CN106540310B - 一种可吸收性快速止血材料及其制备方法 - Google Patents
一种可吸收性快速止血材料及其制备方法 Download PDFInfo
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- CN106540310B CN106540310B CN201611160512.XA CN201611160512A CN106540310B CN 106540310 B CN106540310 B CN 106540310B CN 201611160512 A CN201611160512 A CN 201611160512A CN 106540310 B CN106540310 B CN 106540310B
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Abstract
本发明公开一种可吸收性快速止血材料及其制备方法。该材料包括载药海藻酸钙多孔微球、牡蛎壳粉和羧甲基纤维素钠。将载药海藻酸钙多孔微球和牡蛎壳粉一是作为类分子筛，在与血液接触时能够快速吸收血液中的水分，从而能快速浓缩血液中的有形成分，二是载药海藻酸钙多孔微球和牡蛎壳粉可释放大量的钙离子作用于浓缩在材料表面的凝血因子，加速凝血，缩短止血时间，减少出血量。所用的材料均为天然的高分子多糖和无机盐材料，具有良好的生物相容性、可生物降解、安全无毒性、可吸收性和止血性等特性。本发明的制备工艺简单，而且药物能够在一定的时间内持续稳定的释放，将对医疗领域和社会带来极大的效益。
Description
技术领域
本发明属于生物医用材料领域，具体涉及到一种可吸收性快速止血材料及其制备方法。
背景技术
目前临床上使用的局部止血材料主要有止血纱布、止血纤维、止血绷带等。由于这些材料都不具有被组织吸收，止血时间较长，止血效果较差。与伤口易发生粘连，伤口容易感染等，因不能及时止血、伤口感染而丧生的案例屡见不鲜。快速而有效的止血不仅能减轻伤者的痛苦，甚至关键的时刻能挽救一个人的生命。国内一些新的止血产品如壳聚糖止血贴、明胶海绵、胶原蛋白海绵止血贴等，这些产品还是存在对创伤的粘附性较差、有些适用范围较窄、吸收速率慢、止血时间较长等缺陷。因此，开发出一种具有抗菌功能性和快速止血效果的可吸收性止血材料是十分必要的。
海藻酸作为天然的海洋高分子多糖，主要是从褐藻中提取出线性多糖，不仅具有良好的生物相容性、可降解性，同时还有很好的止血、抗菌性，海藻酸钙在止血过程中钙离子与血液中的钠离子进行离子交换，钙离子进入到血液中发挥其促凝作用，而海藻酸钙变成了吸水性很强的海藻酸钠，吸水后变成凝胶覆盖在伤口表面而提供一个湿润的环境，有利于伤口的愈合。
羧甲基纤维素主要是由纤维素葡萄糖单元中的-OH上的H被羧甲基钠取代所得，是一种水溶性的聚阴离子离子化合物。羧甲基纤维素钠具有生物相容性、可生物降解性、安全无毒、强吸湿性、保水性等特性，羧甲基纤维素钠作为伤口敷料应用时能够将细菌固定在凝胶膜内部，可以更好的保护伤口，促进伤口的愈合。在医疗愈创中具有很好的效果。由羧甲基纤维素钠和海藻酸盐所制备止血材料不仅止血效果突出、避免在换药物时造成二次伤害，可以克服传统止血材料存在的缺陷。
牡蛎壳粉由海洋中牡蛎的外壳制备，牡蛎壳中含有90％以上的碳酸钙，是良好的钙源。我们都知道钙在内源性凝血过程中可以促进凝血因子的生成，加速凝血。另外，牡蛎壳粉本身结构就是多微孔结构，这大大的增加了颗粒的比表面积，牡蛎壳粉的这种结构无形中增加了与纤维蛋白的结合位点，从而使蛋白吸附能力提高，有效加速纤维蛋白聚集在伤口处加速血液凝结，而达到快速止血的目的。所以牡蛎壳粉和海藻酸钙多孔微球一方面增大了与血液接触的比表面积，另一方面可以起到分子筛的作用，快速吸收血液中的水分浓缩凝血因子和血细胞，而其主要成分中的钙离子可以影响凝血因子加速止血。
