CN117024770A - 改性聚乳酸微球-透明质酸混合凝胶及其制备方法和应用 - Google Patents
改性聚乳酸微球-透明质酸混合凝胶及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及生物医用材料领域,尤其涉及改性聚乳酸微球‑透明质酸混合凝胶及其制备方法和应用。所述制备方法包括如下步骤:S1.制备聚乳酸微球;S2.对聚乳酸微球进行改性,得到表面带有羧基的聚乳酸微球;S3.将表面带有羧基的聚乳酸微球进行活化反应,得到表面带有活化羧基的聚乳酸微球;S4.将表面带有活化羧基的聚乳酸微球接枝烟酰胺,得到改性聚乳酸微球;S5.将改性聚乳酸微球与透明质酸钠溶液混合,得到改性聚乳酸微球‑透明质酸混合凝胶。本发明采用亲水性的烟酰胺对PLA微球表面进行改性,提高了PLA微球在透明质酸钠溶液中的分散性和稳定性,解决现有技术在注射过程中易聚集成团、堵注射针的问题。
Description
技术领域
本发明涉及生物医用材料领域,尤其涉及改性聚乳酸微球-透明质酸混合凝胶及其制备方法和应用。
背景技术
近年来,用于美容医疗用途的可注射凝胶发展迅速,可注射凝胶能在注射部位实现微创治疗的美容作用,因而受到广泛关注。
透明质酸(HA)又名玻尿酸,是一种多功能基质,广泛分布于人体各部位。皮肤中也含有大量的透明质酸。人类皮肤成熟和老化过程随着透明质酸的含量和新陈代谢而变化,它可以改善皮肤营养代谢,使皮肤柔嫩、光滑、去皱、增加弹性、防止衰老,在保湿的同时又是良好的透皮吸收促进剂。透明质酸凝胶用于皮下注射,可瞬间深层保湿、增加皮肤弹性与张力,有助恢复肌肤正常油水平衡。但是目前市面上的透明质酸凝胶产品降解期短,很难保证中长效果。要达到长久持续的目的,必须改进在透明质酸凝胶中的添加成分。
中国专利CN104258470A公开了一种聚乳酸微球和交联透明质酸混合凝胶及其制备方法,在透明质酸钠中加入聚乳酸微球,提高透明质酸在体内的抗降解能力,延长作用时间。但是聚乳酸微球的亲水性差,不利于在人体水环境中分散,注射入体后容易集结成块,并且难以在透明质酸凝胶中分散均匀,所以聚乳酸不是理想的注射填充材料。
中国专利CN105126166A公开了一种注射用含两亲性微球的透明质酸混合凝胶及其制备方法,采用两亲水性原料制备亲水性微球,将两亲性微球直接与透明质酸凝胶混合,两亲性微球容易均匀分布在凝胶中,注射入人体后,在人体水环境下不易集结成块。但是采用亲水性的原料一方面增大了原料改性的成本,另一方面亲水性微球和透明质酸钠混合后,由于亲水端暴露在透明质酸钠中,导致微球在透明质酸钠凝胶中不能长期稳定存在,该混合凝胶存在稳定性差、有效期短等缺点。
发明内容
本发明的第一个方面提供了改性聚乳酸微球-透明质酸混合凝胶的制备方法,所述制备方法包括如下步骤:
S1.制备聚乳酸微球;
S2.对聚乳酸微球进行改性,得到表面带有羧基的聚乳酸微球;
S3.将表面带有羧基的聚乳酸微球进行活化反应,得到表面带有活化羧基的聚乳酸微球;
S4.将表面带有活化羧基的聚乳酸微球接枝烟酰胺,得到改性聚乳酸微球;
S5.将改性聚乳酸微球与透明质酸钠溶液混合,得到改性聚乳酸微球-透明质酸混合凝胶。
在一些实施方式中,所述聚乳酸微球的制备方法包括如下步骤:
S1.将聚乳酸溶于有机溶剂中,得到油相;
S2.将表面活性剂溶于水中,得到水相;
S3.将水相加入油相中进行搅拌乳化,除去有机溶剂,洗涤、干燥后得到聚乳酸微球。
在一些实施方式中,所述聚乳酸的特性粘度为1.0-2.0dL/g,优选来源为山东省生物医药科学院有限公司。
在一些实施方式中,所述有机溶剂可以选自本领域常用的种类,包括但不限于乙酸乙酯、甲酸乙酯、甲酸甲酯、乙酸甲酯、丁酮、四氢呋喃、丙酮、乙腈、二甲基亚砜、二氯甲烷、氯仿、三氯乙烯、乙烯乙二醇醚、三乙醇胺。
