CN108815564A - 一种淀粉基止血粉及其制备方法 - Google Patents
一种淀粉基止血粉及其制备方法 Download PDFInfo
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- CN108815564A CN108815564A CN201810822800.XA CN201810822800A CN108815564A CN 108815564 A CN108815564 A CN 108815564A CN 201810822800 A CN201810822800 A CN 201810822800A CN 108815564 A CN108815564 A CN 108815564A
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- starch
- preparation
- styptic powder
- powder
- emulsification
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Classifications
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Abstract
本发明公开了一种淀粉基止血粉的制备方法,该方法包括以下步骤:(1)淀粉改性;(2)乳化交联;(3)分离提纯,干燥灭菌。本发明提供了一种淀粉止血粉,制备过程简单、成本可控,以医用级马铃薯淀粉为原料,经过改性处理,乳化交联度高,成球型良好均匀,且具有多孔结构;同时该产品的生物相容性好,生物细胞毒性小,抗菌效果明显;吸液倍数高,且吸液后迅速形成凝胶覆盖与创伤表面,止血效果好,是一种优良的生物医用产品;可用于临床伤口处理,手术防止器官粘连,以及各种创伤出血。
Description
技术领域
本发明属于医疗用品领域,具体涉及一种以改性马铃薯淀粉为原料的医用止血粉及其制备方法。
背景技术
在创伤损伤或外科手术中,快速有效地止血对挽救生命具有重要的意义。目前,可吸收止血材料,特别是近年研发的新型体内可吸收止血材料,不仅能在极短的时间内使血液凝固而达到快速止血的目的,而且可以在短时间内被人体所吸收。常见的可吸收止血材料有胶原和微纤维胶原、医用止血明胶、氧化纤维素和氧化再生纤维素、氰基丙烯酸类组织胶以及纤维蛋白类止血材料等。这些材料在动物实验及临床应用中都取得了不错的效果,但也都存在一些不足:胶原、明胶类其原料来源于动物组织,是异种蛋白,容易出现排异性,具有潜在的致敏性,吸收速度缓慢会增加伤口的感染风险;纤维素类,人体缺乏使其降解的酶,降解时间长,可能会给病人带来感染等副作用。
淀粉作为一种植物多聚糖,来源广泛,价格低廉,具有很好的生物相容性和降解性,近年来,以淀粉为原料,开发新产品或新应用途径,已成为研究的热门课题。但是,目前淀粉止血材料功能单一,不具备抗菌效果。并且止血机理单一,导致止血效果不如壳聚糖等止血材料。
在现有技术中,已经公开了多种多聚糖止血粉的制备方法,包括集中特定的变性淀粉,如阳离子淀粉、表氯醇交联淀粉、羧甲基淀粉、羟乙基淀粉、预糊化的变性淀粉、预糊化的羟丙基二淀粉磷酸酯、丙烯酸-羧甲基淀粉接枝共聚物等。阳离子淀粉作为止血材料,由于其表面带有的正电荷,用来吸引带负电的红细胞,与其相互作用,从而加速了凝血的过程;另一方面,带正电的变性淀粉与血液接触后能紧紧地贴服于组织,封闭伤口,从而快速止血。
