CN114773626A - 一种美容整形用面部填充水凝胶的制备方法 - Google Patents
一种美容整形用面部填充水凝胶的制备方法 Download PDFInfo
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Abstract
本发明提供了一种美容整形用面部填充水凝胶的制备方法,包括如下步骤:S1、制备改性生物活性玻璃微球;S2、利用所述改性生物活性玻璃微球制备细菌纤维素涂层生物活性玻璃微球粗品;S3、将所述细菌纤维素涂层生物活性玻璃微球粗品进行灭菌后,得到细菌纤维素涂层生物活性玻璃微球;S4、利用所述细菌纤维素涂层生物活性玻璃微球制备出面部填充水凝胶预罐装体;S5、将所述面部填充水凝胶预罐装体进行负压脱气,再加压罐装于注射器中,灭菌,得到所述美容整形用面部填充水凝胶。本发明提供的技术方案的技术效果之一,改性生物活性玻璃微球可以刺激胶原蛋白再生,从而延缓面部衰老。
Description
技术领域
本发明属于医疗美容整形技术领域,具体地说,涉及一种可注射的含细菌纤维素涂层生物活性玻璃微球美容整形用面部填充水凝胶及其制备方法。
背景技术
随着年龄的增长,人体皮肤组织中胶原蛋白的流失速度远高于生成速度,导致胶原蛋白逐渐流失;此外,体内超氧化物歧化酶的合成能力也在逐渐退化,导致氧自由基过量,使皮肤会变得松弛、产生皱纹,尤其是面部轮廓性衰老会日渐加重,包括肉眼可见的皮肤皱纹、深鼻唇沟、皱眉纹、颈部皱纹、口围皱纹、鼻梁塌陷等。此外,一些机械伤害也会导致鼻骨塌陷,烧烫伤会给面部留下疤痕,给人们的日常生活带来不便。另外,部分人群因为先天的鼻梁塌陷、唇腭裂等问题,导致内心自卑,无法正常生活。而且随着生活水平的提高及美容整形技术的发展,美容整形已经逐渐为人们所接受和信任。这些都促进着美容整形技术及材料的发展,特别是注射型美容整形技术及材料,因为注射型美容整形技术容是非手术整形美容,见效快,且使用的材料具有良好的生物相容性。其中透明质酸类产品以其良好的生物相容性、注射后副作用很少和较为持久的塑形效果被整形美容机构广泛使用。
目前使用最广泛的注射型美容整形产品为透明质酸类,但透明质酸类产品有以下缺陷,1、成本较高,一针的花费数千元至上万元。2、维持时间短,在体内6个月左右就基本上完成降解吸收,消费者需要重新进行注射,增加了消费者的负担和痛苦。3、仅对面部起到填充、组织增容的功效,不能促进自身胶原蛋白的合成,无法清除面部皮下组织的氧自由基。4、未考虑注射产品在皮肤注射点出血的情况,特别是对于血友病使用者,因产品本身无止血功能,若出现出血问题,严重会危及生命。5、透明质酸中的交联剂会导致炎症、皮肤过敏等现象。
而作为透明质酸类产品的升级版,童颜针和少女针受到了不少爱美群体的青睐,其维持时间在1-2年,相较于透明质酸,有了较大的提升,但童颜针和少女针的价格也是透明质酸的4-10倍,增加了消费者的经济负担。另外,童颜针的成分之一为聚乳酸,在组织中降解产生小分子乳酸,最后降解生成二氧化碳及酸性物质;而少女针的成分之一为聚己内酯,先降解为小分子己内酯,最后降解为二氧化碳和水;人体组织中的吞噬细胞和巨细胞会吞噬小分子乳酸和己内酯,从而引发炎症。
在公开的中国专利文献中可见诸与注射型美容整形用面部填充相关的技术信息,如CN 113230452A推荐有“一种面部填充剂及其配制方法”,为了克服透明质酸降解快的问题,加入了羟基磷灰石等成分来延长透明质酸的的作用,但生产时间需要5天,工艺较为复杂,且使用的交联剂残留会有引发炎症、过敏等不良反应。又如CN 108744054A一种注射型美容整形用面部填充剂组合物凝胶及其制备方法,与CN 113230452A一样,使用羟基磷灰石来延长透明质酸的的作用,制备工艺简单适合放大生产,且没有使用交联剂,避免了交联剂带来的风险,但相比于交联透明质酸,其降解速度更快,注射部位仅剩羟基磷灰石会带来颗粒感,引发使用者不适,且未从刺激组织自身产生胶原蛋白延缓衰老去设计产品。又如CN113694252A一种软组织充填剂的聚己内酯微球及其制备方法,工艺中使用了丙酮、二氯甲烷等有毒试剂,且微球工艺使用了油相,不适合放大生产。
