Cur-CMC/PVA吸水后，膨胀率可达10倍左右。
前期于平原猪后肢肌肉丰满处构建贯穿伤模型，自由出血5s后，将本发明的止血材料按压填充至贯穿伤口内，材料吸血后快速膨胀，压迫出血点，其材料中的药物快速释放，达到止血的目的。此外，止血材料吸血凝固后，材料的颜色由原来的鲜黄色，变成橘黄色，使其易于与受伤邻近组织颜色明显区分开，为后期手术的顺利实施提供了方便，提高了手术效率，同时耶达到消炎、止痛的效果。

Claims (9)

1.一种用于贯穿伤快速止血材料，为Cur-CMC/PVA，由姜黄素、羧基壳聚糖和聚乙烯醇反应制成, 其制备方法包括以下步骤：
1）羧甲基壳聚糖溶于水/DMSO混合溶剂中，加入二环己基碳二亚胺和二甲氨基吡啶，搅拌1～2 h；
2）滴加含姜黄素的DMSO溶液继续反应，反应结束后，将反应产物在DMSO介质中透析1-2天，再以去离子水为介质透析2～3天，冻干得到Cur-CMC；
3）将Cur-CMC溶于醋酸溶液中，配制质量分数为0.5～0.8 wt.%的Cur-CMC溶液，将聚乙烯醇溶于沸水中，配置成质量分数为0.3～0.6 %的聚乙烯醇溶液，将Cur-CMC溶液与聚乙烯醇溶液等体积混合均匀，得Cur-CMC/PVA共混溶液；
4） 另取PVA以9～12%的质量分数溶于沸水中，降温，加入适量表面活性剂OP-10和甲醛溶液混合得到PVA溶液，另加入适量碳酸氢钠溶液，搅拌20～30 min，再加入浓盐酸，搅拌至溶液体积发泡，继续搅拌至泡沫稳定，得到发泡液；
5）将步骤4）的发泡液与步骤3）的Cur-CMC/PVA共混溶液混合搅拌均匀，加入碳酸氢钠，其中，碳酸氢钠与Cur-CMC/PVA共混液的质量体积比为1:1～1：3，2；泡沫体注入模具，50～60 ℃恒温加热4～65 h，蒸馏水洗至中性，冷冻干燥即得Cur-CMC/PVA止血材料。
2.如权利要求1所述的止血材料，进一步包含一种或多种药物，所述药物选自缩血管药物、促凝剂、抗生素和镇痛药。
3.如权利要求2所述的止血材料，所述缩血管药物为去甲肾上腺素，所述促凝剂为酚磺乙胺。
4.如权利要求2所述的止血材料，所述抗生素为莫匹罗星或多粘菌素。
5.如权利要求2所述的止血材料，所述镇痛药为吗啡或芬太尼。
6.如权利要求1所述的止血材料，所述制备方法的步骤2）中，姜黄素与羧甲基壳聚糖的质量比为1：10，步骤3）中，醋酸溶液的浓度为0.25 %。
7.如权利要求1所述的止血材料，所述制备方法的步骤4）中所述降温是指降至50℃，所述甲醛溶液，浓度为37 %，所述适量碳酸氢钠，其与PVA的质量比为1:5。
8.如权利要求1所述止血材料，所述制备方法的步骤5）中，碳酸氢钠与Cur-CMC/PVA共混液的质量体积比为1:2。
9.如权利要求1所述止血材料，所述制备方法，进一步包括在步骤5）中，在步骤4）的发泡液与步骤3）的Cur-CMC/PVA共混溶液混合时，加入一种或多种药物，所述药物选自缩血管药物、促凝剂、抗生素和镇痛药，混合均匀，可制得含有药物的 Cur-CMC/PVA止血材料。
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