CN114209887A - 一种含可控降解聚酯微球的注射用凝胶 - Google Patents

一种含可控降解聚酯微球的注射用凝胶 Download PDF

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CN114209887A
CN114209887A CN202110972080.7A CN202110972080A CN114209887A CN 114209887 A CN114209887 A CN 114209887A CN 202110972080 A CN202110972080 A CN 202110972080A CN 114209887 A CN114209887 A CN 114209887A
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microspheres
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CN114209887B (zh
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李�杰
付洋
周翠英
伍飞飞
马矢徒
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Hangzhou Singclean Medical Products Co Ltd
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Abstract

本发明提供了一种含可控降解聚酯微球的注射用凝胶，由交联透明质酸钠凝胶、未交联透明质酸钠凝胶、混合脂肪酸甘油酯包裹的聚酯微球和平衡盐溶液组成。依靠混合脂肪酸甘油酯的包裹、疏水作用将聚酯微球与水分隔，本发明解决了聚酯材料在凝胶中易降解问题。同时，混合脂肪酸甘油酯具有的低熔点特性(熔点33℃～39℃)，在产品注射进人体后，混合脂肪酸甘油酯在人体体温作用下熔融、分离，释放被包裹的聚酯微球，使微球可以在人体内降解，实现可控降解特性。本发明所制备的注射用凝胶，未使用时所含的微球能够在常温下无降解或微降解保存，注射使用后填充皱纹区域并释放微球，随着微球在体内降解、刺激皮下胶原生长，达到长效改善皮肤皱纹的效果。

Description

一种含可控降解聚酯微球的注射用凝胶
技术领域：
本发明涉及一种含可控降解聚酯微球的注射用凝胶，属于医学美容材料技术领域。
背景技术：
随着医疗美容行业的发展，用于修复面部皱纹的注射材料越来越受到广泛关注。目前，这些注射材料主要有两大类，一类是以交联透明质酸钠凝胶、胶原蛋白凝胶为代表的填充产品，主要作用机理为皮下填充，注射后使皮下缺陷处得到膨胀填充，抚平皱纹；另一类是以聚左旋乳酸(PLLA)微球为代表的胶原刺激产品，例如美国的SculptraTM，这类产品在降解过程中通过刺激宿主的免疫反应，吸引皮下大量的巨噬细胞和其他免疫细胞，导致成纤维细胞的增殖及其肌成纤维细胞的分化，合成大量的胶原蛋白，从而恢复皮下容量、修复皱纹。
填充类产品注射后可以即时产生美容效果，但受体内酶作用而易降解，因而持续时间短；PLLA微球类产品不受酶影响，在人体内主要通过逐步水解而降解，所以有较长的维持时间，但其作用效果需逐步产生(通常需1～3个月)，无法满足求美者即时改善的需求。因此，两类材料各有优劣，单一材料不能完全满足求美者的需求。
中国专利CN104258470A公开了一种注射用聚乳酸微球和交联透明质酸混合凝胶及其制备方法，将聚乳酸微球与交联透明质酸凝胶混合，得到的混合凝胶能够即时填充美容，同时维持时间较单纯的透明质酸钠凝胶要长。但是，研究发现，PLLA微球在含水环境下不能长时间稳定存在，储存超过1个月时就可能发生微球结构坍塌或微粒黏连等问题。