在一些实施方式中,所述表面活性剂可以选自本领域常用的种类,包括但不限于聚乙烯醇,优选来源为江西阿尔法高科药业有限公司。
在一些实施方式中,S2中通过将聚乳酸微球采用碱液浸泡的方式进行改性,所述碱液包括但不限于本领域常用的种类,例如氢氧化钠、氢氧化钾。
在一些实施方式中,所述聚乳酸微球的粒径为20-50μm。
在一些实施方式中,所述S3中采用EDC(1-乙基-(3-二甲基氨基丙基)碳酰二亚胺)、NHS(N-羟基丁二酰亚胺)、DMTMM(4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐)的至少一种羧基活化剂进行活化反应。
进一步地,所述S3中采用DMTMM(CAS:3945-69-5)进行活化反应。
为了减少皮肤刺激性,所述S4中表面带有活化羧基的聚乳酸微球与烟酰胺的质量比为100:(0.1-5)。
为了进一步提高聚乳酸微球在注射过程中的分散性和稳定性并减少团聚,进一步地,所述聚乳酸微球与烟酰胺的质量比为100:(2-4)。
在一些实施方式中,所述S5中改性聚乳酸微球与透明质酸钠的质量比为(5-25):100。
在一些实施方式中,所述透明质酸钠的特性粘度为15-25dL/g,透明质酸钠的质量浓度为1%-5%,优选来源为江西阿尔法高科药业有限公司。
进一步地,所述透明质酸钠的溶液为透明质酸钠的水溶液、氯化钠溶液或磷酸盐溶液缓冲溶液的任意一种,更进一步地,所述透明质酸钠的溶液为透明质酸钠的磷酸盐缓冲溶液。
本发明的第二个方面提供了改性聚乳酸微球-透明质酸混合凝胶,由上述制备方法制得。
本发明的第三个方面提供了上述混合凝胶在制备注射用美容产品中的应用。
与现有技术相比,本发明具有以下有益效果:
1.本发明通过将烟酰胺接枝到聚乳酸微球表面,所得到的接枝产物可以进一步加速皮肤细胞代谢,促进角质层的修复和美白祛斑的作用,进而延缓细胞衰老,减少紫外线对皮肤的损害。
2.本发明采用亲水性的烟酰胺对PLA微球表面进行改性,使得微球表面覆盖一层亲水性功能涂层材料,从而提高PLA微球在透明质酸钠溶液中的分散性和稳定性,解决现有技术在注射过程中易聚集成团、堵注射针的问题。
3.本发明得到的烟酰胺改性的微球具有良好的亲水性和长降解周期,具有美白、刺激胶原再生等功能,而且烟酰胺毒副作用小,价格适中,是一种多功能、高价值、应用前景广阔的产品。
4.本发明制备的微球体外缓释平稳,经累计溶出率测试,延长了微球在体内的释放周期。
5.本发明制备的微球粒径分布均一、粒径分布窄,制备原料简单易得,制备工艺易放大,有广阔的产业化前景。
附图说明
图1为本发明中实施例2制备的聚乳酸微球的表观形貌图。
图2为本发明中实施例2制备的聚乳酸微球湿热灭菌15min的表观形貌图。
图3为本发明中实施例1和实施例2制备的改性聚乳酸微球的体外累计释放曲线。
具体实施方式
实施例1
改性聚乳酸微球-透明质酸混合凝胶的制备方法,所述制备方法包括如下步骤:
S1.制备聚乳酸微球;
S2.取1g聚乳酸微球,用10mL质量浓度0.5%的氢氧化钠水溶液在室温25℃下浸泡3h,然后离心,用去离子水洗涤3次,得到表面带有羧基的聚乳酸微球;
S3.取1g DMTMM(4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐)加入10mL的磷酸盐缓冲液(PBS)中,溶解后调节pH至4.5±0.5,再加入0.6g表面带有羧基的聚乳酸微球,在45℃中反应2h,然后离心、去离子水洗涤2次,得到表面带有活化羧基的聚乳酸微球;
S4.将0.2g烟酰胺(购自国药公司)溶于10mL PBS缓冲液中,PBS的pH为6,待烟酰胺完全溶解后,加入0.4g表面带有活化羧基的聚乳酸微球,反应2h后进行洗涤、冻干,得到改性聚乳酸微球;