目前,已公开的注射型美容整形用面部填充相关的技术信息均围绕延长透明质酸类产品、聚乳酸为代表的童颜针、聚己内酯为代表的少女针及羟基磷灰石为代表的微瓷晶,这类产品降解快,注射效果维持时间短;使用化学交联剂,有毒性。
发明内容
为了解决上述问题,本发明的任务在于提供一种可注射的含细菌纤维素涂层生物活性玻璃微球美容整形用面部填充水凝胶及其制备方法,该方法能满足工业化放大生产要求并且由该方法制备的含细菌纤维素涂层生物活性玻璃微球美容整形用面部填充水凝胶具有良好的组织填充及抗衰老效果并且使用方便。
一种美容整形用面部填充水凝胶的制备方法,其包括如下步骤:
S1、制备改性生物活性玻璃微球;
S2、利用所述改性生物活性玻璃微球、纳米级透明质酸钠、葡萄糖、蛋白胨、酵母抽提物、苹果酸、六偏磷酸钠、氯化镁、麦汁和去离子水配制成培养基,将木醋杆菌接入所述培养基中,并控制木醋杆菌与培养基的比重,在28~32℃下培养1~3天后,取出改性生物活性玻璃微球清洗,然后在碱液中浸泡,浸泡结束后再次清洗,直至改性生物活性玻璃微球的pH值为6~8,鼓风干燥后,得到细菌纤维素涂层生物活性玻璃微球粗品;
S3、将所述细菌纤维素涂层生物活性玻璃微球粗品分散于2~10%w/w的聚乙二醇水溶液中6~24h,干燥后,进行灭菌,得到细菌纤维素涂层生物活性玻璃微球;
S4、将纳米级羧甲基纤维素钠溶于含0.9%w/w氯化钠的注射用水中,加入ε-聚赖氨酸,混匀后,加入所述细菌纤维素涂层生物活性玻璃微球,使ε-聚赖氨酸与细菌纤维素涂层生物活性玻璃微球中的纳米透明质酸钠交联,自组装,得到面部填充水凝胶预罐装体;
将所述面部填充水凝胶预罐装体进行负压脱气,再加压罐装于注射器中,灭菌,得到所述美容整形用面部填充水凝胶。
作为优选方案,所述改性生物活性玻璃微球的制备方法为:
将改性纳米生物活性玻璃分散于含有0.2~5%w/w增溶剂的去离子水中,分散均匀后,进行喷雾干燥,得到微球粗品1;
将所述微球粗品1按照煅烧曲线进行高温煅烧,得到微球粗品2;
将所述微球粗品2过筛,收集粒径20~50μm的微球,即所述改性生物活性玻璃微球。
作为优选方案,所述改性纳米生物活性玻璃的制备方法为:
称取x1份正硅酸四乙酯溶于去离子水中,调节pH值2-3,搅拌至溶液澄清透明,得到第一溶液;
称取x2份硼酸三正丁酯,溶于第一溶液,搅拌至溶液澄清透明,得到第二溶液;
向第二溶液加入氨水,搅拌30-120min,得到第三溶液;
向第三溶液加入x3份入磷酸三乙酯,搅拌30-90min,得到第四溶液;
向第四溶液加入x4份四水合硝酸钙,搅拌30-90min,得到第五溶液;
将第五溶液转移至反应釜中,在140-220℃条件下反应12-24h,得到第六溶液;
将第六溶液进行过滤,去离子水清洗,如此反复3次后,进行冷冻干燥,得到改性纳米生物活性玻璃。
作为优选方案,x1:x2:x3:x4=(40~50):(10~20):(4~8):(30~40),且x1+x2+x3+x4=100。
作为优选方案,所述喷雾干燥的操作中,控制进口温度为250-300℃,出口温度为100-150℃,进料速度为20-50mL/min,进气风量为500-1000L/h,喷嘴直径为0.8-1.2mm;所述增溶剂为非离子型增溶剂;所述煅烧曲线为:从室温以2℃/min的升温速率升温至300℃,并在300℃保持60min,再以3℃/min的升温速率升温至600℃,并在600℃保持120min。
作为优选方案,所述纳米级透明质酸钠的制备方法为:将透明质酸钠溶于去离子水中,搅拌均匀,在200~300MPa的压力下进行均质,将均质后的溶液进行在不超过10Pa的真空度、-50℃的温度下冷冻干燥,得到纳米级透明质酸钠。
作为优选方案,所述改性生物活性玻璃微球、纳米级透明质酸钠、葡萄糖、蛋白胨、酵母抽提物、苹果酸、六偏磷酸钠、氯化镁和麦汁的质量比为:(50~200):(1~10):(10~50):(5~10):(0.5~5):(0.2~4):(0.5~5):(0.2~2):(10~20);所述木醋杆菌与所述培养基的比重是将体积重量比控制为(200-1000)μL∶1000g;步骤S3中所述的灭菌的条件为:采用湿热灭菌柜,在温度为121℃下灭菌20-60min。