发明内容：
针对上述现有技术的缺陷，本发明提出一种含可控降解聚酯微球的注射用凝胶。本发明所述的注射用凝胶在未使用时凝胶中的微球能够在常温下无降解或微降解，皮下注射使用后可在人体体温作用下释放聚酯微球，加快微球在体内降解速率。为此，本发明采用以下技术方案：
一种含可控降解聚酯微球的注射用凝胶，其特征在于，包括交联透明质酸钠凝胶、未交联透明质酸钠凝胶和混合脂肪酸甘油酯包裹的聚酯微球以及平衡盐溶液。
未使用时，所述注射用凝胶中的微球能够在常温下保持稳定，无降解或微降解，皮下注射使用后可在人体体温作用下释放聚酯微球，加快微球在体内降解速率。
本发明所述的可控降解特性是通过如下原理实现的：
所述注射用凝胶在制备时，先制备聚酯微球混合脂肪酸甘油酯包裹的聚酯微球，命名为第一微球，然后制备交联透明质酸钠凝胶包裹在第一微球之外的凝胶块，再加入未交联透明质酸钠凝胶，搅拌分散均匀，获得所述注射用凝胶。
进一步地，聚酯微球混合脂肪酸甘油酯包裹的聚酯微球的制备步骤包括：
1)将混合脂肪酸甘油酯溶于溶剂中，配置成0.5％～6％的溶液；所述溶剂优选易挥发的良溶剂，比如石油醚、乙醚、三氯甲烷等；
2)搅拌下，将聚酯微球加入到所述的溶液中，使微球均匀分散；
3)抽滤，将微球与溶液分离，微球放入常温鼓风箱内干燥，即得混合脂肪酸甘油酯包裹的聚酯微球。
其中，所述的混合脂肪酸甘油酯包括34型、36型和38型(熔点分别为： 33～35℃、35～37℃和37～39℃)的一种或多种。优选的可使用38型，以提高产品常温下稳定性。
所述的聚酯微球包括聚左旋乳酸微球、聚己内酯微球、乙交酯丙交酯共聚物微球和聚对二氧环己酮微球的一种或多种，其粒径范围为3～65μm。依靠混合脂肪酸甘油酯的包裹、疏水作用将聚酯微球与水分隔，本发明解决了聚酯材料在凝胶中易降解、难保存的问题。同时，混合脂肪酸甘油酯具有的低熔点特性(熔点 33℃～39℃)，在凝胶注射进人体后，混合脂肪酸甘油酯在人体体温作用下熔融、分离，释放被包裹的聚酯微球，使微球可以在人体内降解，实现可控降解特性。
进一步地，所述含可控降解聚酯微球的注射用凝胶由以下步骤制备，该方法操作简单、易于实施：
S1：制备混合脂肪酸甘油酯包裹的聚酯微球；
S2：将透明质酸钠干粉溶于纯化水中，然后向溶液中加入交联剂搅拌混匀，再加入混合脂肪酸甘油酯包裹的聚酯微球，搅拌均匀后反应2～18h形成含微球的交联透明质酸钠凝胶；所述交联剂可采用二乙烯基砜或丁二醇二缩水甘油醚；
S3：将上述含微球的交联透明质酸钠凝胶破碎成1～2cm3的小凝胶块，然后用平衡盐溶液浸泡、透析；
S4：用分散机均质透析后的凝胶，然后加入未交联透明质酸钠凝胶，搅拌分散均匀；
S5：灌装、灭菌，得成品。
所述未交联透明质酸钠凝胶由透明质酸钠干粉溶于平衡盐溶液所制。
优选地：
所述的混合脂肪酸甘油酯包裹的聚酯微球投料量占产品总质量的3％～30％；
透明质酸钠以干粉计，投料量占产品总质量的1.2％～2.5％；
所述的平衡盐溶液为渗透压为200～400mOsmol/L、pH为6.5～7.5的氯化钠溶液或磷酸盐缓冲溶液。
本发明的含可控降解聚酯微球的注射用凝胶可改善人体皮肤的皮下容量，修复皮肤的皱纹、褶皱、疤痕和老化。本发明提供的含可控降解聚酯微球的注射用凝胶，在注射植入后在交联透明质酸钠凝胶的作用下可即刻填充皮下组织、抚平皱纹；3～6月后，在交联透明质酸钠凝胶逐渐被降解吸收的同时，逐步降解聚酯的微球可刺激皮下免疫反应，使自体生成胶原蛋白，继续填补并维持12～20个月皮下容量。
综上，本发明具有以下优异性：
(1)本发明制备了一种混合脂肪酸甘油酯包裹的聚酯微球，依靠混合脂肪酸甘油酯的包裹、疏水作用将聚酯微球与水分隔，使该微球常温下在凝胶内无降解或微降解，解决了聚酯材料在凝胶中易降解、难保存的问题。