杜宝堂等将马铃薯生淀粉进行糊化、酶解、乳化交联等处理,制得MMPH多孔微球,该工艺较为复杂,且制备出的淀粉微球吸水速率较慢,粘附性较差,对于大面积渗血止血效果不佳(《医疗卫生装备》,2014,35(3):23-25)。
中国专利CN201510171482.1公开植物原淀粉和醚化淀粉,经射线辐照处理后,得到反应活性较好的两种淀粉,混合后进行乳化交联反应,抽提洗涤制得淀粉止血粉。γ射线辐照对淀粉改性过程具有复杂性,通过控制不同的辐照剂量,可以生产具有不同接枝活性和不同聚合分子量的变性淀粉。纯淀粉经60Coγ射线辐照,会发生降解,且伴随着氧化、水解等过程。辐照技术存在明显局限性,需要专门设备来提供辐射源,需要提供安全防护措施,导致生产成本大幅提高;并且由于高辐射剂量下的感官性状变化,需要控制好合适的辐照剂量;并且由于各国的历史、生活习惯及法规差异,目前世界各国允许辐照的医疗用品种类差别较大。
中国专利CN201710072673.1和CN201610865770.1分别公开一种复合淀粉止血粉和一种复合微孔交联淀粉止血粉,其中以海藻酸钠、羧甲基纤维素钠和马铃薯淀粉复配为原料,海藻酸钠和羧甲基纤维素钠能够形成二聚体并同其他链形成汇合点,最终形成凝胶网络,使得马铃薯淀粉形成微孔的结构,增强整个淀粉止血剂的吸水性,以改善使用单一马铃薯淀粉的止血效果。但是由于没有进行离子交联的海藻酸钠形成的凝胶在溶液中可逆,借助乳化剂而形成的止血颗粒球形完整性差,分散不均匀,颗粒之间可能会发生粘连影响颗粒的形成。
鉴于如上原因,有必要克服现有技术的上述问题,提供一种止血效果优良,生物相容性好,具有抗菌效果的止血粉。
发明内容
针对现有技术中存在的问题,本发明的目的是提供一种淀粉基止血粉及其制备方法,其制备的止血粉止血效果好,生物相容性好,且无抗原性等反应,适用于渗血、动静脉出血及手术难以达到部位出血的止血。
为了实现上述目的,本发明采用如下技术方案:
一种淀粉基止血粉的制备方法,包括如下步骤:
(1)马铃薯淀粉原料进行糊化、改性后制得变性淀粉;
(2)将步骤(1)所得变性淀粉在乳化剂中乳化、交联后,制得交联淀粉;
(3)将步骤(2)所得交联淀粉进行分离提纯,干燥灭菌,得到所述淀粉基止血粉。
上述步骤(1)中的淀粉质量浓度在1%到20%之间,糊化温度在40℃~80℃,糊化时间在20min~120min;糊化处理后调节pH至8~12。
上述步骤(1)中淀粉改性剂为2-氯乙基二乙胺,其质量浓度为1%~10%,反应时间为5~24h。
上述步骤(2)中乳化剂为吐温60、吐温80、司盘60、司盘80中的一种或多种。
上述步骤(2)中乳化剂首先溶于油相,加热搅拌均匀10~50min,再向溶液中滴加步骤(1)所得变性淀粉。
上述油相为液体石蜡、航空煤油、植物油中的一种;上述乳化剂占油相质量比的0.1%~10%,上述油相与淀粉水溶液的体积比在3~6:1。
上述步骤(2)中交联剂为环氧氯丙烷,上述交联剂占油相质量比的0.2%~10%。
上述步骤(2)中变性淀粉的乳化时间为0.5~12h,乳化温度为35℃~80℃,乳化交联过程搅拌速度为100rpm/min~1000rpm/min,交联时间为1~72h。
本发明公开了一种上述方法制备得到的淀粉基止血粉。
本发明还提供了上述淀粉基止血粉的用途,用于有血创面以提供止血作用、防粘连作用、抑菌作用以及封闭伤口作用中的一种或其组合;所述有血创面为哺乳动物、鸟类、爬行动物组织的体表、体内组织器官或体腔内组织或体腔内器官。
由于上述技术方案的运用,本发明设计了一种淀粉基止血粉具有以下优点:
本发明通过对天然淀粉进行改性,使其模拟微孔多聚糖止血机理,对淀粉进行改性,在淀粉分子链上引入特定基团,使之具有优于于普通微孔多聚糖的止血、抗菌功效。