发明内容
为了克服现有技术中止血材料的功能单一、止血效果不理想的缺点与不足，本发明的首要目的在于提供一种可吸收性快速止血材料。
本发明的另一目的在于提供上述可吸收性快速止血材料的制备方法。
本发明将羧甲基纤维素钠、载药海藻酸钙多孔微球、牡蛎壳粉混合在一起制备的复合止血材料，优点有四：第一，所有的材料均具有良好的生物相容性、可吸收性等特性；第二，海藻酸钙多孔微球和牡蛎壳粉的多孔结构能够快速吸收血液中的水分，快速浓缩血液中的有形成分与创口处；第三，羧甲基纤维素钠中混合了海藻酸钙多孔微球和牡蛎壳粉，不仅克服了单一羧甲基纤维素钠成膜后易碎的缺陷，同时也避免了海藻酸钙多孔微球和牡蛎壳粉随血液进入血管造成血栓的风险，也能够防止被血液冲散影响止血效果；第四，将具有抗菌性的药物季鏻盐加入其中对药物起到缓释的作用，从而降低了药物的毒性。这些物质的有机结合使得材料的止血效果更佳。
本发明的目的通过下述技术方案实现：
一种可吸收性快速止血材料，以羧甲基纤维素钠为微球载体，以海藻酸钙多孔微球为药物载体。
所述的可吸收性快速止血材料，包括载药海藻酸钙多孔微球、牡蛎壳粉和羧甲基纤维素钠；所述的载药海藻酸钙多孔微球包括海藻酸钠、致孔剂和抗菌剂。
所述的载药海藻酸钙多孔微球中抗菌剂的质量分数为10％～50％，优选为20％～30％；
所述的海藻酸钠与致孔剂的重量比为(1.5～2.5)：(0.25～1)；优选为2：(0.25～1)。
所述的致孔剂为NaCl或蔗糖，优选过200目筛。
所述的载药海藻酸钙多孔微球与羧甲基纤维素钠的重量比为(1～2)：3。
所述的牡蛎壳粉与羧甲基纤维素钠的重量比为(0.25～1)：3；优选为(0.5～1)：3；
所述的抗菌剂优选为烯丙基三苯基溴化鏻，其结构式如式1所示：
所述的载药海藻酸钙多孔微球的制备方法，包括如下步骤：
1)将海藻酸钠粉末溶于去离子水配成海藻酸钠溶液，加入抗菌剂，再加入致孔剂；搅拌均匀后静置脱泡，作为A液；
2)在油相中加入Span80和Tween80两种乳化剂混合均匀，作为B液；
3)配制3～5％的氯化钙溶液作为载药海藻酸钙多孔微球的交联剂，作为C液；
4)按照水油比1:5～1:10的比例将A液加入到B液中，恒温搅拌，形成混合D液；
5)将C液滴加到D液中，控制滴速0.1～0.5d/s，滴毕后继续反应，之后加入0.5～1倍油相体积的异丙醇固化；然后离心、洗涤、干燥，获得载药海藻酸钙多孔载药微球。
步骤1)中所述的海藻酸钠溶液的质量分数为1.5～2.5wt％；优选为2wt％。
步骤2)中所述的油相为液体石蜡或异辛烷。
步骤2)中所述的Span80和Tween80在B液中的体积百分比分别为2～4％和0.5～1.5％；优选为为3％和1％。
步骤3)中所述的氯化钙溶液优选为5％的氯化钙溶液；
步骤4)中所述的恒温搅拌的条件为在40～50℃的恒温水浴、450～500rpm的转速下搅拌15～20min；优选为在50℃的恒温水浴、500rpm的转速下搅拌15min。
步骤5)中所述的C液的体积是A液的1/2。
步骤5)中所述的滴速优选为0.5d/s。
步骤5)中所述的继续反应的时间为30min～60min，优选为45min。
步骤5)中所述的固化的时间为10～30min，优选为15min。
步骤5)中所述的洗涤用的洗涤液为石油醚或乙醚，及异丙醇或无水乙醇。
所述的牡蛎壳粉是过200目筛的牡蛎壳粉。
所述的牡蛎壳粉是将牡蛎壳用5％氢氧化钠浸泡48h，超声去除表面角质层和棱柱层后干燥，然后行星球磨24h，得到粗制粉，然后用蒸馏水按照0.5Kg/L的比例配成浆液后高速乳化剪切机(转速2500rpm)研磨8h，最后浆液过滤，烘干，再次用行星球磨12h后过200目筛，即得牡蛎壳粉。
所述的牡蛎壳来自湛江牡蛎。
所述的可吸收性快速止血材料的制备方法，包括如下步骤：
