CN114159336A - 可快速溶解的生物修复冻干敷料及其制备方法 - Google Patents
可快速溶解的生物修复冻干敷料及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种可快速溶解的生物修复冻干敷料及其制备方法。所述的生物冻干敷料通过将由普鲁兰多糖0.5%~3%、海藻酸钠0.1%~1%、甘露糖醇0.5%~12%、海藻糖0.01%~10%、重组人源胶原蛋白0.001%~2%、氨基酸复合液5%~30%、余量为水组成的敷料原液冷冻干燥后制得。本发明采用合适的骨架剂比例使冻干敷料有快速溶解的特性,利用重组人源胶原蛋白与氨基酸复合液的协同增效以及对冻干工艺的控制,提高细胞增殖活性。本发明的冻干敷料经人体测试表明具有促进屏障修复和缩短修复时间的功效。
Description
技术领域
本发明属于医用敷料技术领域,涉及一种可快速溶解的生物修复冻干敷料及其制备方法。
背景技术
医疗美容在注射类、激光类、射频类、超声波类均快速发展。激光类产品如光子嫩肤、皮秒、点阵激光,可应用于嫩肤、去红血丝、祛斑、祛疤等。基本原理是采用对人体有益、透过能力较强、人体组织吸收率较高的光波波段,利用激光对生物组织的刺激作用,改善皮肤。术后护理是长期工作,影响后期修复效果和副作用的出现。
术后护理一般建议:(1)立即使用冰袋冷敷,遵循冰敷5分钟后休息1分钟原则,以冷源去除后患者不痛或无灼烧感为宜,一般30分钟左右;(2)激光后遵医嘱使用抗炎或者创面修复敷料,以加快愈合时间,提高愈合质量为宗旨,防止感染,引发激发瘢痕;(3)做好物理防晒和使用防晒霜(SPF30)产品,避免色素沉着。
术后激光穿透,会造成皮肤屏障损伤,部分激光类还有创面损伤。因此使用的敷料需要具有减少创面修复时间、防止感染、修复皮肤经皮水分流失屏障(TEWL)功能。另外还要求不添加防腐剂或者成分温和。
发明内容
本发明的目的在于提供一种可快速溶解的生物修复冻干敷料及其制备方法。该生物修复冻干敷料不含防腐剂,能够有效促进表皮重建、减少创面修复时间,修复皮肤TEWL值。
实现本发明目的的技术方案如下:
可快速溶解的生物冻干敷料原液,按质量分数计,由以下成分组成:普鲁兰多糖0.5%~3%,海藻酸钠0.1%~1%,甘露糖醇0.5%~12%,海藻糖0.01%~10%,重组人源胶原蛋白0.001%~2%,氨基酸复合液5%~30%,余量为水;所述的氨基酸复合液按质量分数计,由以下成分组成:氯化钠0.5%~0.7%,葡萄糖0.05%~0.15%,甘氨酸0.08%~0.2%,脱氧核糖核酸0.08%~0.2%,精氨酸0.02%~0.04%,亮氨酸0.02%~0.04%,异亮氨酸0.02%~0.04%,丙氨酸0.01%~0.02%,谷氨酸0.01%~0.02%,丝氨酸0.01%~0.02%,余量为水。
优选地,所述的生物修复冻干敷料原液中,普鲁兰多糖0.5%~1%,海藻酸钠0.1%~0.2%,甘露糖醇1%~5%,海藻糖0.5%~5%。
在本发明具体实施方式中,采用的可快速溶解的生物冻干敷料原液,按质量分数计,由以下成分组成:普鲁兰多糖0.5%,海藻酸钠0.1%,甘露糖醇5%,海藻糖1%,重组人源胶原蛋白0.01%,氨基酸复合液30%,余量为水。
优选地,重组人源胶原蛋白由保藏编号为CGMCC No.5021的巴斯德毕赤酵母Pichia pastoris发酵产生。
本发明的生物修复冻干敷料原液中,普鲁兰多糖、海藻酸钠、甘露糖醇和海藻糖作为骨架剂,重组人源胶原蛋白和氨基酸复合液作为活性物。
