CN115068688A - 一种可吸收面部填充材料及其制备方法和应用 - Google Patents
一种可吸收面部填充材料及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种可吸收面部填充材料及其制备方法和应用，其解决了现有材料出现红肿、凹陷、感染等副作用、注射后保持时间不易控、除了物理支撑和吸水并无其他功效的技术问题，其含有如下质量份数比的组分：胶原蛋白、壳聚糖、透明质酸钠、增稠剂、左旋聚乳酸、聚己内酯和交联剂的质量份数比为5:2:2:(1.2～1.6):1:1:0.02，本发明可用于面部皱纹、凹陷的填充与修复材料的制备领域。
Description
技术领域
本发明涉及一种美容材料及其制备方法和应用，具体地说，涉及一种可吸收面部填充材料及其制备方法和应用。
背景技术
随着社会的发展、科技的进步、生活水平的提高，人们越来越注重自己的外貌。但高压力的工作、不规律的饮食与作息以及年龄的衰老导致人们面部皮肤的透明质酸与胶原蛋白加速流失，导致面部皮肤凹陷、皱纹等一些列问题。目前市面较多的面部填充材料为交联透明质酸钠又名玻尿酸，透明质酸具有吸水保湿与支撑的作用，医生通过注射后用手塑性可以起到面部填充的作用。但临床上面部填充后部分患者出现局部红肿、凹陷、感染等副作用，且玻尿酸注射后保持时间不易控，除此之外，玻尿酸除了物理支撑和吸水并无其他功效。而新型的胶原蛋白填充物，除了可以提供物理的支撑外，还可以弥补面部胶原蛋白的流失，拥有更高的生物相容性与抗老化的功效。
胶原蛋白是人体含量最多的蛋白质，也是人体非常重要的一种蛋白质，广泛分布在骨骼、肌腱、软骨、韧带、肠壁、皮肤等人体器官中。人体中的胶原蛋白根据生理功能和作用的不同，大致可分为5个类型:I型胶原蛋白:90％以上的胶原蛋白都是I型，它主要存在于成人皮肤、肌腱、骨组织；Ⅱ型胶原蛋白主要由软骨细胞产生，多存在于骨骼、关节、肌腱等组织；Ⅲ型胶原蛋白主要存在干婴儿皮肤或血管内膜，肠道；IV型胶原蛋白主要存在于基底层；V型胶原蛋白多位于细胞表面、头发、胎盘等处。婴儿皮肤中Ⅲ型胶原蛋白的含量占到80％以上，因此具有优异的弹性和修复功能。成人皮肤中的Ⅲ型胶原蛋白因为年龄的增加流失而减少，同时成人真皮已经不具有合成Ⅲ型胶原蛋白的能力，只能合成I型胶原蛋白，因此像伤口的愈合经常会留下瘢痕。随着年龄的增大，Ⅲ型胶原蛋白的流失越来越快，尤其25岁以后，皮肤中Ⅲ型胶原蛋白的合成速度赶不上流失速度，最终导致皱纹、松弛等衰老现象。
壳聚糖是甲壳素N-脱乙酰基的产物，甲壳素、壳聚糖、纤维素三者具有相近的化学结构，纤维素在C2位上是羟基，甲壳素、壳聚糖在C2位上分别被一个乙酰氨基和氨基所代替，甲壳素和壳聚糖具有生物降解性、细胞亲和性和生物效应等许多独特的性质，尤其是含有游离氨基的壳聚糖，是天然多糖中唯一的碱性多糖。壳聚糖为天然多糖甲壳素脱除部分乙酰基的产物，具有生物降解性、生物相容性、无毒性、抑菌、抗癌、降脂、增强免疫等多种生理功能，广泛应用于食品添加剂、纺织、农业、环保、美容保健、化妆品、抗菌剂、医用纤维、医用敷料、人造组织材料、药物缓释材料、基因转导载体、生物医用领域、医用可吸收材料、组织工程载体材料、医疗以及药物开发等众多领域和其他日用化学工业。