(2)本发明提供的产品在注射进人体后，混合脂肪酸甘油酯在人体体温作用下熔融、分离，释放被包裹的聚酯微球，使微球可以在人体内降解，实现可控降解特性。
(3)本发明提供的产品在注射植入后可即刻填充、抚平皱纹，随后逐步降解聚酯的微球可刺激皮下免疫反应，使自体生成胶原蛋白，继续填补并维持 12～20个月皮下容量，实现较长时间的美容效果。
附图说明
图1和图2为本发明实施例1所制备的混合脂肪酸甘油酯(38型)包裹的 PLLA微球与未包裹的PLLA微球的扫描电镜对比图；其中：图1混合脂肪酸甘油酯(38型)包裹的PLLA微球，图2未包裹的PLLA微球。
图3为本发明实施例1所制备产品和对照产品在25℃下PLLA微球的降解曲线对比图。
图4为本发明实施例1所制备产品在不同储存温度条件下PLLA微球的降解曲线图。
具体实施方式：
以下通过介绍本发明的实施例，以进一步阐明本发明实质性特点和显著的进步，但本发明决非限于实施例。
实施例1：
S1：制备混合脂肪酸甘油酯包裹的PLLA微球：将38型混合脂肪酸甘油酯溶于石油醚中配置成2％的溶液；搅拌下，将PLLA微球加入到溶液中，使微球均匀分散；抽滤，将微球与溶液分离，微球放入常温鼓风箱内直至干燥，即得混合脂肪酸甘油酯包裹的PLLA微球；
S2：将10.0g透明质酸钠(干粉)溶于100mL纯化水中，然后向溶液中加入120μL交联剂二乙烯基砜搅拌混匀，再加入30.5g混合脂肪酸甘油酯包裹的 PLLA微球，搅拌均匀后反应2～18h形成含微球的交联透明质酸钠凝胶；
S3：将上述凝胶破碎成1～2cm3的小凝胶块，然后用平衡盐溶液浸泡、透析；
S4：用分散机均质透析后的凝胶，然后加入其质量10％的未交联透明质酸钠凝胶(由透明质酸钠干粉溶于平衡盐溶液所制)，搅拌分散均匀；
S5：灌装、灭菌，得成品。
同步骤S2～S5制备含未包裹混合脂肪酸甘油酯的PLLA微球的凝胶，作为对照组。
图1显示了混合脂肪酸甘油酯(38型)包裹的PLLA微球的微观形貌，与图2未包裹的微球相比，经步骤S1处理后，微球的光滑表面明显附着了一层较为粗糙的混合脂肪酸甘油酯。
图3显示的是常温(25℃)下含混合脂肪酸甘油酯包裹的PLLA微球的凝胶 (本实施例)与含未包裹混合脂肪酸甘油酯的PLLA微球的凝胶(对照组)中 PLLA微球的降解速率对比，通过玻璃酸酶解离凝胶，提取出两组凝胶中的PLLA 微球，然后再试用乌氏粘度计测量微球的特性粘度。从图可看出，在常温下，本实施例凝胶中的PLLA微球在8周时间内仅有少许特性粘度下降，说明PLLA分子降解很少；而对照组凝胶中的PLLA微球，在保存2周后降解明显，第8周时已降解至低特性粘度状态。
图4显示了所制备凝胶在25℃保存4周，然后37℃保存至12周的降解曲线图。从图可看出，在常温25℃储存条件下，PLLA微球在凝胶中4周内几乎未降解；而当温度升至37℃下，降解明显，体现了该样品中PLLA微球的可控降解特性。
实施例2：
S1：制备混合脂肪酸甘油酯包裹的聚己内酯(PCL)微球：将36型混合脂肪酸甘油酯溶于三氯甲烷中配置成6％的溶液；搅拌下，将PCL微球加入到溶液中，使微球均匀分散；抽滤，将微球与溶液分离，微球放入常温鼓风箱内直至干燥，即得混合脂肪酸甘油酯包裹的PCL微球；
S2：将10.0g透明质酸钠(干粉)溶于100mL纯化水中，然后向溶液中加入120μL交联剂二乙烯基砜搅拌混匀，再加入11.4g混合脂肪酸甘油酯包裹的 PCL微球，搅拌均匀后反应2～18h形成含微球的交联透明质酸钠凝胶；
S3：将上述凝胶破碎成1～2cm3的小凝胶块，然后用平衡盐溶液浸泡、透析；
S4：用分散机均质透析后的凝胶，然后加入其质量10％的未交联透明质酸钠凝胶(由透明质酸钠干粉溶于平衡盐溶液所制)，搅拌分散均匀；
S5：灌装、灭菌，得成品。
实施例3：