S5.称取0.36g改性聚乳酸微球加入到2mL含1.7wt%透明质酸钠(特性粘度为22dL/g)的超纯水中,得到改性聚乳酸微球-透明质酸混合凝胶。
所述聚乳酸微球的制备方法包括如下步骤:
S1.将3.0g聚乳酸(特性粘度为1.12dL/g)溶于60mL二氯甲烷中,得到油相;
S2.将6g聚乙烯醇溶于600mL水中,得到水相;
S3.将水相加入油相中1500rpm进行搅拌乳化5h,除去有机溶剂,用乙醇的质量分数为10%的乙醇水溶液洗涤3次,冻干后得到聚乳酸微球。
所述冻干的程序为:
第一梯度:温度设置为-40℃,冻干时间设置为5h;
第二梯度:温度设置为-25℃,冻干时间设置为5h;
第三梯度:温度设置为25℃,冻干时间设置为5h;
第四梯度:温度设置为40℃,冻干时间设置为9h;
各梯度间升温速率为1℃/min。
本实施例所采用的原料来源均与发明内容中优选来源相同。
实施例2
改性聚乳酸微球-透明质酸混合凝胶的制备方法,具体实施方式同实施例1,不同之处在于,所述制备方法包括如下步骤:
S1.制备聚乳酸微球;
S2.取1g聚乳酸微球,用10mL质量浓度0.5%的氢氧化钠水溶液在室温25℃下浸泡3h,然后离心,用去离子水洗涤3次,得到表面带有羧基的聚乳酸微球;
S3.取2g DMTMM(4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐)加入10mL的磷酸盐缓冲液(PBS)中,溶解后调节pH至4.5±0.5,再加入0.6g表面带有羧基的聚乳酸微球,在45℃中反应2h,然后离心、去离子水洗涤2次,得到表面带有活化羧基的聚乳酸微球;
S4.将0.2g烟酰胺(购自国药公司)溶于10mL PBS缓冲液中,PBS的pH为6,待烟酰胺完全溶解后,加入0.4g表面带有活化羧基的聚乳酸微球,反应2h后进行洗涤、冻干,得到改性聚乳酸微球;
S5.称取0.2g改性聚乳酸微球加入到2mL含1.7wt%透明质酸钠(特性粘度为22dL/g)的磷酸盐缓冲溶液(pH=7.4)中,得到改性聚乳酸微球-透明质酸混合凝胶。
所述聚乳酸微球的制备方法包括如下步骤:
S1.将2.5g聚乳酸(特性粘度为1.51dL/g)溶于50mL二氯甲烷中,得到油相;
S2.将5g聚乙烯醇溶于500mL水中,得到水相;
S3.将水相加入油相中1500rpm进行搅拌乳化5h,除去有机溶剂,用乙醇的质量分数为10%的乙醇水溶液洗涤3次,冻干后得到聚乳酸微球。
实施例3
改性聚乳酸微球-透明质酸混合凝胶的制备方法,具体实施方式同实施例1,不同之处在于,所述制备方法包括如下步骤:
S1.制备聚乳酸微球;
S2.取1.1g聚乳酸微球,用10mL质量浓度1%的氢氧化钠水溶液在室温25℃下浸泡过夜,然后离心,用去离子水洗涤3次,得到表面带有羧基的聚乳酸微球;
S3.取1g DMTMM(4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐)加入10mL的磷酸盐缓冲液(PBS)中,溶解后调节pH至4.5±0.5,再加入0.8g表面带有羧基的聚乳酸微球,在45℃中反应2h,然后离心、去离子水洗涤2次,得到表面带有活化羧基的聚乳酸微球;
S4.将0.1g烟酰胺(购自国药公司)溶于10mL PBS缓冲液中,PBS的pH为6,待烟酰胺完全溶解后,加入0.6g表面带有活化羧基的聚乳酸微球,反应2h后进行洗涤、冻干,得到改性聚乳酸微球;
S5.称取0.36g改性聚乳酸微球加入到2mL含1.7wt%透明质酸钠(特性粘度为15dL/g)的磷酸盐缓冲溶液(pH=7.4)中,得到改性聚乳酸微球-透明质酸混合凝胶。
所述聚乳酸微球的制备方法包括如下步骤:
S1.将3g聚乳酸(特性粘度为1.67dL/g)溶于60mL二氯甲烷中,得到油相;
S2.将6g聚乙烯醇溶于600mL水中,得到水相;