本发明提供的淀粉止血粉,制备过程简单、成本可控,以医用级马铃薯淀粉为原料,经过改性处理,乳化交联度高,成球型良好均匀,该淀粉止血粉微球的粒径为20~180μm,其中粒径在50~150μm的微球占总微球颗粒量不低于70%;且具有多孔结构。同时本发明公开的止血粉生物相容性好,吸液倍数高,吸水速度快,且吸液后迅速形成凝胶覆盖与创伤表面,止血效果好,具有优异的抗菌性,是一种优良的生物医用产品。
本发明提供的止血粉对生物细胞毒性小,抗菌效果明显,可用于临床伤口处理,手术防止器官粘连,以及各种创伤出血。
附图说明
图1为实施例2中制备的淀粉基止血粉的扫描电镜图谱;
图2为实施例2中制备的淀粉基止血粉的体外止血试验;
图3为实施例3中制备的淀粉基止血粉的皮肤刺激试验。
具体实施方式
通过以下实施例提供的具体实施方案,对本发明的上述内容进行进一步详细说明,对于本研究领域的技术人员而言,不应将此理解为本发明上述主题的范围仅限于以下实例;凡基于本发明上述内容所实现的技术均属于本发明的范围。
下面实施例中所使用的实验方法如无特殊说明,均为常规方法;下述实施例中所用的试剂、材料、仪器等,如无特殊说明,均可从商业途径得到。
实施例1
(1)淀粉的糊化:称取10g马铃薯淀粉溶于600mL纯化水中,75℃加热搅拌糊化30min,搅拌均匀后用氢氧化钠溶液调节pH至8~12,得糊化后的淀粉溶液;
(2)淀粉的改性:称取1g的2-氯乙基二乙胺溶于10mL水中,加入到上述糊化后的淀粉溶液中,70℃继续反应5小时,得改性后的淀粉溶液;
(3)油相的制备:称取液体石蜡500mL,加入2g吐温-80,50℃下搅拌10min,待用。
(4)乳化交联:将改性后的淀粉滴加到油相中,在70℃下搅拌反应40min,然后加入10mL环氧氯丙烷进行交联反应2h,反应结束后静置。
(5)分离沉淀:静置后倒掉上层流动液体,对下层乳白液进行离心再分离。
(6)提纯干燥:离心后的乳白体用无水乙醇进行清洗,清洗后抽滤,然后40℃真空干燥。干燥后的粉末进行过筛网处理,得包装前产品。
(7)包装灭菌:上述过筛后的产品经聚乙烯瓶包装后塑封,然后灭菌。
实施例2
(1)淀粉的糊化:称取10g马铃薯淀粉溶于800mL纯化水中,50℃加热搅拌糊化60min,搅拌均匀后用氢氧化钠溶液调节pH至8~12,得糊化后的淀粉溶液;
(2)淀粉的改性:称取3g 2-氯乙基二乙胺溶于50mL水中,加入到上述糊化后的淀粉溶液中,70℃继续反应10小时,得改性后的淀粉溶液;
(3)油相的制备:称取航空煤油1200mL,加入10g吐温-80,10g司盘-80在60℃下搅拌30min,待用。
(4)乳化交联:将改性后的淀粉滴加到上述油相中,在60℃下搅拌反应60min,然后加入50mL环氧氯丙烷进行交联反应5h,反应结束后静置。
(5)分离沉淀:静置后倒掉上层流动液体,对下层乳白液进行离心再分离。
(6)提纯干燥:离心后的乳白体用无水乙醇进行清洗,清洗后抽滤,然后40℃真空干燥。干燥后的粉末进行过筛网处理,得包装前产品。
(7)包装灭菌:上述过筛后的产品经聚乙烯瓶包装后塑封,然后灭菌。
上述所得的淀粉止血粉进行扫描电镜拍摄,见图1。该淀粉止血粉微球的粒径为20~180μm,其中粒径在50~150μm的微球占总微球颗粒量不低于70%。
上述所得的淀粉止血粉进行止血试验,止血效果见图2。
10mL试管中取2mL兔血,加入0.5mg肝素钠,兔血和肝素混合后起到长效抗凝效果,血液流动性好。然后取上述止血粉50mg加入到兔血中,轻轻晃动5~10秒,观察可得,形成大量血块,说明快速激活了凝血机制。进行显微镜观察,如图2左图显微照片可知,显微镜下,正常血液中血红细胞分布均匀,无聚集现象,而加入止血粉后的血液血红细胞聚集明显,局部浓度增高,加速激活凝血过程。
