CN113041212A - 一种自组装凝胶祛痘微针贴片及其制备方法和应用 - Google Patents
一种自组装凝胶祛痘微针贴片及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于医用化妆品领域,涉及一种祛痘微针,特别是指一种自组装凝胶祛痘微针贴片及其制备方法和应用。该制备方法首先利用小分子调节剂和载疏水药物的聚合物胶束,静置自组装制备机械性能优异的壳聚糖‑天然阴离子多糖天然水凝胶。其次,将天然水凝胶采用真空注入法构筑无痛高效、给药可控、兼备抗菌修复功能的祛痘微针贴片。该自组装凝胶不仅避免了化学交联剂的使用,而且提高了疏水药物的利用率。构筑的凝胶祛痘微针作用皮肤后,针体和基底不仅可以实现快速脱离,还可以对疏水药物进行可控释放,避免了针体再次拔出对伤口造成的风险。
Description
技术领域
本发明属于医用化妆品领域,涉及一种祛痘针,特别是指一种自组装凝胶祛痘微针贴片及其的制备方法和应用。
背景技术
痤疮是一种好发于青春期并主要累及面部的毛囊皮脂腺的慢性炎症性皮肤病,其发病主要与性激素水平、皮脂腺大量分泌、痤疮丙酸杆菌增殖,毛囊皮脂腺导管的角化异常及炎症等因素相关。痤疮不仅会影响患者面貌,还会给患者身心健康带来较大影响。
目前,针对痤疮的治疗有多种手段,可分为局部治疗、系统治疗以及其他方式的治疗。市面上治疗痤疮的产品大多是通过凝胶或者乳液剂型利用传统涂抹方式使用,由于其透皮给药渗透性差,患者长期使用会出现刺激红肿及瘢痕或黑色素沉淀,严重的甚至会引起皮肤过敏。微针作为一种新型经皮给药手段,集注射给药和传统透皮给药的双重优势,起到快速起效、无痛无痕、及时终止给药的效果而引起广泛关注。
目前,微针按照经皮给药的方式主要分为四类:用于皮肤预处理的固体微针、涂层微针、空心微针和可溶性微针。固体微针由于硅材料易断裂的特性,实际应用中容易残留在皮肤内部造成隐患,因此对于硅微针的研究已经逐渐减少。而涂层微针的载药量受制于微针针体表面积的影响,通常载药量较小,极大得限制了它的应用范围。中空微针结构较为复杂,对制作的工艺要求高,从而增加了制作成本和难度。因此越来越多的人开始致力于可溶性微针的研究,可溶性微针是指有效药物成分随着可溶性聚合物基底材料直接溶解在皮肤中并释放的一类微针,与其他类型微针相比,具有给药效率高、安全性好、制备简单等优点。
专利CN107375111A公开了一种可溶性祛痘微针,构筑微针的高分子材料为质量浓度15%~20%的透明质酸,由于透明质酸溶液具有很高的粘稠度,既不利于在微针模板中成型,而且可溶性微针机械强度较弱。另外,祛痘有效成分过多,提取工艺复杂,不利于工业化生产。专利CN108607157A公开了一种可溶性交联-非交联透明质酸复合微针,解决了目前美容营养物质由于皮肤表皮中角质层的屏障作用导致的物质透皮吸收难以及吸收效率低造成物质浪费大等关键问题,但是其中使用的化学交联剂存在一定的安全问题。专利CN105148322A公开了一种在37oC下利用简单共混的形式制备可注射水凝胶的方法,水凝胶包括壳聚糖、透明质酸和β-甘油磷酸钠,增加了水凝胶保湿、抑菌的产品效果,但是其可注射水凝胶机械强度很弱,不足以构筑机械性能优异的可溶性微针。专利CN 104707241A中公开了一种两段式微针阵列及其制备方法。该专利中微针下段基座采用生物可降解不溶于水的高分子材料,上段尖端用以承载药物,制备材料为生物可降解的可溶性高分子材料。该微针阵列能够有效穿刺表皮,实现载药段与针体快速分离。但是该专利中制备的微针,载入皮内的针尖为可溶性高分子材料,基本不具有缓释功能。