S3.将水相加入油相中1500rpm进行搅拌乳化5h,除去有机溶剂,用乙醇的质量分数为10%的乙醇水溶液洗涤3次,冻干后得到聚乳酸微球。
实施例4
改性聚乳酸微球-透明质酸混合凝胶的制备方法,具体实施方式同实施例1,不同之处在于,所述制备方法包括如下步骤:
S1.制备聚乳酸微球;
S2.取1g聚乳酸微球,用10mL质量浓度0.5%的氢氧化钠水溶液在室温25℃下浸泡3h,然后离心,用去离子水洗涤3次,得到表面带有羧基的聚乳酸微球;
S3.取1g DMTMM(4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐)加入10mL的磷酸盐缓冲液(PBS)中,溶解后调节pH至4.5±0.5,再加入0.6g表面带有羧基的聚乳酸微球,在45℃中反应2h,然后离心、去离子水洗涤2次,得到表面带有活化羧基的聚乳酸微球;
S4.将0.1g烟酰胺(购自国药公司)溶于10mL PBS缓冲液中,PBS的pH为6,待烟酰胺完全溶解后,加入0.4g表面带有活化羧基的聚乳酸微球,反应2h后进行洗涤、冻干,得到改性聚乳酸微球;
S5.称取0.36g改性聚乳酸微球加入到2mL含1.7wt%透明质酸钠(特性粘度为15dL/g)的磷酸盐缓冲溶液(pH=7.0)中,得到改性聚乳酸微球-透明质酸混合凝胶。
所述聚乳酸微球的制备方法包括如下步骤:
S1.将5g聚乳酸(特性粘度为1.51dL/g)溶于100mL二氯甲烷中,得到油相;
S2.将10g聚乙烯醇溶于1000mL水中,得到水相;
S3.将水相加入油相中1500rpm进行搅拌乳化5h,除去有机溶剂,用乙醇的质量分数为10%的乙醇水溶液洗涤3次,冻干后得到聚乳酸微球。
对比例1
聚乳酸微球-透明质酸混合凝胶的制备方法,所述制备方法包括如下步骤:
S1.制备聚乳酸微球;
S2.称取0.36g聚乳酸微球,加入到2mL含1.5%透明质酸钠(特性粘度为22dL/g)的磷酸盐缓冲溶液(pH=7.4)中,得到聚乳酸微球和透明质酸混合凝胶。
聚乳酸微球的制备方法:
S1.将3g聚乳酸(特性粘度为1.671dL/g)溶于60mL二氯甲烷中,得到油相;
S2.将6g聚乙烯醇溶于600mL水中,得到水相;
S3.将水相加入油相中1500rpm进行搅拌乳化5h,除去有机溶剂,用乙醇的质量分数为10%的乙醇水溶液洗涤3次,冻干后得到聚乳酸微球。
性能测试
1.形貌测试:采用WD300-48LT生物显微镜观察实施例1~4和对比例1制备得到的聚乳酸微球形貌,结果计入表1,形貌图见图1-2。
2.粒径测试:采用粒度及粒度分布测定法测定实施例1~4和对比例1-3制备得到的微球的粒径。具体方法为:选择0.5%质量浓度的吐温80为分散剂,分别取30mg实施例1~4和对比例1-3制备得到的微球冻干粉末,分别加入2mL分散剂中,待样品分散均匀后,通过粒度激光分光光度仪测定其粒径,平行测量3次,测量结果取平均值,计入表1。
3.烟酰胺接枝率测试:分别称取实施例1~4制备得到的微球各50mg,将称取的微球分别放入100mL的容量瓶中,加入20mL乙腈,超声分散,用超纯水进行定容,超声萃取30min,然后分别用移液枪移取10mL上清液,用紫外可见分光光度计测定各上清液中烟酰胺的浓度。计算接枝率,计算公式为:
接枝率=(微球内的药物含量/微球的总重量)×100%;结果计入表1。
4.改性微球体外溶出测试:分别称取50mg实施例1~2制备得到的微球,将称取的微球分别放入10mL PBS(pH=7.4)中进行药物释放实验,在1h、3h、1d、3d、7d时分别用移液枪移取10mL上清液,同时补回10mL PBS(pH=7.4),用紫外可见分光光度计测定各上清液中烟酰胺的浓度,各时间点后的累计溶出率(%)=100%×(C1+C 2+…C n)×V/L,其中Cn为各时间点取出后的烟酰胺浓度,V为各时间点的固定取样体积(因为是全部取出,再补充同样体积的介质,所以取样体积等同于溶出介质体积),L为烟酰胺接枝的的总含量。累计溶出率结果计入表2,释放曲线见图3。