透明质酸钠，化学式为(C14H20NO11Na)n，是人体内一种固有的成分，是一种葡聚糖醛酸，它广泛存在于胎盘、羊水、晶状体、关节软骨、皮肤真皮层等组织、器官中。它分布在细胞质、细胞间质中，对其中所含的细胞和细胞器官本身起润滑与滋养作用，同时提供细胞代谢的微环境。透明质酸可配合其他促进细胞再生除皱药物制成一种凝胶，通过注射方法使用。保湿作用是透明质酸钠在化妆品中最重要的作用，与其他保湿剂相比，周围环境的相对湿度对其保湿性的影响较小。
乳酸分子中有一个不对称的碳原子，具有旋光性，因此聚乳酸也分为右旋聚乳酸(PDLA)，左旋聚乳酸(PLLA)，外消旋聚乳酸(PDLLA)，非旋光性聚乳酸(Meso-PLA)。PLA是重要的生物可降解高分子材料，它的特点是无毒、无刺激性、可生物降解吸收、强度高、可塑性好、易加工成型。降解周期为2～12个月。PLLA是重要的生物可降解高分子材料，它的特点是无毒、无刺激性、可生物降解吸收、强度高、可塑性好、易加工成型。降解周期为2～12个月。还可以根据加入修饰剂的不同来改变降解周期。PLLA在生物体内经过酶分解，最终形成二氧化碳和水，具有良好的生物兼容性。
聚己内酯又称聚ε-己内酯，是通过ε-己内酯单体在金属阴离子络合催化剂催化下开环聚合而成的高分子有机聚合物，通过控制聚合条件，可以获得不同的分子量。其外观为白色固体粉末，无毒，不溶于水，易溶于多种极性有机溶剂。PCL具有良好的生物相容性、良好的有机高聚物相容性，以及良好的生物降解性，可用作细胞生长支持材料，可与多种常规塑料互相兼容，自然环境下6-12个月即可完全降解。此外，PCL还具有良好的形状记忆温控性质，被广泛应用于药物载体、增塑剂、可降解塑料、纳米纤维纺丝、塑形材料的生产与加工领域。
发明内容
本发明为了解决现有材料易出现红肿、凹陷、感染等副作用、注射后保持时间不易控、除了物理支撑和吸水并无其他功效的技术问题，提供一种颗粒细腻、颜色较浅、接近于无色或淡黄色、粘弹性良好、粘度适中、流动性好、稳定不易分层、具有再生及锁水功效的可吸收面部填充材料。
为此，本发明提供一种可吸收面部填充材料，其含有如下质量份数比的组分：胶原蛋白(Col)、壳聚糖(CS)、透明质酸钠(HA)、增稠剂、左旋聚乳酸(PLLA)、聚己内酯(PCL)和交联剂的质量份数比为5:2:2:(1.2～1.6):1:1:0.02。
优选的，所述胶原蛋白的分子量为1500～5000；所述左旋聚乳酸与聚己内酯平均粒径分布为50μm；所述壳聚糖分中黏度壳聚糖其黏度为200mpa.s；所述透明质酸钠分子量为10w～20w；所述增稠剂为羧甲基纤维素(CMC)。
优选的，所述交联剂为京尼平。
优选的，所述胶原蛋白可以通过猪皮通过水解制备，也可市购获得，例如罗恩公司的R096735；麦克林公司的C823256；Perfemiker公司的PA21265。本发明选取的胶原蛋白均为灭菌的生物级或医药级，分子量优选为1500～5000。
优选的，所述壳聚糖可通过本领域中已知办法制得，也可通过市购获得，例如麦克林公司的C804729；罗恩公司的R096769；Perfemiker公司的PA20255；阿拉丁公司的C105802等。发明选取的壳聚糖均为生物级或医药级，脱乙酰度大于90％。
优选的，所述透明质酸钠可通过本领域中已知办法制得，也可通过市购获得，例如源叶公司的S24592；毕佳索公司的KOUX7Z9P；毕得公司的BD01423295。本发明选取的透明质酸钠均为灭菌的生物级或医药级，分子量优选为40w～100w。
优选的，所述左旋聚乳酸微球可通过本领域中已知办法制得，也可通过市购获得，例如麦克林公司的P875095。本发明选取的左旋聚乳酸均为生物级或医药级，粒径分布优选为50μm。