可快速溶解的生物修复冻干敷料的制备方法,包括如下步骤:
步骤1:按敷料原液的比例,将普鲁兰多糖、海藻酸钠、甘露糖醇、海藻糖加入水中,加热至60℃±5℃均质至完全溶解,降温至40℃以下,加入重组人源胶原蛋白和氨基酸复合液,得到敷料原液;
步骤2:将敷料原液进行除菌过滤后,注入成型模具或包材中,进行冷冻干燥,先在-40℃~-25℃下冻结成型,再将冻结产品带着模具或者脱离模具后,在-35℃~-10℃一次干燥,最后在30℃以下二次干燥,灭菌,得到生物修复冻干敷料。
本发明的生物修复冻干敷料的溶解速度与海藻糖、普鲁兰多糖和海藻酸钠含量相关,当三者含量不在上述数值范围内时,溶解速度变慢,溶解时间达到3分钟以上,不利于后续应用。本发明通过调控三者的比例,在获得较快的溶解速度时,还获得具有合适的机械性能的冻干敷料,便于包装和取用,否则有的冻干敷料机械性能不好,运输后无完整外形,成为散粉,如图3所示。
优选地,步骤2中,成型模具的形状为饼状、球状、膜状、条状或者含基布的面膜状。
优选地,步骤2中,冻结温度为-45℃~-40℃。
优选地,步骤2中,冻结维持时间为2~5h。
优选地,步骤2中,一次干燥的升温时间为10±1h,升温至一次干燥温度后的保持时间为10±1h。
优选地,步骤2中,二次干燥温度为20℃~30℃,更优选为20℃~25℃。
优选地,步骤2中,二次干燥时间为16±1h。
优选地,步骤2中,灭菌方法为电子束辐照或者γ射线辐照灭菌。
与现有技术相比,本发明具有以下优点:
本发明的生物修复冻干敷料的溶解速度快,使用方便。将重组人源胶原蛋白复配氨基酸复合液,通过二者的协同作用,表现出更高的表皮重建修复力。体外实验表明本发明的生物修复冻干敷料具有较强的表皮细胞修复力。人体实验表明本发明的生物修复冻干敷料对皮肤水分流失的修复力有显著效果,利于术后屏障修复和损伤修复。
附图说明
图1为实施例1中各样品的细胞增殖试验结果图。
图2为对比例1和实施例1~2样品的细胞增殖试验结果图。
图3为海藻糖、普鲁兰多糖和海藻酸钠不在本发明数值范围内制得的冻干敷料经运输后的实物图。
具体实施方式
下面结合实施例和附图对本发明作进一步详述。
本发明中的原料和试剂如无特殊说明,均可通过市场购买获得。氨基酸复合液购自代理商江苏聚源生物技术有限公司;动物脐带提取物购自江苏物恒生物科技有限公司;MetaTrix APL 3购自NORTUER(INCI名为野草莓果提取物、野大豆籽提取物、苹果果实细胞培养物提取物);羊胎素购自大连爱尚妮生物工程有限公司;nanoMSColigopeptiedes购自RESPERA。PhytoCellTec Alp Rose购自mebellebiochemistry。各原料的浓度的设置结合原料推荐的起效量和等价水平设计。表皮细胞生长因子(EGF)和角质细胞生长因子(KGF)为本实验室冷冻样品(购自福建龙生生物),该原料已被化妆品行业禁止添加。间充质细胞培养液(MSC溶液)购自园中北科的研发样品。重组人源胶原蛋白小分子肽购自江苏聚源生物技术有限公司。
测试例1
复配溶液的细胞相容性实验:
1.样品:
1号:30%动物脐带提取物;
2号:30%动物脐带提取物+0.01%重组人源胶原蛋白
3号:nanoMSColigopeptiedes
4号:30%氨基酸复合液
5号:5%MetaTrix APL 3
6号:4%PhytoCellTec Alp Rose
7号:0.01%重组人源胶原蛋白+30%氨基酸复合液
8号:MSC溶液
9号:30%羊胎素
10号:10%羊胎素
11号:0.01%重组人源胶原蛋白+10%羊胎素;
