CN113967128B - 一种去除海藻酸盐敷料中热原的方法 - Google Patents
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Abstract
本发明提供了一种去除海藻酸盐敷料中热原的方法,涉及到生物医用材料的技术领域。本发明采用0.1mol/L的氢氧化钠溶液浸泡4h来去除热原(内毒素);然后用无热原水或弱酸水洗去残留的碱液及杂质,实现其除热原的目的。本发明工艺流程及操作简单,便于规模化应用,解决了现有海藻酸盐敷料类产品中热原不合格的问题,进一步保证了产品的安全性。
Description
技术领域
本发明涉及到生物医用材料的技术领域,特别是指一种海藻酸盐敷料除热原的方法和应用。
背景技术
近年来各国老龄化问题日趋严重,糖尿病、肥胖症等发病率持续增长,老年群体多发的褥疮、难愈性溃疡等慢性伤口护理需求日益增加,医用敷料市场需求有较大增长空间。
海藻酸盐医用敷料成份为海藻酸盐,是在海藻中提取的天然多糖碳水化合物,为一种天然纤维素。由藻酸盐组成的藻酸盐敷料,是一款高吸收性能的功能性伤口敷料,该医用敷料接触到伤口渗出液后,能形成柔软的凝胶,为伤口愈合提供理想的湿润环境,促进伤口愈合,缓解伤口疼痛。临床主要适用于中、重度渗出以及有腔隙的伤口,如压疮、褥疮伤口;糖尿病足溃疡伤口、下肢静脉/动脉溃疡伤口;烧伤科烧伤供皮区创面及难愈性烧伤创面。
作为医疗器械产品,最首要的是安全性指标。安全性指标包括多方面,生物相容性是最为直接的证据,但由于生物相容性耗时长,成本高,一般只作为注册和周期性的检验。虽然目前各国对海藻酸盐敷料的准入和法规要求各有差异,但总体指导思想是控制产品风险。随着全球范围对医疗器械质量管理规范要求的不断收严,在医疗器械产品注册方面会提出更加严格的检测内容。
目前涉及到海藻酸盐敷料除热原的文献资料及专利未检索发现,通过前期调研发现现有市场上的海藻酸盐敷料产品,大部分也都存在热原问题,因此现在海藻酸盐敷料迫切需要一种除热原的方法,来保证产品的安全性,满足产品的注册要求及临床应用的需求。本发明提供了一种去除海藻酸盐敷料中热原的方法,该方法工艺流程及操作简单,便于规模化应用,可以解决现有海藻酸盐敷料类产品中热原不合格的问题,进一步保证了产品的安全性。
发明内容
本发明提出了一种去除海藻酸盐敷料中热原的方法,可以解决现有藻酸盐敷料产品的热原不合格问题。为了解决上述技术问题,本发明采用以下技术方案予以实现。
一种去除海藻酸盐敷料中热原的方法,包括如下步骤:
(1)卷材分切:将海藻酸盐敷料卷材分切成所需要的规格尺寸,如10cm×10cm;
(2)碱处理:用20%-30%的酒精溶液配制0.1mol/L的氢氧化钠溶液,将10cm×10cm海藻酸盐敷料放在0.1mol/L的氢氧化钠溶液中,浸泡4h,离心;
(3)洗涤:将步骤(2)离心后的海藻酸盐敷料放在20%-30%的酒精溶液中循环洗涤2h,离心,重复用20%-30%的酒精洗涤至溶液PH在6-7之间。或者第一遍洗涤液加入适量弱酸调至PH在5左右,循环洗涤2h,离心,然后用20%-30%的酒精洗涤至溶液PH为6-7之间。
(4)脱水:将步骤(3)离心后的海藻酸盐敷料依次放在60%、90%的酒精溶液中浸泡脱水2h,离心;
(5)包装、灭菌:离心后的敷料晾干至水分小于25%,符合要求后,包装、打码、灭菌。
在上述方法中所述的海藻酸盐敷料不仅限于纯海藻酸盐敷料,也包括其他改性的不与氢氧化钠发生反应的海藻酸盐敷料,如含活性炭的海藻酸盐敷料等。
在上述方法中所述生产环境为10万级洁净车间,所述的水为无热原纯化水,所述的氢氧化钠、酒精、乳酸等均为药用辅料级。
在上述方法中所述中涉及到与物料溶液接触的容器具、搅拌齿等需要使用前进行除热原操作。
在上述方法中步骤(1)、(3)所述不限于10cm×10cm的海藻酸盐敷料,10cm×10cm的海藻酸盐敷料按照每升溶液投入5-15片的比例处理。
在上述方法中步骤(1)所述用20%-30%的酒精溶液配置0.1M的氢氧化钠是防止海藻酸盐敷料在碱液中发生溶胀。
在上述方法中步骤(1)所述离心时,海藻酸盐敷料要平铺在离心机侧壁上,尽量避免敷料出现褶皱等情况。