优选的，所述聚己内酯微球可通过本领域中已知办法制得，也可通过市购获得，例如麦克林公司的P871874；玛雅公司的105570。本发明选取的聚己内酯均为灭菌的生物级或医药级，分子量优选为8w。
本发明同时提供一种可吸收面部填充材料的制备方法，其包括以下步骤：(a)胶原蛋白溶解：常温下，将胶原蛋白加入去离子水中搅拌溶液3min，静置10min消除气泡；(b)壳聚糖溶解：常温下，将壳聚糖加入去离子水中搅拌分散，并向其中加入质量百分数1％的冰醋酸，充分搅拌6h溶解；(c)透明质酸钠溶解：在60℃的油浴条件下，将HA与BDDE的NaOH溶液加入去离子水中充分搅拌加热8小时，然后透析72h得到透明有流动性的凝胶；(d)共混与交联：胶原蛋白壳聚糖、透明质酸钠以5:2:2-15:2:2的质量分数比例共混搅拌10min，向其加入质量百分数0.02％的京尼平交联24h；(e)向其中加入质量百分数1％的PLLA、PCL搅拌充分混合后分别加入质量百分数1.2％-1.6％的CMC，盖上封口膜搅拌3h；(f)倒入孔板放置4℃冰箱保存。
由于上述技术方案应用，本发明与现有技术相比有下列优点：本发明为胶原蛋白(Col)、左旋聚乳酸(PLLA)、聚己内酯(PCL)、壳聚糖(CS)、透明质酸钠(HA)共混体系。胶原蛋白作为主体，可以为面部补充流失的胶原蛋白；壳聚糖具有生物降解性、生物相容性、无毒性、抑菌、增强免疫等多种生理功能；透明质酸具有保水并提供支撑的能力；左旋聚乳酸和聚己内酯微球能刺激皮肤的胶原蛋白再生。五种材料的共混一方面解决了传统玻尿酸功能性的单一，拥有更高的生物相容性，刺激面部胶原蛋白的再生，体系的粘度和流动性可控等优点；另一方面本发明相比于传统玻尿酸可以更好的控制降解速率，为患者带来便利。
附图说明
图1为本发明中可吸收面部填充材料制备方法的工艺流程图。
具体实施方式
下面将结合实施例对本发明进行进一步说明。
实施例1
如图1所示，本发明提供可吸收面部填充材料制备方法的工艺方法，具体如下：
(a)胶原蛋白溶解：常温下，取5g麦克林公司的C823256胶原蛋白加入100mL的去离子水中，放置在磁力搅拌器上充分搅拌溶解3min配制溶液，并静置10min消除泡沫。
(b)壳聚糖溶解：常温下，将2g麦克林公司的C804729壳聚糖加入100mL去离子水中，将其放置在磁力搅拌器上分散均匀，在搅拌的同时向其中加入质量分数1％的冰醋酸，调整转速充分搅拌6h得到壳聚糖水溶液；
(c)透明质酸钠溶解：在60℃的油浴条件下，取2g源叶公司的S24592透明质酸钠加入100mL BDDE与NaOH水溶液中充分搅拌，搅拌同时加热维持8小时；得到的产物在透析缸中透析，每12h换一次水，共换3次水后将产物放置6孔板内冷冻干燥得到交联透明质酸钠。取2g上述产物，搅拌条件下加入100mL去离子水中配置成溶液。
(d)共混与交联：将(a)(b)(c)制备的胶原蛋白、壳聚糖、透明质酸钠以1:1:1的质量比例共混，放置在磁力搅拌器上搅拌10min，搅拌的同时向其加入质量分数0.02％的京尼平继续搅拌10min；关闭搅拌在常温下交联24h。
(e)在常温搅拌状态下，向交联后的溶液中加入质量分数1％麦克林公司的P875095左旋聚乳酸与玛雅公司的105570聚己内酯，搅拌10min充分混合；分成三份，分别加入质量分数1.2％-1.6％的CMC，盖上封口膜在磁力搅拌器上继续搅拌3h；