12号:EGF 625IU+KGF 625IU;
13号:重组人源胶原蛋白0.01%;
14号:重组人源胶原蛋白小分子肽0.01%。
以分别添加1~14号样品的培养基作为培养液,在96孔平底板内分别接种Hacat细胞(人角质形成细胞),每个样品设置5个平行孔,2D培养48小时,采用MTT检测细胞活性,结果如图1所示。从图1可以看出,其中9号样品浑浊,废弃。结果显示12号阳性对照组细胞活力121%,13号重组人源胶原蛋白细胞活力109%,7号重组人源胶原蛋白0.01%+氨基酸复合液30%细胞活力最高,达到137%,高于4号30%氨基酸复合液的细胞活力113%。由此可见,重组源胶原蛋白与氨基酸复合液的细胞相容性最好,可用于进一步应用。
对比例1
(1)敷料原液,按重量百分比计,由以下成分组成:普鲁兰多糖0.5%,海藻酸钠0.1%,甘露糖醇5%,海藻糖1%,重组人源胶原蛋白0.01%,氨基酸复合液30%,余量为水。
(2)面膜式液体敷料原液:在敷料原液的基础上再加入抑菌剂对羟基苯乙酮和1,2-己二醇,具体为:普鲁兰多糖0.5%,海藻酸钠0.1%,甘露糖醇5%,海藻糖1%,重组人源胶原蛋白0.01%,氨基酸复合液30%,对羟基苯乙酮0.5%,1,2-己二醇0.5%,余量为水。
(3)面膜式液体敷料的制备:按比例,将水、普鲁兰多糖、海藻酸钠、对羟基苯乙酮加热至60±5℃,搅拌至透明均匀,然后降温至40℃,加入海藻糖、甘露糖醇、重组人源胶原蛋白、氨基酸复合液、1,2-己二醇,搅拌至澄清透明。测试其pH=7.32,过滤,采用经辐照灭菌后、含面膜布的铝塑袋中包装,得到面膜式液体敷料。
实施例1
(1)敷料原液,按重量百分比计,由以下成分组成:普鲁兰多糖0.5%,海藻酸钠0.1%,甘露糖醇5%,海藻糖1%,重组人源胶原蛋白0.01%,氨基酸复合液30%,余量为水。
(2)生物修复冻干敷料的制备:将水、普鲁兰多糖、海藻酸钠加热至60±5℃,搅拌至透明均匀,然后降温至40℃,加入海藻糖、甘露糖醇、重组人源胶原蛋白、氨基酸复合液,搅拌至澄清透明。测试其pH=7.18,过滤,灌装到西林瓶中,进行冷冻干燥,冷冻干燥的具体条件为:冷冻温度为-38℃,冻结时间为2h;一次干燥条件为:设定温度:-10℃,设定时间:600min,维持时间600min,真空值-0.3mbar;二次干燥条件为:温度30℃,16h,冻干完成。
实施例2
与实施例1大致相同,唯一不同的是二次干燥温度为25℃,7h。
测试例1
细胞增殖活性测试
将实施例1~2和对比例1制备的敷料进行细胞增殖活性测试,其中实施例1~2制得的冻干敷料水溶后加入培养基中,对比例1制得的液体敷料直接加入培养基中,在96孔平底板内分别接种Hacat细胞(人角质形成细胞),每个样品设置5个平行孔,2D培养48小时,采用MTT检测细胞活性,结果如图2所示。
从图2可以看出,对比例1的面膜式液体敷料放置48h后,细胞增殖活力已经接近0,实施例1的冻干敷料不含防腐剂,细胞增殖活力相较于对比例1提高18.31%.实施例2细胞增殖活力相较于对比例1提高19.38%,说明冻干过程中二次干燥温度≤25℃时,冻干敷料的细胞活性更好。
测试例2
皮肤水分流失测试
征集20名志愿者,平均年龄55±5岁,在其手臂前臂外侧皮肤上反复涂抹月桂基磺酸钠(SLS),反复刺激构建皮肤屏障损伤模型。然后将志愿者平均分为2组,分别涂抹对比例1的液体敷料和实施例2的冻干敷料同比例水溶后的溶液,每天使用2次产品,连续14天,利用皮肤水分流失测试仪VapoMeter在前臂接触后读取TEWL值,结果如表1所示。与对比例1相比,实施例2使皮肤TEWL值减少了30%(P<0.05)。表明实施例2的冻干敷料更适用于术后表皮重建的修复,利于皮肤屏障的修复。