羧甲基纤维素钠溶于去离子水制成羧甲基纤维素钠溶液，加入载药海藻酸钙多孔微球，再加入牡蛎壳粉，然后加入塑化剂，混合均匀，在冰点以下预冻，然后经真空冷冻干燥后，用紫外灯辐射灭菌，最后获得可吸收快速止血材料。
所述的羧甲基纤维素钠溶液的质量分数为2％～3％，优选为3％。
所述的塑化剂是丙三醇。
所述的塑化剂的加入量为羧甲基纤维素钠质量的20％。
所述的冰点以下预冻的条件是温度为-80～-20℃，冷冻时间6～8h，优选是温度为-20℃，冷冻时间8h。
所述的真空冷冻干燥的时间为24h～48h，优选为48h。
所述的紫外灯辐射灭菌的时间为5～8h，优选为5～6h。
本发明相对于现有技术，具有如下的优点及效果：
(1)本发明所采用的材料均为天然的高分子多糖和无机盐材料，具有良好的生物相容性、可生物降解、安全无毒性、可吸收性等特性。
(2)本发明将载药海藻酸钙多孔微球和牡蛎壳粉一方面作为类分子筛，在与血液接触时能够快速吸收血液中的水分，从而能快速浓缩血液中的有形成分，另一方面载药海藻酸钙多孔微球和牡蛎壳粉可以释放大量的钙离子作用于浓缩在材料表面的凝血因子，加速凝血，缩短止血时间，减少出血量。
(3)本发明将抗菌剂烯丙基三苯基溴化鏻包埋在海藻酸钙多孔微球中，这样微球对药物可以起到缓释作用，从而降低药物的毒性，针对创口长久持续的给药直至伤口愈合。
(4)本发明将羧甲基纤维素钠制备成海绵是因为海绵的多孔性能吸收大量的血液中的水，另外，海绵的多孔结构能够为血液中的有形成分提供足够的空间，而聚集在材料上。
(5)本发明的可吸收性快速止血材料的制备工艺简单，使用的可降解的天然物质对环境无污染，无毒副作用，而且药物能够在一定的时间内持续稳定的释放，将对医疗领域和社会带来极大的效益。
附图说明
图1是实施例1得到的载药海藻酸钙多孔微球的SEM图。
图2是实施例1得到的载药海藻酸钙多孔微球表面的局部放大的SEM图。
图3是实施例1制得的可吸收性快速止血材料的SEM图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1
在100mL去离子水中加入0.25g的NaCl和0.4g的抗菌剂待完全溶解后，再加入2g海藻酸钠搅拌均匀得到混合溶液A，将溶液A按照水油比1:5加入到含有3％span80和1％Tween80的液体石蜡溶液B中，50℃恒温水浴，500rpm转速下搅拌15min，得到混合溶液D，然后按照1/2(Ca2+/海藻酸钠)的体积比滴加5％CaCl2溶液C，控制滴速1d/2s，待滴毕继续反应45min，然后加入0.5倍(液体石蜡)体积的异丙醇固化15min，离心、洗涤、干燥，即得载药海藻酸钙多孔微球。
将3g羧甲基纤维素钠、1g载药海藻酸钙多孔微球和0.5g牡蛎壳粉溶于100mL去离子水中，再加入20％(相对羧甲基纤维素钠的质量)丙三醇，调成糊状溶液，搅拌均匀后，注模，压膜，-20℃预冻8h，然后-70℃冷冻干燥48h，得到复合海绵，复合止血海绵经过紫外灯辐照5h，即为可吸收性快速止血材料。
对本实施例得到的载药海藻酸钙多孔微球进行微观结构的观察，结果如图1和图2所示，本发明所制得的微球具有良好的球形结构和分散性(图1)，由于致孔剂的作用在微球表面的局部放大图(图2)中可以清晰的看到有较多的孔洞分布。图3为本实施例制得的可吸收性快速止血材料的SEM图，从图中可以看到微球和牡蛎壳粉很好的分散在止血材料中。
实施例2
在100mL去离子水中加入1g的蔗糖和0.6g的抗菌剂待完全溶解后加入2g海藻酸钠搅拌均匀得到混合溶液A，将溶液A按照水油比1:10加入到含有3％Span80和1％Tween80的异辛烷溶液中，50℃恒温水浴，500rpm转速下搅拌15min，得到混合溶液D，然后按照按照1/2(Ca2+/海藻酸钠)的体积比滴加5％CaCl2溶液C，控制滴速1d/2s，待滴毕继续反应45min，然后加入1倍(异辛烷)体积的异丙醇固化15min，离心、洗涤、干燥，即得载药海藻酸钙多孔微球。