(f)得到的材料在4℃冰箱中保存。
本实例制得的面部填充经过各项测试，制品材料颗粒细腻，颜色较浅，接近于无色或较浅的乳白色；有一定粘弹性，弹性模量在260-275kPa；剪切黏度适中可流动，0.3rad/min转速下为4000mpa.s-11000mpa.s，3rad/min转速下为2600mpa.s-7800mpa.s，30rad/min转速下为420mpa.s-710mpa.s；可注射推挤，推挤力为6.8N-9.3N；稳定不分层；平均粒径分布50微米左右；材料可在六个月内完全降解；细胞毒性低。
实施例2
如图1所示，本发明提供可吸收面部填充材料制备方法的工艺方法，具体如下：
(a)胶原蛋白溶解：常温下，取10g麦克林公司的C823256胶原蛋白加入100mL的去离子水中，放置在磁力搅拌器上充分搅拌溶解3min配制溶液，并静置10min消除泡沫。
(b)壳聚糖溶解：常温下，将2g麦克林公司的C804729壳聚糖加入100mL去离子水中，将其放置在磁力搅拌器上分散均匀，在搅拌的同时向其中加入质量分数1％的冰醋酸，调整转速充分搅拌6h得到壳聚糖水溶液；
(c)透明质酸钠溶解：在60℃的油浴条件下，取2g源叶公司的S24592透明质酸钠加入100mL BDDE与NaOH水溶液中充分搅拌，搅拌同时加热维持8小时；得到的产物在透析缸中透析，每12h换一次水，共换3次水后将产物放置6孔板内冷冻干燥得到交联透明质酸钠。取2g上述产物，搅拌条件下加入100mL去离子水中配置成溶液。
(d)共混与交联：将(a)(b)(c)制备的胶原蛋白、壳聚糖、透明质酸钠以1:1:1的质量比例共混，放置在磁力搅拌器上搅拌10min，搅拌的同时向其加入质量分数0.02％的京尼平继续搅拌10min；关闭搅拌在常温下交联24h。
(e)在常温搅拌状态下，向交联后的溶液中加入质量分数1％麦克林公司的P875095左旋聚乳酸与玛雅公司的105570聚己内酯，搅拌10min充分混合；分成三份，分别加入质量分数1.2％-1.6％的CMC，盖上封口膜在磁力搅拌器上继续搅拌3h；
(f)得到的材料在4℃冰箱中保存。
本实例制得的面部填充经过各项测试，制品材料颗粒细腻，颜色略显黄色；有一定粘弹性，弹性模量在280-300kPa；剪切黏度适中可流动，0.3rad/min转速下为7500mpa.s-17000mpa.s，3rad/min转速下为4100mpa.s-9800mpa.s，30rad/min转速下为550mpa.s-850mpa.s；可注射推挤，推挤力为7.3N-9.8N；稳定不分层；平均粒径分布50微米左右；材料可在六个月内完全降解；细胞毒性低。
实施例3
如图1所示，本发明提供可吸收面部填充材料制备方法的工艺方法，具体如下：
(a)胶原蛋白溶解：常温下，取15g麦克林公司的C823256胶原蛋白加入100mL的去离子水中，放置在磁力搅拌器上充分搅拌溶解3min配制溶液，并静置10min消除泡沫。
(b)壳聚糖溶解：常温下，将2g麦克林公司的C804729壳聚糖加入100mL去离子水中，将其放置在磁力搅拌器上分散均匀，在搅拌的同时向其中加入质量分数1％的冰醋酸，调整转速充分搅拌6h得到壳聚糖水溶液；
(c)透明质酸钠溶解：在60℃的油浴条件下，取2g源叶公司的S24592透明质酸钠加入100mL BDDE与NaOH水溶液中充分搅拌，搅拌同时加热维持8小时；得到的产物在透析缸中透析，每12h换一次水，共换3次水后将产物放置6孔板内冷冻干燥得到交联透明质酸钠。取2g上述产物，搅拌条件下加入100mL去离子水中配置成溶液。