S1：制备混合脂肪酸甘油酯包裹的PLLA微球：将37型混合脂肪酸甘油酯溶于乙醚中配置成0.5％的溶液；搅拌下，将PLLA微球加入到溶液中，使微球均匀分散；抽滤，将微球与溶液分离，微球放入常温鼓风箱内直至干燥，即得混合脂肪酸甘油酯包裹的PLLA微球；
S2：将10.0g透明质酸钠(干粉)溶于100mL纯化水中，然后向溶液中加入120μL交联剂二乙烯基砜搅拌混匀，再加入51.0g混合脂肪酸甘油酯包裹的 PLLA微球，搅拌均匀后反应2～18h形成含微球的交联透明质酸钠凝胶；
S3：将上述凝胶破碎成1～2cm3的小凝胶块，然后用平衡盐溶液浸泡、透析；
S4：用分散机均质透析后的凝胶，然后加入其质量10％的未交联透明质酸钠凝胶(由透明质酸钠干粉溶于平衡盐溶液所制)，搅拌分散均匀；
S5：灌装、灭菌，得成品。
本领域的技术人员容易理解，以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

1.一种含可控降解聚酯微球的注射用凝胶，其特征在于，包括交联透明质酸钠凝胶、未交联透明质酸钠凝胶和混合脂肪酸甘油酯包裹的聚酯微球以及平衡盐溶液。
2.如权利要求1所述的一种含可控降解聚酯微球的注射用凝胶，其特征在于，未使用时，所述注射用凝胶中的微球能够在常温下保持稳定，无降解或微降解，皮下注射使用后可在人体体温作用下释放聚酯微球，加快微球在体内降解速率。
3.根据权利要求1或2所述的一种含可控降解聚酯微球的注射用凝胶，其特征在于，所述注射用凝胶制备时，先制备聚酯微球混合脂肪酸甘油酯包裹的聚酯微球，命名为第一微球，然后制备交联透明质酸钠凝胶包裹在第一微球之外的凝胶块，再加入未交联透明质酸钠凝胶，搅拌分散均匀，获得所述注射用凝胶。
4.根据权利要求3所述的一种含可控降解聚酯微球的注射用凝胶，其特征在于，聚酯微球混合脂肪酸甘油酯包裹的聚酯微球的制备步骤包括：
1)将混合脂肪酸甘油酯溶于溶剂中配置成0.5％～6％的溶液；
2)搅拌下，将聚酯微球加入到所述的溶液中，使微球均匀分散；
3)抽滤，将微球与溶液分离，微球放入常温鼓风箱内干燥，即得混合脂肪酸甘油酯包裹的聚酯微球。
5.根据权利要求1或2所述的一种含可控降解聚酯微球的注射用凝胶，其特征在于，所述的混合脂肪酸甘油酯包括34型、36型和38型的一种或多种。
6.根据权利要求1或2或3或4或5所述的一种含可控降解聚酯微球的注射用凝胶，其特征在于，所述的聚酯微球包括聚左旋乳酸微球、聚己内酯微球、乙交酯丙交酯共聚物微球和聚对二氧环己酮微球的一种或多种，其粒径范围为3～65μm。
7.根据权利要求3所述的一种含可控降解聚酯微球的注射用凝胶，其特征在于，由以下步骤制备：
S1：制备混合脂肪酸甘油酯包裹的聚酯微球；
S2：将透明质酸钠干粉溶于纯化水中，然后向溶液中加入交联剂搅拌混匀，再加入混合脂肪酸甘油酯包裹的聚酯微球，搅拌均匀后反应2～18h形成含微球的交联透明质酸钠凝胶；
S3：将上述含微球的交联透明质酸钠凝胶破碎成1～2cm3的小凝胶块，然后用平衡盐溶液浸泡、透析；
S4：用分散机均质透析后的凝胶，然后加入未交联透明质酸钠凝胶，搅拌分散均匀；
S5：灌装、灭菌，得成品。
8.根据权利要求6所述的一种含可控降解聚酯微球的注射用凝胶，其特征在于，所述的混合脂肪酸甘油酯包裹的聚酯微球投料量占产品总质量的3％～30％；所述的透明质酸钠以干粉计，投料量占产品总质量的1.2％～2.5％；
所述的平衡盐溶液为渗透压为200～400mOsmol/L、pH为6.5～7.5的氯化钠溶液或磷酸盐缓冲溶液。
9.根据权利要求6所述的一种含可控降解聚酯微球的注射用凝胶，其特征在于，未交联透明质酸钠凝胶由透明质酸钠干粉溶于平衡盐溶液所制。
10.根据权利要求1或2所述的一种含可控降解聚酯微球的注射用凝胶，其特征在于，可改善人体皮肤的皮下容量，修复皮肤的皱纹、褶皱、疤痕和老化。
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