作为优选方案,所述纳米级羧甲基纤维素钠的制备方法为:将羧甲基纤维素钠溶于去离子水中,搅拌均匀,在300~400MPa的压力下进行均质,将均质后的溶液进行在不超过10Pa的真空度、-50℃的温度下冷冻干燥,得到纳米级羧甲基纤维素钠。
作为优选方案,所述ε-聚赖氨酸与纳米级透明质酸钠的质量比为1:1。
作为优选方案,所述聚乙二醇选自聚乙二醇200、聚乙二醇400、聚乙二醇600中的一种。
本发明制备的可注射的含细菌纤维素涂层生物活性玻璃微球美容整形用面部填充水凝胶的作用机制如图1所示:羧甲基纤维素钠水凝胶填充到皮下组织,会瞬时填充组织,消除皱纹及沟壑;改性生物活性玻璃微球会刺激胶原蛋白再生,能长效保持面部除皱效果;改性生物活性玻璃微球会改变组织微环境,使pH保持弱碱性,从而抑制微生物,预防注射部位感染;细菌纤维素涂层延缓了改性生物活性玻璃的降解速率。
本发明提供的技术方案的技术效果之一,改性生物活性玻璃微球可以刺激胶原蛋白再生,从而延缓面部衰老;之二,改性生物活性玻璃微球含有氧化硼,可以调节组织碱性微环境,协同ε-聚赖氨酸起到抑菌效果;之三,水凝胶中的纳米级羧甲基纤维素钠,可以浓缩凝血因子,促进渗血部位快速止血;之四,羧甲基纤维素钠凝胶可以固定改性生物活性玻璃微球,防止微球在注射后出现位移;之五,细菌纤维素涂层延缓了改性生物活性玻璃的降解速率,大于24个月;之六,一种可注射的含细菌纤维素涂层生物活性玻璃微球美容整形用面部填充水凝胶的生产工艺更简单,能满足工业化放大生产要求。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述,本发明的其它特征、目的和优点将会变得更明显:
图1为本发明得到的面部填充水凝胶在美容整形时的作用机制图;
图2为本发明方法实施例1制备的改性纳米生物活性玻璃扫描电镜图片;
图3为本发明方法实施例1制备的改性生物活性玻璃扫描电镜图片,(B1)为过筛前电镜图,(B2)为过筛后电镜图。
图4为本发明中制备面部填充水凝胶的对成纤维细胞增殖图;
图5为本发明中改良培养基制备细菌纤维素膜数码照片;
图6为本发明中制备的面部填充水凝胶微球中硅离子缓释图。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明,但不以任何形式限制本发明。应当指出的是,对本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进。这些都属于本发明的保护范围。
实施例1
A)制备改性纳米生物活性玻璃,包括以下步骤:
(A-1)称取50份正硅酸四乙酯溶于去离子水中,加入硝酸,调节pH值2-3,搅拌至溶液澄清透明,得到第一溶液;
(A-2)称取10份硼酸三正丁酯,溶于第一溶液,搅拌至溶液澄清透明,得到第二溶液;
(A-3)向第二溶液加入氨水,搅拌30min,得到第三溶液;
(A-4)向第三溶液加入4份入磷酸三乙酯,搅拌30min,得到第四溶液;
(A-5)向第四溶液加入36份四水合硝酸钙,搅拌60min,得到第五溶液;
(A-6)将第五溶液转移至反应釜中,在140℃条件下反应24h,得到第六溶液;
(A-7)将第六溶液进行过滤,去离子水清洗,如此反复3次后,进行冷冻干燥,得到改性纳米生物活性玻璃;
B)制备改性生物活性玻璃微球,包括以下步骤:
(B-1)称取150g步骤A)得到的改性纳米生物活性玻璃分散于1000mL去离子水中,搅拌均匀去离子水含0.2%w/w的聚乙二醇15-羟基硬脂酸酯,搅拌均匀,得到第七溶液;
(B-2)使用喷雾干燥器对第七溶液进行喷雾干燥,进口温度为250℃,出口温度为100℃,进料速度为20mL/min,进气风量为500L/h,喷嘴直径为0.8mm,得到微球粗品1;
(B-3)将得到的微球粗品1放入马弗炉,并按照煅烧曲线进行高温煅烧,从室温以2℃/min的升温速率升温至300℃,并在300℃保持60min,再以3℃/min的升温速率升温至600℃并且在600℃保持120min,得到微球粗品2;
(B-4)将得到的微球粗品2使用600目筛网进行过筛,保留20-50μm的微球,即为所需的改性生物活性玻璃微球;