将3g羧甲基纤维素钠、2g载药海藻酸钙多孔微球和1g牡蛎壳粉加入100mL去离子水中，再加入20％(相对羧甲基纤维素钠的质量)丙三醇调成糊状，搅拌均匀，注模，压膜，在-20℃预冻8h，然后-70℃冷冻干燥48h，得到复合海绵，复合止血海绵经过紫外灯辐照6h，即为可吸收性快速止血材料。
由实施例1、2制得的可吸收性快速止血材料针对SD鼠的股动脉和新西兰兔耳动脉部位出血模型的止血效果，经过多次的实验，结果表明，本材料在这两个实验中均可在1～3min中内完成止血，且出血量少。另外，抗菌剂药物缓释结果表明，药物可以在4天内持续有效的释放，且最大累积释放率可达78.4％。本发明所述的可吸收性快速止血材料的制备方法简单易行。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (7)
1.一种可吸收性止血材料，其特征在于它以羧甲基纤维素钠为微球载体，以海藻酸钙多孔微球为药物载体；
包括载药海藻酸钙多孔微球、牡蛎壳粉和羧甲基纤维素钠；其中，所述的载药海藻酸钙多孔微球是由海藻酸钠、致孔剂和抗菌剂主要原料制备得到；
所述的载药海藻酸钙多孔微球中抗菌剂的质量分数为10％～50％；所述的抗菌剂为烯丙基三苯基溴化鏻；
所述的海藻酸钠与致孔剂的重量比为(1.5～2.5)：(0.25～1)；
所述的致孔剂为NaCl或蔗糖；
所述的载药海藻酸钙多孔微球与羧甲基纤维素钠的重量比为(1～2)：3；
所述的牡蛎壳粉与羧甲基纤维素钠的重量比为(0.25～1)：3。
2.根据权利要求1所述的可吸收性止血材料，其特征在于：
所述的载药海藻酸钙多孔微球是由下述步骤制备得到的：
1)将海藻酸钠粉末溶于去离子水中配制成海藻酸钠溶液，加入抗菌剂，再加入致孔剂；搅拌均匀后静置脱泡，得到的溶液作为A液；
2)往油相中加入Span80和Tween80两种乳化剂，混合均匀，得到的溶液作为B液；
3)配制3～5％的氯化钙溶液，作为C液，它作为载药海藻酸钙多孔微球的交联剂；
4)按照水油比1:5～1:10将A液加入到B液中，恒温搅拌，得到的混合溶液为D液；
5)在滴速0.1～0.5d/s下，将C液滴加到D液中，滴毕后继续反应，之后加入0.5～1倍油相体积的异丙醇进行固化；然后离心、洗涤、干燥，获得所述的载药海藻酸钙多孔微球。
3.根据权利要求2所述的可吸收性止血材料，其特征在于：
步骤1)中所述的海藻酸钠溶液的质量分数为1.5～2.5wt％；
步骤2)中所述的油相为液体石蜡或异辛烷；
步骤2)中所述的Span80和Tween80在B液中的体积百分比分别为2～4％和0.5～1.5％。
4.根据权利要求2所述的可吸收性止血材料，其特征在于：
步骤4)中所述的恒温搅拌的条件为在恒温水浴中在温度40～50℃、转速450～500rpm的条件下搅拌15～20min；
步骤5)中所述的C液的体积是A液的1/2；
步骤5)中所述的继续反应的时间为30min～60min；
步骤5)中所述的固化的时间为10～30min。
5.权利要求1～4任一项所述的可吸收性止血材料的制备方法，其特征在于包括如下步骤：
羧甲基纤维素钠溶于去离子水制成羧甲基纤维素钠溶液，加入载药海藻酸钙多孔微球，再加入牡蛎壳粉，然后加入塑化剂，混合均匀，在冰点以下预冻，然后经真空冷冻干燥后，用紫外灯辐射灭菌，最后获得可吸收止血材料。
6.根据权利要求5所述的可吸收性止血材料的制备方法，其特征在于：
所述的羧甲基纤维素钠溶液的质量分数为2％～3％；
所述的塑化剂是丙三醇。
7.根据权利要求5所述的可吸收性止血材料的制备方法，其特征在于：
所述的冰点以下预冻的条件是温度为-80～-20℃，冷冻时间6～8h；
所述的真空冷冻干燥的时间为24h～48h；
所述的紫外灯辐射灭菌的时间为5～8h。
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