在上述方法中步骤(2)所述,洗涤时用水或第一遍加弱酸洗涤中和敷料表面的残留的氢氧化钠和其他水溶性杂质。
在上述方法中步骤(2)所述10cm×10cm的海藻酸盐敷料按照每升溶液投入5-10片的比例处理。
本发明提供了一种去除海藻酸盐敷料中热原的处理方法,鉴于海藻酸盐敷料的特殊性质,一般高温、吸附、氧化剂、酸处理等都不适用,本方法采用0.1M的氢氧化钠浸泡4h来去除热原(内毒素);然后用无热原水或弱酸水洗去残留的碱液及杂质,实现其除热原的目的。
具体实施方式
以下结合实施例对本发明作进一步详细描述:
实施例1一种去除海藻酸盐敷料中热原的方法
(1)将理化合格的海藻酸盐敷料卷材分切成10cm×10cm的片材;
(2)用30%的酒精溶液,配制2L 0.1mol/L的氢氧化钠溶液;
(3)将30片10cm×10cm藻酸盐敷料投入到2L氢氧化钠溶液中,浸泡4h,4h后,将藻酸盐敷料取出,平铺在离心机侧壁上5000r/min进行离心2min;
(4)将步骤(3)离心的藻酸盐敷料投入到3L 30%的酒精溶液中,同时开启搅拌1500r/min使溶液循环,浸泡洗涤2h后,取出敷料平铺在离心机侧壁上5000r/min进行离心2min;
(5)重复步骤(4)进行洗涤4遍,检测最后一遍洗涤溶液PH为6.53;
(6)将步骤(5)离心后的敷料投入到2L 60%的酒精溶液中,浸泡脱水2h后,取出敷料平铺在离心机侧壁上5000r/min进行离心2min;
(7)将步骤(6)离心后的敷料投入到2L 90%的酒精溶液中,浸泡脱水2h后,取出敷料平铺在离心机侧壁上5000r/min进行离心2min;
(8)将步骤(7)离心后的敷料晾干2天,水分检测为19%,合格后包装、打码、灭菌、检测热原。
实施例2一种去除海藻酸盐敷料中热原的方法
(1)将理化合格的海藻酸盐敷料卷材分切成10cm×10cm的片材;
(2)用30%的酒精溶液配制0.1mol/L的氢氧化钠溶液25L;
(3)将250片分切好的10cm×10cm的敷料,放入步骤(1)配好的氢氧化钠溶液中,浸泡4h,4h后取出离心2min;
(4)将步骤(2)离心后的敷料放入50L的30%酒精溶液中,开启搅拌使溶液循环,洗涤2h后,离心,重复洗涤4遍,检测最后一遍洗涤液PH为6.41;
(5)将步骤(3)洗涤离心后的敷料依次放入25L的60%、90%的酒精溶液中脱水2h,离心;
(6)将步骤(4)离心后的敷料晾干2天至水分18%,合格后,包装、打码、灭菌、检测热原。
实施例3一种去除海藻酸盐敷料中热原的方法
(1)将理化合格的海藻酸盐敷料卷材分切成10cm×10cm的片材;
(2)用30%的酒精溶液,配制2L的0.1mol/L的氢氧化钠溶液;
(3)按照每升溶液投入15片的10cm×10cm的藻酸盐敷料比例,将30片10cm×10cm藻酸盐敷料投入到2L氢氧化钠溶液中,浸泡4h;4h后,将藻酸盐敷料取出,离心机内5000r/min进行离心2min;
(4)配制3L 30%的酒精溶液,加入乳酸调节后其溶液PH在5.4,将步骤(3)离心后敷料放入到配好的溶液中,同时开启搅拌1500r/min使溶液循环,浸泡洗涤2h后,取出敷料,离心机内5000r/min进行离心2min;
(5)将步骤(4)离心后的藻酸盐敷料投入到3L 30%的酒精溶液中,同时开启搅拌1500r/min使溶液循环,浸泡洗涤2h后,取出敷料,离心机内5000r/min进行离心2min;在重复步骤(5)洗涤三遍,检测洗涤液PH为6.12;
(6)将步骤(5)离心后的敷料投入到2L 60%的酒精溶液中,浸泡脱水2h后,取出敷料,离心机内5000r/min进行离心2min;
(7)将步骤(6)离心后的敷料投入到2L 90%的酒精溶液中,浸泡脱水2h后,取出敷料,离心机内5000r/min进行离心2min;
(8)将步骤(7)离心的敷料晾干2天至水分为20%,合格后,包装、打码、灭菌、检测热原。
实施例4未额外除热原的海藻酸盐敷料生产方法
(1)卷材分切:将海藻酸盐敷料卷材分切成所需要的规格尺寸,如10cm×10cm;
(2)将步骤(1)分切的10cm×10cm敷料包装、打码、灭菌、检测热原。