C)制备细菌纤维素涂层生物活性玻璃微球,包括以下步骤:
(C-1)制备纳米级透明质酸钠:将20g透明质酸钠溶于1L去离子水中,搅拌均匀,使用高压均质机进行均质,均质压力为200MPa,时间1min,将均质后的溶液进行冷冻干燥得到纳米级透明质酸钠;
(C-2)配置培养基:培养基配制,在每1000g重量的所述培养基中含有:步骤(B)得到的改性生物活性玻璃微球50g、步骤(C-1)得到的纳米级透明质酸钠1g、葡萄糖10g、蛋白胨5g、酵母抽提物0.5g、苹果酸0.2g、六偏磷酸钠0.5g、氯化镁0.2g和麦汁10g,余为去离子水;
(C-3)细菌纤维素膜制备,将木醋杆菌接入由步骤(C-1)得到的培养基中并且控制木醋杆菌与培养基的比重,在30±2℃下培养1天,培养结束后,取出生物活性玻璃微球清洗,而后在碱液中浸泡,浸泡结束后再次清洗,直至生物活性玻璃微球的pH值为6-8,60℃鼓风干燥24h,得到细菌纤维素涂层生物活性玻璃微球粗品;
(C-4)将步骤(C-3)得到的细菌纤维素涂层生物活性玻璃微球粗品分散于2%w/w的聚乙二醇200水溶液中6h,干燥后,引入灭菌装置灭菌并且控制灭菌装置灭菌的工艺参数,采用湿热灭菌柜在温度为121℃下灭菌20min,灭菌后得到细菌纤维素涂层生物活性玻璃微球。
D)制备美容整形用面部填充水凝胶,包括以下步骤:
(D-1)制备纳米级羧甲基纤维素钠:将5g羧甲基纤维素钠溶于1L去离子水中,搅拌均匀,使用高压均质机进行均质,均质压力为300MPa,时间2min,将均质后的溶液进行冷冻干燥得到纳米级羧甲基纤维素钠;
(D-2)制备面部填充水凝胶预罐装体:称取适量纳米级羧甲基纤维素钠于1000mL含0.9%wt氯化钠的注射用水中,搅拌均匀,加入1gε-聚赖氨酸,搅拌均匀后,再加入步骤C)得到的细菌纤维素涂层生物活性玻璃微球150g,使ε-聚赖氨酸与细菌纤维素涂层生物活性玻璃微球中的纳米透明质酸钠交联,自组装,得到面部填充水凝胶预罐装体;
(D-3)将步骤(D-2)面部填充水凝胶预罐装体进行负压脱气,再加压罐装于注射器中,灭菌,得到可注射的含细菌纤维素涂层生物活性玻璃微球美容整形用面部填充水凝胶,记为样品1。
使用扫描电镜对步骤(A)、(B)得到的改性纳米生物活性玻璃及改性生物活性玻璃微球进行观察,图2表明改性纳米生物活性玻璃粒径为10-60nm,图3表明过筛前改性生物活性玻璃微球粒径为20-80um,过筛后改性生物活性玻璃微球粒径为40-50um。
实施例2
A)制备改性纳米生物活性玻璃,包括以下步骤:
(A-1)称取46份正硅酸四乙酯溶于去离子水中,加入硝酸,调节pH值2-3,搅拌至溶液澄清透明,得到第一溶液;
(A-2)称取18份硼酸三正丁酯,溶于第一溶液,搅拌至溶液澄清透明,得到第二溶液;
(A-3)向第二溶液加入氨水,搅拌90min,得到第三溶液;
(A-4)向第三溶液加入6份入磷酸三乙酯,搅拌60min,得到第四溶液;
(A-5)向第四溶液加入30份四水合硝酸钙,搅拌30min,得到第五溶液;
(A-6)将第五溶液转移至反应釜中,在180℃条件下反应20h,得到第六溶液;
(A-7)将第六溶液进行过滤,去离子水清洗,如此反复3次后,进行冷冻干燥,得到改性纳米生物活性玻璃;
B)制备改性生物活性玻璃微球,包括以下步骤:
(B-1)称取200g步骤A)得到的改性纳米生物活性玻璃分散于1000mL去离子水中,搅拌均匀去离子水含2%w/w的聚乙二醇15-羟基硬脂酸酯,搅拌均匀,得到第七溶液;
(B-2)使用喷雾干燥器对第七溶液进行喷雾干燥,进口温度为260℃,出口温度为120℃,进料速度为40mL/min,进气风量为800L/h,喷嘴直径为1.0mm,得到微球粗品1;
(B-3)将得到的微球粗品1放入马弗炉,并按照煅烧曲线进行高温煅烧,从室温以2℃/min的升温速率升温至300℃,并在300℃保持60min,再以3℃/min的升温速率升温至600℃并且在600℃保持120min,得到微球粗品2;
(B-4)将得到的微球粗品2使用650目筛网进行过筛,保留20-50μm的微球,即为所需的改性生物活性玻璃微球;