实施例3
(1)淀粉的糊化:称取15g马铃薯淀粉溶于600mL纯化水中,80℃加热搅拌糊化20min,搅拌均匀后用氢氧化钠溶液调节pH至8~12,得糊化后的淀粉溶液;
(2)淀粉的改性:称取4g 2-氯乙基二乙胺溶于50mL水中,加入到上述糊化后的淀粉溶液中,70℃继续反应5小时,得改性后的淀粉溶液;
(3)油相的制备:称取液体石蜡1800mL,加入4g吐温-80,4g司盘-80在60℃下搅拌30min,待用。
(4)乳化交联:将改性后的淀粉滴加到上述油相中,在60℃下搅拌反应60min,然后加入50mL环氧氯丙烷进行交联反应5h,反应结束后静置。
(5)分离沉淀:静置后倒掉上层流动液体,对下层乳白液进行离心再分离。
(6)提纯干燥:离心后的乳白体用无水乙醇进行清洗,清洗后抽滤,然后40℃真空干燥。干燥后的粉末进行过筛网处理,得包装前产品。
(7)包装灭菌:上述过筛后的产品经聚乙烯瓶包装后塑封,然后灭菌。
对比例1
(1)淀粉糊化:称取10g马铃薯淀粉加入500mL纯化水中,搅拌至糊化,再加入5g的羧甲基纤维素钠,并用氢氧化钠溶液来调节pH至11。
(2)油相的制备:将500mL的植物油加入到反应釜中,待升温到70℃,加入10g的司班80和10g吐温80的混合物。
(3)乳化交联:将糊化的淀粉混合入上述油相中,加入20mL的环氧氯丙烷反应24h,取料。
(4)分离沉淀:加入无水乙醇与乙酸乙酯分离物料,倾去上层油相。
(5)提纯干燥:离心后的乳白体用无水乙醇进行清洗,清洗后抽滤,然后40℃真空干燥。干燥后的粉末进行过筛网处理,得包装前产品。
(6)包装灭菌:上述过筛后的产品经聚乙烯瓶包装后塑封,然后灭菌。
对比例2
(1)淀粉的糊化:称取10g马铃薯淀粉溶于800mL纯化水中,50℃加热搅拌糊化60min,搅拌均匀后用氢氧化钠溶液调节pH至8~12,得糊化后的淀粉溶液;
(2)淀粉的改性:称取3g 2-氯乙基二乙胺溶于50mL水中,加入到上述糊化后的淀粉溶液中,70℃继续反应10小时,得改性后的淀粉溶液;
(3)油相的制备:称取航空煤油1200mL,加入10g吐温-80,10g司盘-80在60℃下搅拌30min,待用。
(4)乳化交联:将改性后的淀粉滴加到上述油相中,在60℃下搅拌反应60min,然后加入50mL环氧氯丙烷进行交联反应5h,反应结束后静置。
(5)酯化改性:将交联后的变性淀粉加入三偏磷酸钠溶液5mL,35℃下搅拌反应制得羟丙基二淀粉磷酸酯溶液;
(5)超声处理:再将此羟丙基二淀粉磷酸酯溶液(冰浴)置于超声波细胞粉碎机中,用450w功率作用3min(作用2s间歇2s)。
(6)分离沉淀:静置后倒掉上层流动液体,对下层乳白液进行离心再分离。
(7)提纯干燥:离心后的乳白体用无水乙醇进行清洗,清洗后抽滤,然后40℃真空干燥。干燥后的粉末进行过筛网处理,得包装前产品。
(8)包装灭菌:上述过筛后的产品经聚乙烯瓶包装后塑封,然后灭菌。
对比例3
(1)淀粉的酶解:称取100g马铃薯淀粉和10g淀粉酶溶于250mL磷酸盐缓冲液(pH=5)中,搅拌均匀,在45℃下进行水解反应8h,在4000r/min的转速下离心分离,并真空干燥,得到酶解淀粉。
(2)油相的制备:称取1000mL的植物油,加入10g吐温-80,10g司盘-80在60℃下搅拌30min,待用。
(3)乳化交联:将10g酶解后的淀粉滴加到上述油相中,在60℃下搅拌反应20min,然后加入20mL三偏磷酸钠进行交联反应5h,反应结束后静置。