实施例5热原检测方法
根据《中国药典》2015年版第四部热原检查技术要求进行检测。
(1)样品制备:按0.1g样品:1ml浸提介质的比例,浸提介质为0.9%氯化钠注射液,37℃,72h制备试验液,临用前用0.22μm的一次性无菌针头式滤器过滤后,用于耳缘静脉注射给药。全过程在无菌环境的超净工作台中进行。与样品接触的试验用器皿为无菌、无热原。
(2)实验兔子准备:每批次准备新西兰兔3只雄兔,动物适应环境1周以上,在此期间内,体重不减轻,精神、食欲、排泄等无异常现象。试验前7日内预测体温,进行挑选。挑选试验的条件与检查供试品时相同,仅不注射药液,每隔30分钟测量体温1次,共测8次,8次体温均在38.0-39.6℃的范围内,且最高与最低体温相差不超过0.4℃的家兔,方可供热原检测用。
(3)实验方法:试验前测定两次体温,相隔30分钟。两次体温之差不得超过0.2℃,以此两次体温的平均值作为该兔的正常体温。当日使用的兔子,正常体温应在38.0~39.6℃的范围内,且同组各兔间正常体温之差不得超过1℃。测定其正常体温后15分钟以内,自耳静脉缓缓注入10ml/kg体重并温热至约38度的样品浸提液,然后每隔30分钟按前法测量其体温1次,共测6次,以6次体温中最高的一次减去正常体温,即为该兔体温的升高温度。
(4)试验观察及结果判断:在初试的3只家兔中,体温升高均低于0.6℃,并且3只家兔体温升高总和低于1.3℃,判定样品的热原检查符合规定。
在初试的3只家兔中,体温升高0.6℃或高于0.6℃的家兔超过1只;或3只家兔的体温升高总和超过1.3℃,均判定样品的热原检查不符合规定。当家兔升温为负值时,均以0℃计。
表一 实施例1-4热原检测结果
以上实施例仅用以说明本发明的技术方案,而非对其进行限制;尽管参照前述实施例对本发明进行了详细的说明,对于本领域的普通技术人员来说,依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或替换,并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。
Claims (5)
1.一种去除海藻酸盐敷料中热原的方法,其特征在于,包括如下步骤:
1)卷材分切:将海藻酸盐敷料卷材分切成所需要的规格尺寸,其中包括纯海藻酸盐敷料以及其他改性的不与氢氧化钠发生反应的海藻酸盐敷料;
2)碱处理:用低浓度酒精溶液配制氢氧化钠溶液,将步骤1)分切的海藻酸盐敷料按一定比例放在配好的氢氧化钠溶液中,浸泡时间4-5小时,离心2-3min;低浓度酒精为20%-30%的酒精溶液,氢氧化钠浓度为0.1mol/L;
3)洗涤:将步骤2)离心后的海藻酸盐敷料按一定比例放在低浓度酒精溶液中多次循环洗涤至溶液pH在6-7之间;或在第一遍洗涤液加入适量弱酸调至洗涤液偏酸性,循环洗涤2-3h,离心2-3min,然后用低浓度酒精洗涤至溶液pH为6-7之间;所述低浓度酒精为20%-30%的酒精溶液,弱酸为乳酸或柠檬酸,偏酸性为pH在5.5±0.1;
4)脱水:将步骤3)离心后的海藻酸盐敷料分别在60%、90%的酒精溶液中浸泡脱水2-3h,离心2-3h;
5)包装、灭菌:步骤4)离心后的敷料晾干至水分小于25%后,包装、打码、灭菌;
其中涉及到与物料溶液接触的容器具、搅拌齿需要使用前进行除热原。
2.根据权利要求1所述的去除海藻酸盐敷料中热原的方法,其特征在于,生产环境为10万级洁净车间,水为无热原纯化水,所述的氢氧化钠以及酒精均为药用辅料级。
3.根据权利要求1所述的去除海藻酸盐敷料中热原的方法,其特征在于,所述海藻酸盐敷料尺寸为10cm×10cm,10cm×10cm的海藻酸盐敷料每升溶液投入5-15片。
4.根据权利要求1所述的去除海藻酸盐敷料中热原的方法,其特征在于,海藻酸盐敷料每升溶液投入5-10片。
5.根据权利要求1所述的去除海藻酸盐敷料中热原的方法,其特征在于,步骤2)、步骤3)或步骤4)中,离心时,海藻酸盐敷料要平铺在离心机侧壁上。
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