C)制备细菌纤维素涂层生物活性玻璃微球,包括以下步骤:
(C-1)制备纳米级透明质酸钠:将36g透明质酸钠溶于1L去离子水中,搅拌均匀,使用高压均质机进行均质,均质压力为240MPa,时间1min,将均质后的溶液进行冷冻干燥得到纳米级透明质酸钠;
(C-2)配置培养基:培养基配制,在每1000g重量的所述培养基中含有:步骤(B)得到的改性生物活性玻璃微球120g、步骤(C-1)得到的纳米级透明质酸钠4g、葡萄糖25g、蛋白胨7g、酵母抽提物2g、苹果酸2.5g、六偏磷酸钠2.5g、氯化镁1.2g和麦汁14g,余为去离子水;
(C-3)细菌纤维素膜制备,将木醋杆菌接入由步骤(C-2)得到的培养基中并且控制木醋杆菌与培养基的比重,在30±2℃下培养2天,培养结束后,取出生物活性玻璃微球清洗,而后在碱液中浸泡,浸泡结束后再次清洗,直至生物活性玻璃微球的pH值为6-8,60℃鼓风干燥36h,得到细菌纤维素涂层生物活性玻璃微球粗品;
(C-4)将步骤(C-3)得到的细菌纤维素涂层生物活性玻璃微球粗品分散于5%w/w的聚乙二醇400水溶液中12h,干燥后,引入灭菌装置灭菌并且控制灭菌装置灭菌的工艺参数,采用湿热灭菌柜在温度为121℃下灭菌20min,灭菌后得到细菌纤维素涂层生物活性玻璃微球。
D)制备美容整形用面部填充水凝胶,包括以下步骤:
(D-1)制备纳米级羧甲基纤维素钠:将15g羧甲基纤维素钠溶于1L去离子水中,搅拌均匀,使用高压均质机进行均质,均质压力为360MPa,时间2min,将均质后的溶液进行冷冻干燥得到纳米级羧甲基纤维素钠;
(D-2)制备面部填充水凝胶预罐装体:称取适量纳米级羧甲基纤维素钠于1000mL含0.9%wt氯化钠的注射用水中,搅拌均匀,加入4gε-聚赖氨酸,搅拌均匀后,再加入步骤C)得到的细菌纤维素涂层生物活性玻璃微球240g,使ε-聚赖氨酸与细菌纤维素涂层生物活性玻璃微球中的纳米透明质酸钠交联,自组装,得到面部填充水凝胶预罐装体;
(D-3)将步骤(D-2)面部填充水凝胶预罐装体进行负压脱气,再加压罐装于注射器中,灭菌,得到可注射的含细菌纤维素涂层生物活性玻璃微球美容整形用面部填充水凝胶,记为样品2。
实施例3
A)制备改性纳米生物活性玻璃,包括以下步骤:
(A-1)称取40份正硅酸四乙酯溶于去离子水中,加入硝酸,调节pH值2-3,搅拌至溶液澄清透明,得到第一溶液;
(A-2)称取12份硼酸三正丁酯,溶于第一溶液,搅拌至溶液澄清透明,得到第二溶液;
(A-3)向第二溶液加入氨水,搅拌120min,得到第三溶液;
(A-4)向第三溶液加入8份入磷酸三乙酯,搅拌90min,得到第四溶液;
(A-5)向第四溶液加入40份四水合硝酸钙,搅拌90min,得到第五溶液;
(A-6)将第五溶液转移至反应釜中,在220℃条件下反应12h,得到第六溶液;
(A-7)将第六溶液进行过滤,去离子水清洗,如此反复3次后,进行冷冻干燥,得到改性纳米生物活性玻璃;
B)制备改性生物活性玻璃微球,包括以下步骤:
(B-1)称取300g步骤A)得到的改性纳米生物活性玻璃分散于1000mL去离子水中,搅拌均匀去离子水含5%w/w的聚乙二醇15-羟基硬脂酸酯,搅拌均匀,得到第七溶液;
(B-2)使用喷雾干燥器对第七溶液进行喷雾干燥,进口温度为300℃,出口温度为150℃,进料速度为50mL/min,进气风量为1000L/h,喷嘴直径为1.2mm,得到微球粗品1;
(B-3)将得到的微球粗品1放入马弗炉,并按照煅烧曲线进行高温煅烧,从室温以2℃/min的升温速率升温至300℃,并在300℃保持60min,再以3℃/min的升温速率升温至600℃并且在600℃保持120min,得到微球粗品2;
(B-4)将得到的微球粗品2使用800目筛网进行过筛,保留20-50μm的微球,即为所需的改性生物活性玻璃微球;
C)制备细菌纤维素涂层生物活性玻璃微球,包括以下步骤:
(C-1)制备纳米级透明质酸钠:将60g透明质酸钠溶于1L去离子水中,搅拌均匀,使用高压均质机进行均质,均质压力为300MPa,时间1min,将均质后的溶液进行冷冻干燥得到纳米级透明质酸钠;