表1
表2
效果评价
1、分散性评价
相同质量的实施例2和对比例1制备的微球冻干粉在水溶液中的分散性比较,实施例2在水相体系中分散性较佳,1min内可实现完全分散,具体结果见表3。
表3
实施例2 | 对比例1 | |
混悬时间 | 30s | 5min |
改性后的微球具有快速分散的优势,微球采用烟酰胺改性后,改性后的微球具有良好的亲水性,加入到透明质酸钠中会快速分散,无团聚现象。
2、通针性评价
采用1mL针管,26G针头,分别对实施例1-4和对比例1制备的混合凝胶进行通针性测试,测试发现,对比例在注射过程中易堵针头,烟酰胺改性的微球和透明质酸钠复合后,通针性优于对比例。
3、湿热灭菌稳定性评价
分别称取0.4g的实施例2和对比例1的微球冻干粉到西林瓶,加入2g的超纯水、不同pH的PBS,压盖,放入灭菌高压锅中湿热灭菌,温度设置为121℃,时间为15min。
灭菌后,取出观察样品的外观、形貌、粒径及pH值的测定。
微球理化性质:经过灭菌前后对比,微球的外观、形貌和粒径均未发生变化,微球的粒径未发生变化。
溶液pH值:对实施例1-4和对比例1所得的混合凝胶进行pH测试。表4实施例1-4和对比例所得的混合凝胶的pH值。
表4
溶液中pH测试发现,微球和不同的透明质酸钠溶液混合灭菌,pH变化不同,当微球分散在pH=7.0和pH=7.4的PBS中时,pH值变化不大。
结果表明,本发明的改性聚乳酸微球和透明质酸溶液(pH为7.0和pH为7.4的磷酸盐缓冲溶液)混合凝胶,具有良好的分散性和优异的稳定性,改性微球形态均一,烟酰胺体外释放平稳,混合凝胶通针性较佳,可用于填充类医美领域。
Claims (10)
1.改性聚乳酸微球-透明质酸混合凝胶的制备方法,其特征在于,所述制备方法包括如下步骤:
S1.制备聚乳酸微球;
S2.对聚乳酸微球进行改性,得到表面带有羧基的聚乳酸微球;
S3.将表面带有羧基的聚乳酸微球进行活化反应,得到表面带有活化羧基的聚乳酸微球;
S4.将表面带有活化羧基的聚乳酸微球接枝烟酰胺,得到改性聚乳酸微球;
S5.将改性聚乳酸微球与透明质酸钠溶液混合,得到改性聚乳酸微球-透明质酸混合凝胶。
2.根据权利要求1所述的制备方法,其特征在于,所述聚乳酸微球的制备方法包括如下步骤:
S1.将聚乳酸溶于有机溶剂中,得到油相;
S2.将表面活性剂溶于水中,得到水相;
S3.将水相加入油相中进行搅拌乳化,除去有机溶剂,洗涤、干燥后得到聚乳酸微球。
3.根据权利要求2所述的制备方法,其特征在于,所述聚乳酸的特性粘度为1.0-2.0dL/g。
4.根据权利要求3所述的制备方法,其特征在于,所述聚乳酸微球的粒径为20-50μm。
5.根据权利要求1所述的制备方法,其特征在于,所述透明质酸钠的特性粘度为15-25dL/g,透明质酸钠的质量浓度为1%-5%。
6.根据权利要求1所述的制备方法,其特征在于,所述S3中采用EDC、NHS、DMTMM中的至少一种羧基活化剂进行活化反应。
7.根据权利要求1所述的制备方法,其特征在于,所述S4中表面带有活化羧基的聚乳酸微球与烟酰胺的质量比为100:(0.1-5)。
8.根据权利要求1所述的制备方法,其特征在于,所述S5中改性聚乳酸微球与透明质酸钠的质量比为(5-25):100。
9.改性聚乳酸微球-透明质酸混合凝胶,其特征在于,根据权利要求1-8任一项所述的制备方法制得。
10.权利要求9所述的混合凝胶在制备注射用美容产品中的应用。
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