(d)共混与交联：将(a)(b)(c)制备的胶原蛋白、壳聚糖、透明质酸钠以1:1:1的质量比例共混，放置在磁力搅拌器上搅拌10min，搅拌的同时向其加入质量分数0.02％的京尼平继续搅拌10min；关闭搅拌在常温下交联24h。
(e)在常温搅拌状态下，向交联后的溶液中加入质量分数1％麦克林公司的P875095左旋聚乳酸与玛雅公司的105570聚己内酯，搅拌10min充分混合；分成三份，分别加入质量分数1.2％-1.6％的CMC，盖上封口膜在磁力搅拌器上继续搅拌3h；
(f)得到的材料在4℃冰箱中保存。
本实例制得的面部填充经过各项测试，制品材料颗粒细腻，颜色较黄；有一定粘弹性，弹性模量在315-335kPa；剪切黏度适中可流动，0.3rad/min转速下为11000mpa.s-24500mpa.s，3rad/min转速下为7800mpa.s-13500mpa.s，30rad/min转速下为650mpa.s-1000mpa.s；可注射推挤，推挤力为7.9N-10.5N；稳定不分层；平均粒径分布50微米左右；材料可在六个月内完全降解；细胞毒性低。
表1：实施例1～3及对比例的组分含量及性能
随着体系中胶原蛋白含量的提高，制品材料的粘度、推挤力、弹性模量明显上升；随着体系中羧甲基纤维素含量的提高，制品材料粘度急剧上升，推挤力与弹性模量上升但变化较小；体系中粒径分布主要取决于左旋聚乳酸微球与聚己内酯微球；壳聚糖的加入一方面提高体系的生物相容性，另一方面提高体系粘度从而减少增稠剂的用量。
惟以上所述者，仅为本发明的具体实施例而已，当不能以此限定本发明实施的范围，故其等同组件的置换，或依本发明专利保护范围所作的等同变化与修改，皆应仍属本发明权利要求书涵盖之范畴。
Claims (5)
1.一种可吸收面部填充材料，其特征是，含有如下质量份数比的组分：胶原蛋白、壳聚糖、透明质酸钠、增稠剂、左旋聚乳酸、聚己内酯和交联剂的质量份数比为5:2:2:(1.2～1.6):1:1:0.02。
2.根据权利要求1所述的可吸收面部填充材料，其特征在于，所述胶原蛋白的分子量为1500～5000；所述左旋聚乳酸与聚己内酯平均粒径分布为50μm；所述壳聚糖分中黏度壳聚糖其黏度为200mpa.s；所述透明质酸钠分子量为10w～20w；所述增稠剂为羧甲基纤维素。
3.根据权利要求1所述的可吸收面部填充材料，其特征在于，所述交联剂为京尼平。
4.如权利要求1～3任一所述可吸收面部填充材料的制备方法，其特征是，包括如下步骤：
(a)胶原蛋白溶解：常温下，将胶原蛋白加入去离子水中搅拌，静置；
(b)壳聚糖溶解：常温下，将壳聚糖加入去离子水中搅拌分散，并向其中加入冰醋酸，充分搅拌，溶解；
(c)透明质酸钠溶解：将HA与BDDE的NaOH溶液加入去离子水中充分搅拌加热，然后透析，得到凝胶；
(d)共混与交联：胶原蛋白、壳聚糖、透明质酸钠以一定比例共混搅拌，向其加入京尼平交联；
(e)向其中加入左旋聚乳酸、聚己内酯，搅拌充分混合后，分别加入增稠剂羧甲基纤维素，盖上封口膜搅拌；
(f)倒入孔板放置冰箱保存。
5.如权利要求1～3任一所述的可吸收面部填充材料在制备用于面部皱纹、凹陷的填充与修复材料中的应用。
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