(C-2)配置培养基:培养基配制,在每1000g重量的所述培养基中含有:步骤(B)得到的改性生物活性玻璃微球200g、步骤(C-1)得到的纳米级透明质酸钠10g、葡萄糖50g、蛋白胨10g、酵母抽提物5g、苹果酸4g、六偏磷酸钠5g、氯化镁2g和麦汁20g,余为去离子水;
(C-3)细菌纤维素膜制备,将木醋杆菌接入由步骤(C-2)得到的培养基中并且控制木醋杆菌与培养基的比重,在30±2℃下培养3天,培养结束后,取出生物活性玻璃微球清洗,而后在碱液中浸泡,浸泡结束后再次清洗,直至生物活性玻璃微球的pH值为6-8,60℃鼓风干燥36h,得到细菌纤维素涂层生物活性玻璃微球粗品;
(C-4)将步骤(C-3)得到的细菌纤维素涂层生物活性玻璃微球粗品分散于10%w/w的聚乙二醇600水溶液中24h,干燥后,引入灭菌装置灭菌并且控制灭菌装置灭菌的工艺参数,采用湿热灭菌柜在温度为121℃下灭菌20min,灭菌后得到细菌纤维素涂层生物活性玻璃微球。
D)制备美容整形用面部填充水凝胶,包括以下步骤:
(D-1)制备纳米级羧甲基纤维素钠:将20g羧甲基纤维素钠溶于1L去离子水中,搅拌均匀,使用高压均质机进行均质,均质压力为400MPa,时间2min,将均质后的溶液进行冷冻干燥得到纳米级羧甲基纤维素钠;
(D-2)制备面部填充水凝胶预罐装体:称取适量纳米级羧甲基纤维素钠于1000mL含0.9%wt氯化钠的注射用水中,搅拌均匀,加入10gε-聚赖氨酸,搅拌均匀后,再加入步骤C)得到的细菌纤维素涂层生物活性玻璃微球300g,使ε-聚赖氨酸与细菌纤维素涂层生物活性玻璃微球中的纳米透明质酸钠交联,自组装,得到面部填充水凝胶预罐装体;
(D-3)将步骤(D-2)面部填充水凝胶预罐装体进行负压脱气,再加压罐装于注射器中,灭菌,得到可注射的含细菌纤维素涂层生物活性玻璃微球美容整形用面部填充水凝胶,记为样品3。
实施例4
步骤(A)、(B)、(D)与实施例1保持一致;步骤(C)如下:
C)制备载纳米级透明质酸钠的生物活性玻璃微球,包括以下步骤:
(C-1)制备纳米级透明质酸钠:将20g透明质酸钠溶于1L去离子水中,搅拌均匀,使用高压均质机进行均质,均质压力为200MPa,时间1min,将均质后的溶液进行冷冻干燥得到纳米级透明质酸钠;
(C-2)步骤(B)得到的改性生物活性玻璃微球50g、步骤(C-1)得到的纳米级透明质酸钠1g溶于1000mL去离子水;
(C-3)在30±2℃下浸渍1天,取出生物活性玻璃微球清洗,而后在碱液中浸泡,浸泡结束后再次清洗,直至生物活性玻璃微球的pH值为6-8,60℃鼓风干燥24h,得到负载纳米级透明质酸钠的生物活性玻璃微球粗品;
(C-4)将步骤(C-3)得到的负载纳米级透明质酸钠的生物活性玻璃微球粗品分散于2%w/w的聚乙二醇200水溶液中6h,干燥后,引入灭菌装置灭菌并且控制灭菌装置灭菌的工艺参数,采用湿热灭菌柜在温度为121℃下灭菌20min,灭菌后得到细菌纤维素涂层生物活性玻璃微球。
得到对照品1。
实施例5
硼酸三正丁酯添加量为0g,其它步骤与实施例2保持一致,得到对照品2。
实施例6
ε-聚赖氨酸添加量为0g,其它步骤与实施例2保持一致,得到对照品3。
实施例7:抑菌能力测试
对样品1、样品2、样品3、对照品2、对照品3的抑菌性能进行检测,同时以市场销售产品注射用交联透明质酸钠凝胶作为性能比对。按照GB 15979-2002的方法进行检测,测试菌种为金黄色葡萄球菌。测试结果如表1所示:
表1
T(24h) | |
样品1 | >90% |
样品2 | >90% |
样品3 | >90% |
对照品2 | 85.7% |
对照品3 | 64.1% |
市售产品 | —— |
结果表明实施例1、2、3制备的样品1、2、3具有较强的抑菌效果,主要是因为产品中ε-聚赖氨酸与B2O3协同抗菌,ε-聚赖氨酸可以破坏细胞膜结构,导致细胞死亡,而B2O3的弱碱性会破坏微生物的微环境,进而抑菌细菌繁殖;对照品2无B2O3,对照品3无ε-聚赖氨酸,因此抑菌性能低于样品1、2、3。而市售产品不具有抑菌性能。
实施例8成纤维细胞增殖试验