(4)分离沉淀:静置后倒掉上层流动液体,对下层乳白液进行离心再分离。
(6)提纯干燥:离心后的乳白体用无水乙醇进行清洗,清洗后抽滤,然后40℃真空干燥。干燥后的粉末进行过筛网处理,得包装前产品。
(7)包装灭菌:上述过筛后的产品经聚乙烯瓶包装后塑封,然后灭菌。
对比例4
(1)淀粉的酶解:称取100g马铃薯淀粉和10g淀粉酶溶于250mL磷酸盐缓冲液(pH=5)中,搅拌均匀,在45℃下进行水解反应8h,在4000r/min的转速下离心分离,并真空干燥,得到酶解淀粉。
(2)淀粉的羧甲基化:将8g一氯乙酸溶于乙醇,并用0.3mol/L的氢氧化钠溶液将其调至中性后,混合到80g乙醇溶解的上述制备的微孔淀粉中,充分搅匀后移入恒温槽,在50℃下,以45r/min持续搅拌保温进行反应,4h后反应完成,加入乙酸中和pH至6.5,过滤,用乙醇洗涤3次,干燥24h,制得羧甲基微孔淀粉。
(3)沸腾凝聚:将上述羧甲基淀粉置于沸腾机内在45℃,加入蒸馏水,经过凝聚、制丸,制成变性淀粉材料。颗粒粒径在50-500μm的微球占总微球颗粒量不低于90%。
一、止血粉的吸盐水倍率以及吸水速率的检测:
淀粉吸盐水倍率采用自然过滤法测定,准确称取0.5g上述止血粉,分别放入盛有100mL盐水(0.9%NaCl溶液)中,将离心管封口,在室温下充分溶胀。用不锈钢筛网过滤,至基本无水滴落,测定止血粉质量,吸水率按下式计算:
Q=(m2-m1)/m1,
式中,Q为吸水倍率,g/g;m1为吸水前止血粉的质量,g;m2为吸水后止血粉的质量,g。
淀粉的吸水速率通过坐滴法测定,利用德国Dataphysics公司OCA40Micro视频接触角测量仪。上述各止血粉的吸盐水倍率和吸水速率结果如表1所示。
表1.止血粉的吸盐水倍率和吸水速率性能比较
本发明的方法制备得到的变性淀粉止血粉,其吸盐水倍率和吸水速率均接近于或高于对比例1-4中制备的止血粉,吸水速率快,更有效。
二、止血粉的皮肤刺激试验和致敏试验
上述实施例1-3所得的淀粉止血粉依据GB/T 14233.2-2005、GB/T 16886.10-2005《医疗器械生物学评价第10部分:刺激与迟发型超敏反应试验》进行试验。具体为:除吸收容量外,按照0.2g/mL的比例加入浸提介质(浸提介质:生理盐水和植物油)浸提,在(37±1)℃,(72±2)h制备试验液,取试验液按照GB/T 16886.10-2005中规定的试验方法进行。
将试验样品单次直接接触兔脊柱两侧的皮肤24h,将纱布块同法接触作为对照。与接触后(1±0.1)h、(24±2)h、(48±2)h、和(72±2)h,对接触部位红斑、水肿记分,甲酸原发性刺激指数(PII)。试验结果显示,该止血粉样品家兔原发性刺激指数(PII)为0.0,说明实施例1-3所制备止血粉试验液无皮肤致敏反应。
三、止血粉的细胞毒性试验
将上述实施例1-3所得的淀粉止血粉依据GB/T 16886.5-2016《医疗器械生物学评价第5部分:体外细胞毒性试验》MTT比色法进行。具体为:将制备好的L929成纤维细胞悬浮液接种与培养板中,培养24h后去除上清。阳性对照组加入淀粉止血粉试验液,阴性对照组加入阴性对照试验液,空白对照组加入新鲜的细胞培养液,继续培养72h。通过观察细胞形态,计算细胞相对增值率,结果显示,实施例1-3所制备的止血粉的细胞毒性分级为1级,符合临床使用要求。
四、止血粉的抑菌效果
将上述实施例1-3所制得的淀粉止血粉,进行抗菌试验,利用最小抑菌浓度MIC(mg/L)评价抑菌效果。通过微孔稀释方法,将100μL不同浓度的实施例1-3分别加入到96微孔板中,10μL相同浓度(104CFU/mL)的细菌培养液加入每个微孔中,37℃培养24h后观察,没有可见的细菌生长的微孔中最少的浓度即为最小抑菌浓度(MIC)。