表1实施例2和对比例的皮肤水分流失测试
综上所述,本发明一方面通过调控骨架剂中海藻糖、普鲁兰多糖和海藻酸钠三者含量,控制冻干敷料的机械性能和溶解速度,使其满足运输和使用需求;另一方面,通过对活性成分进行优化,以重组人源胶原蛋白与氨基酸复合液复配作为活性成分,提高冻干敷料的细胞增殖活性,作为冻干敷料使用时可有效减少皮肤水分流失,更适用于术后表皮重建的修复,利于皮肤屏障的修复;再一方面,控制冷冻干燥过程中的二次干燥温度在30℃以下甚至25℃以下,进一步提高冻干敷料的细胞增殖活性。
Claims (10)
1.可快速溶解的生物冻干敷料原液,其特征在于,按质量分数计,由以下成分组成:普鲁兰多糖0.5%~3%,海藻酸钠0.1%~1%,甘露糖醇0.5%~12%,海藻糖0.01%~10%,重组人源胶原蛋白0.001%~2%,氨基酸复合液5%~30%,余量为水;所述的氨基酸复合液按质量分数计,由以下成分组成:氯化钠0.5%~0.7%,葡萄糖0.05%~0.15%,甘氨酸0.08%~0.2%,脱氧核糖核酸0.08%~0.2%,精氨酸0.02%~0.04%,亮氨酸0.02%~0.04%,异亮氨酸0.02%~0.04%,丙氨酸0.01%~0.02%,谷氨酸0.01%~0.02%,丝氨酸0.01%~0.02%,余量为水。
2.根据权利要求1所述的生物冻干敷料原液,其特征在于,普鲁兰多糖0.5%~1%,海藻酸钠0.1%~0.2%,甘露糖醇1%~5%,海藻糖0.5%~5%。
3.根据权利要求1所述的生物冻干敷料原液,其特征在于,按质量分数计,由以下成分组成:普鲁兰多糖0.5%,海藻酸钠0.1%,甘露糖醇5%,海藻糖1%,重组人源胶原蛋白0.01%,氨基酸复合液30%,余量为水。
4.根据权利要求1所述的生物冻干敷料原液,其特征在于,重组人源胶原蛋白由保藏编号为CGMCC No.5021的巴斯德毕赤酵母Pichia pastoris发酵产生。
5.可快速溶解的生物修复冻干敷料,其特征在于,通过以下步骤制得:
步骤1:按权利要求1~4任一所述的敷料原液的比例,将普鲁兰多糖、海藻酸钠、甘露糖醇、海藻糖加入水中,加热至60℃±5℃均质至完全溶解,降温至40℃以下,加入重组人源胶原蛋白和氨基酸复合液,得到敷料原液;
步骤2:将敷料原液进行除菌过滤后,注入成型模具或包材中,进行冷冻干燥,先在-40℃~-25℃下冻结成型,再将冻结产品带着模具或者脱离模具后,在-35℃~-10℃一次干燥,最后在30℃以下二次干燥,灭菌,得到生物修复冻干敷料。
6.根据权利要求5所述的生物修复冻干敷料,其特征在于,步骤2中,成型模具的形状为饼状、球状、膜状、条状或者含基布的面膜状;冻结温度为-45℃~-40℃,冻结维持时间为2~5h。
7.根据权利要求5所述的生物修复冻干敷料,其特征在于,步骤2中,一次干燥的升温时间为10±1h,升温至一次干燥温度后的保持时间为10±1h。
8.根据权利要求5所述的生物修复冻干敷料,其特征在于,步骤2中,二次干燥温度为20℃~30℃。
9.根据权利要求5所述的生物修复冻干敷料,其特征在于,步骤2中,二次干燥温度为20℃~25℃,二次干燥时间为16±1h。
10.根据权利要求5所述的生物修复冻干敷料,其特征在于,步骤2中,灭菌方法为电子束辐照或者γ射线辐照灭菌。
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