利用CCK-8试剂盒检测小鼠真皮成纤维细胞在样品2对照品2上的增殖情况,同时以市场销售产品注射用交联透明质酸钠凝胶作为性能比对。步骤:将小鼠皮肤真皮成纤维细胞接种于实验样品表面,分别培养1天、3天、7天,接种密度为每个样品104个细胞,于每个检测时间点将300μL培养液和40μL CCK-8溶液加入培养板中,于37℃下培养4h,从培养板中移出100μL细胞培养液,转移至新的培养板中,利用酶标仪进行检测,结果见图4
结果显示样品2、对照品2的细胞增殖效果均好于市售产品,表明生物活性玻璃微球可以更好的促进细胞增殖,且样品2的增殖效果高于对照品2,说明B2O3可以增强生物活性玻璃微球细胞增殖的能力。
实施例9粘度测试
粘度大的样品可以有效防止生物活性玻璃微球在注射部位发生位移,因此粘度是注射美容产品的重要参数。使用粘度仪测量样品2、对照品2的粘度,同时以市场销售产品注射用交联透明质酸钠凝胶作为性能比对。结果见表2:
粘度(mPa·s) | |
样品2 | 4.5×10<sup>4</sup> |
对照品2 | 3.2×10<sup>4</sup> |
市售产品 | 3.1×10<sup>4</sup> |
结果显示对照品2与市售产品粘度无明显差异,而对照品未使用交联剂,仅对羧甲基纤维素钠、透明质酸钠进行高压均质处理,纳米级凝胶网络更为致密,市售产品使用交联剂后粘度与对照品2基本一致,说明高压均质处理对样品的粘度有重要作用。而样品2,添加了交联剂ε-聚赖氨酸,其粘度得到了较大提升,约增加45%。
实施例10细菌纤维素膜对比试验
本发明的技术特征在于细菌纤维素涂层制备所用培养基添加了聚乙二醇,其它专利未添加该试剂,聚乙二醇可以改善细菌纤维素膜的透光率。
配置培养基:培养基配制,在每1000g重量的所述培养基中含有:葡萄糖50g、蛋白胨10g、酵母抽提物5g、苹果酸4g、六偏磷酸钠5g、氯化镁2g和麦汁20g,余为去离子水;
细菌纤维素膜制备:将木醋杆菌接入培养基中并且控制木醋杆菌与培养基的比重,在30±2℃下培养3天,培养结束后,取出细菌纤维素膜清洗,而后在碱液中浸泡,浸泡结束后再次清洗,直至pH值为6-8,60℃鼓风干燥36h,得到细菌纤维素膜粗品;
将步骤得到的细菌纤维膜粗品分散于5%w/w的聚乙二醇400水溶液中6h,干燥后,引入灭菌装置灭菌并且控制灭菌装置灭菌的工艺参数,采用湿热灭菌柜在温度为121℃下灭菌20min,灭菌后得到细菌纤维素膜,记为样品4,未添加聚乙二醇400的样品记为对照品4,并进行数码拍照,见图5。表明聚乙二醇改善了细菌纤维素膜的透光率,使其从白色凝胶薄膜变为透明凝胶薄膜。
实施例11降解试验
产品的降解速率决定了注射美容保持效果,测试样品为样品1、对照品1,测试溶液为模拟体液,分别在1、3、6、12、24月时间段观察样品的形态与硅离子释放曲线。
从图6可以可见硅离子释放曲线,对照品1中硅离子在6个月累计释放量达90%,在第12个月的时候完全释放;而样品1中硅离子前6个月累计释放量仅30%,24个月累计释放量68%。表明细菌纤维素涂层延缓了生物活性玻璃微球中硅离子的释放,延长微球的降解时间,从而提高组织填充、去除皱纹的时间。
此外,通过扫描电镜,也可以发现,对照品1中微球在6个月的时候基本降解为颗粒,24个月的时候颗粒消失;而样品1中微球在6个月的时候还保持着微球结构,24个月的时候降解为颗粒,该结果与硅离子释放曲线相吻合。
以上对本发明的具体实施例进行了描述。需要理解的是,本发明并不局限于上述特定实施方式,本领域技术人员可以在权利要求的范围内做出各种变形或修改,这并不影响本发明的实质内容。
Claims (10)
1.一种美容整形用面部填充水凝胶的制备方法,其特征在于,包括如下步骤:
S1、制备改性生物活性玻璃微球;
S2、利用所述改性生物活性玻璃微球、纳米级透明质酸钠、葡萄糖、蛋白胨、酵母抽提物、苹果酸、六偏磷酸钠、氯化镁、麦汁和去离子水配制成培养基,将木醋杆菌接入所述培养基中,并控制木醋杆菌与培养基的比重,在28~32℃下培养1~3天后,取出改性生物活性玻璃微球清洗,然后在碱液中浸泡,浸泡结束后再次清洗,直至改性生物活性玻璃微球的pH值为6~8,鼓风干燥后,得到细菌纤维素涂层生物活性玻璃微球粗品;