表2.实施例1-3的止血粉溶液的抗菌性能比较
本发明实施例中制备的止血粉的抗菌效果明显,且对人体细胞毒性小。
五、止血粉对动物出血模型的止血效果(兔股动脉损伤模型)
将上述实施例1-3所得的淀粉止血粉,作为试验组。以不使用淀粉止血粉为对照组。
试验用新西兰白化兔两只,用7号针头对股动脉进行穿刺喷血。试验组使用止血粉后以纱布覆盖按压,对照组直接用纱布覆盖按压,三分钟后观察止血效果。
试验组的止血粉遇血后立即吸血,并与血液形成粘性的胶状体有效覆盖伤口,在1分钟内均可有效地控制创面出血,同时,止血粉遇血后与创面组织紧密粘附,促进凝血,并形成对创面出血点破损血管的封闭作用,凝血块与按压手套或纱布敷料不发生粘连,揭开手套或纱布时不会破坏凝血块,造成二次出血。对照组止血失败,三分钟后出血点仍在不停出血。
以上所述,仅是本发明的较佳实施例而已,并非是对本发明作其它形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型,仍属于本发明技术方案的保护范围。
Claims (10)
1.一种淀粉基止血粉的制备方法,其特征在于:包括如下步骤:
(1)马铃薯淀粉原料进行糊化、改性后制得变性淀粉;
(2)将步骤(1)所得变性淀粉在乳化剂中乳化、交联后,制得交联淀粉;
(3)将步骤(2)所得交联淀粉进行分离提纯,干燥灭菌,得到所述淀粉基止血粉。
2.根据权利要求1所述的制备方法,其特征在于:所述步骤(1)中的淀粉质量浓度在1%到20%之间,糊化温度在40℃~80℃,糊化时间在20min~120min;糊化处理后调节pH至8~12。
3.根据权利要求1所述的制备方法,其特征在于:所述步骤(1)中淀粉改性剂为2-氯乙基二乙胺,其质量浓度为1%~10%,反应时间为5~24h。
4.根据权利要求1所述的制备方法,其特征在于:所述步骤(2)中乳化剂为吐温60、吐温80、司盘60、司盘80中的一种或多种。
5.根据权利要求4所述的制备方法,其特征在于:所述步骤(2)中乳化剂首先溶于油相,加热搅拌均匀10~50min,再向溶液中滴加步骤(1)所得变性淀粉。
6.根据权利要求5所述的制备方法,其特征在于:所述油相为液体石蜡、航空煤油、植物油中的一种;所述乳化剂占油相质量比的0.1%~10%,所述油相与淀粉水溶液的体积比在3~6:1。
7.根据权利要求1所述的制备方法,其特征在于:所述步骤(2)中交联剂为环氧氯丙烷,所述交联剂占油相质量比的0.2%~10%。
8.根据权利要求1所述的制备方法,其特征在于:所述步骤(2)中变性淀粉的乳化时间为0.5~12h,乳化温度为35℃~80℃,乳化交联过程搅拌速度为100rpm/min~1000rpm/min,交联时间为1~72h。
9.一种权利要求1-8任一项所述方法制备的淀粉基止血粉。
10.一种权利要求9所述淀粉基止血粉的用途,其特征在于:用于有血创面以提供止血作用、防粘连作用、抑菌作用以及封闭伤口作用中的一种或其组合;所述有血创面为哺乳动物、鸟类、爬行动物组织的体表、体内组织器官或体腔内组织或体腔内器官。
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CN116421771B (zh) * | 2023-04-10 | 2024-05-07 | 东莞博捷生物科技有限公司 | 一种新型多孔淀粉止血粉及其制备方法和应用 |
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