S3、将所述细菌纤维素涂层生物活性玻璃微球粗品分散于2~10%w/w的聚乙二醇水溶液中6~24h,干燥后,进行灭菌,得到细菌纤维素涂层生物活性玻璃微球;
S4、将纳米级羧甲基纤维素钠溶于含0.9%w/w氯化钠的注射用水中,加入ε-聚赖氨酸,混匀后,加入所述细菌纤维素涂层生物活性玻璃微球,使ε-聚赖氨酸与细菌纤维素涂层生物活性玻璃微球中的纳米透明质酸钠交联,自组装,得到面部填充水凝胶预罐装体;
S5、将所述面部填充水凝胶预罐装体进行负压脱气,再加压罐装于注射器中,灭菌,得到所述美容整形用面部填充水凝胶。
2.如权利要求1所述的美容整形用面部填充水凝胶的制备方法,其特征在于,所述改性生物活性玻璃微球的制备方法为:
将改性纳米生物活性玻璃分散于含有0.2~5%w/w增溶剂的去离子水中,分散均匀后,进行喷雾干燥,得到微球粗品1;
将所述微球粗品1按照煅烧曲线进行高温煅烧,得到微球粗品2;
将所述微球粗品2过筛,收集粒径20~50μm的微球,即所述改性生物活性玻璃微球。
3.如权利要求2所述的美容整形用面部填充水凝胶的制备方法,其特征在于,所述改性纳米生物活性玻璃的制备方法为:
称取x1份正硅酸四乙酯溶于去离子水中,调节pH值2-3,搅拌至溶液澄清透明,得到第一溶液;
称取x2份硼酸三正丁酯,溶于第一溶液,搅拌至溶液澄清透明,得到第二溶液;
向第二溶液加入氨水,搅拌30-120min,得到第三溶液;
向第三溶液加入x3份入磷酸三乙酯,搅拌30-90min,得到第四溶液;
向第四溶液加入x4份四水合硝酸钙,搅拌30-90min,得到第五溶液;
将第五溶液转移至反应釜中,在140-220℃条件下反应12-24h,得到第六溶液;
将第六溶液进行过滤,去离子水清洗,如此反复3次后,进行冷冻干燥,得到改性纳米生物活性玻璃。
4.如权利要求3所述的美容整形用面部填充水凝胶的制备方法,其特征在于,x1:x2:x3:x4=(40~50):(10~20):(4~8):(30~40),且x1+x2+x3+x4=100。
5.如权利要求2所述的美容整形用面部填充水凝胶的制备方法,其特征在于,所述喷雾干燥的操作中,控制进口温度为250-300℃,出口温度为100-150℃,进料速度为20-50mL/min,进气风量为500-1000L/h,喷嘴直径为0.8-1.2mm;所述增溶剂为非离子型增溶剂;所述煅烧曲线为:从室温以2℃/min的升温速率升温至300℃,并在300℃保持60min,再以3℃/min的升温速率升温至600℃,并在600℃保持120min。
6.如权利要求1所述的美容整形用面部填充水凝胶的制备方法,其特征在于,所述纳米级透明质酸钠的制备方法为:将透明质酸钠溶于去离子水中,搅拌均匀,在200~300MPa的压力下进行均质,将均质后的溶液进行在不超过10Pa的真空度、-50℃的温度下冷冻干燥,得到纳米级透明质酸钠。
7.如权利要求1所述的美容整形用面部填充水凝胶的制备方法,其特征在于,所述改性生物活性玻璃微球、纳米级透明质酸钠、葡萄糖、蛋白胨、酵母抽提物、苹果酸、六偏磷酸钠、氯化镁和麦汁的质量比为:(50~200):(1~10):(10~50):(5~10):(0.5~5):(0.2~4):(0.5~5):(0.2~2):(10~20);所述木醋杆菌与所述培养基的比重是将体积重量比控制为(200-1000)μL∶1000g;步骤S3中所述的灭菌的条件为:采用湿热灭菌柜,在温度为121℃下灭菌20-60min。
8.如权利要求1所述的美容整形用面部填充水凝胶的制备方法,其特征在于,所述纳米级羧甲基纤维素钠的制备方法为:将羧甲基纤维素钠溶于去离子水中,搅拌均匀,在300~400MPa的压力下进行均质,将均质后的溶液进行在不超过10Pa的真空度、-50℃的温度下冷冻干燥,得到纳米级羧甲基纤维素钠。
9.如权利要求1所述的美容整形用面部填充水凝胶的制备方法,其特征在于,所述ε-聚赖氨酸与纳米级透明质酸钠的质量比为1:1。
10.如权利要求1所述的美容整形用面部填充水凝胶的制备方法,其特征在于,所述聚乙二醇选自聚乙二醇200、聚乙二醇400、聚乙二醇600中的一种。
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