综上所述,由于可溶性微针多为天然高分子材料,其机械性能的强弱直接导致微针刺入皮肤的能力。其次由于基底材料的溶解可能造成药物快速释放,达不到可控释药的目的,同时制备包埋药物的可溶性微针的前提条件要求药物具有很好的水溶性,所以在水中溶解度低的疏水药物制成的可溶性微针中药物含量极低,不能满足实际应用的需求。因此,制备一种机械性能优异、可控释药、可以包埋疏水药物并且实现针体和基底快速分离的凝胶微针在化妆品领域具有重要的意义。
发明内容
为解决上述技术问题,本发明提出一种自组装凝胶祛痘微针贴片及其的制备方法和应用。
本发明的技术方案是这样实现的:
一种自组装凝胶祛痘微针贴片的制备方法,步骤如下:
(1)将壳聚糖溶于醋酸溶液中,室温搅拌得壳聚糖醋酸溶液,将天然阴离子聚合物粉末溶于蒸馏水中,配制天然阴离子聚合物水溶液;
(2)将两亲性三嵌段共聚物与疏水药物按比例溶解于有机溶剂中,形成混合溶液,然后旋蒸去除有机溶剂,得疏水药物薄膜,疏水药物薄膜经溶胀水化、冷冻干燥后得包埋疏水药物的聚合物胶束;
(3)向步骤(1)的壳聚糖醋酸溶液中加入小分子调节剂,搅拌至溶液由粘稠变澄清透明,再加入步骤(1)的天然阴离子聚合物水溶液,搅拌至至溶液由澄清变浑浊,最后加入步骤(2)的聚合物胶束,搅拌至溶液由澄清变浑浊,静置自组装得高强度的天然水凝胶;
(4)将步骤(3)的天然水凝胶真空注入微针模板,使得针体和基底全部注满,待微针自然干燥脱模即得自组装水凝胶祛痘微针贴片。
所述步骤(1)中壳聚糖脱乙酰度>90%,醋酸溶液的质量浓度为1wt%,壳聚糖在醋酸溶液中的浓度为2wt%-3wt%。
所述天然阴离子聚合物为透明质酸钠、藻酸钠、果胶、羧甲基纤维素钠、黄原胶、卡拉胶、聚γ-谷氨酸钠中的一种或多种,其平均分子量达到100kDa-2000kDa,浓度为0.8wt%-1.2wt%。
所述步骤(2)中两亲性三嵌段共聚物为泊洛沙姆188、泊洛沙姆237、泊洛沙姆338、普朗尼克F127中的一种或几种;疏水药物为阿达帕林、他扎罗汀或水杨酸中的任一种;两亲性三嵌段共聚物与疏水药物的质量比为(100-300):5;有机溶剂为四氢呋喃或二甲基亚砜。
所述溶胀水化的操作为将疏水药物薄膜于45-65℃水浴溶胀15min,然后加入等温的蒸馏水进行水化得胶束溶液,再过0.22μm的过滤膜,过滤物进行后续操作。
所述步骤(3)中小分子调节剂为α-甘油磷酸钠、β-甘油磷酸钠及它们的水合物中的一种或几种;所述天然水凝胶中壳聚糖、小分子调节剂、天然阴离子聚合物、聚合物胶束的质量比为((3-5):(0.3-1.5):(3-5):(0.1-0.3);静置自组装的时间为10-15h。
所述步骤(4)中真空注入的操作为在-0.8kPa、37℃的真空作用下注入25min,去除基底气泡后反复重新注入,直至气泡不再出现。
所述微针的结构为四棱锥形、圆锥体形或蚊子针形,微针针体高度为300-800μm,微针针体底面边长为100-500μm,针尖直径为5-10μm。
上述的方法制备的自组装凝胶祛痘微针贴片。
上述的自组装凝胶祛痘微针贴片在制备治疗痤疮的药剂中的应用。
本发明具有以下有益效果:
(1)本发明制备的自组装壳聚糖-天然阴离子聚合物凝胶在静置自组装过程中,首先通过小分子调节剂的弱碱性成功夺取壳聚糖NH3+的质子,减弱其链间的静电斥力及氢键作用,从而增加壳聚糖本身的溶解性,其次天然阴离子聚合物的加入,会与阳离子壳聚糖发生强的静电相互作用,这时候适量的小分子调节剂可以通过中和壳聚糖链上的NH3+,使得壳聚糖和天然阴离子聚合物之间氢键作用增强,静电相互作用减弱从而避免聚沉现象,从而实现水凝胶机械性能由弱到强的过程。最后通过加入载药聚合物胶束,进一步形成巨型交联点增强水凝胶的机械性能,也表现出出色的能量耗散能力。制备的高强度水凝胶不仅避免了化学交联剂的使用,而且通过聚合物胶束复合提高了疏水药物的利用率。
(2)本发明制备的自组装凝胶祛痘微针采用生物相容性优异的天然高分子,当微针针体刺入皮肤时,壳聚糖和天然阴离子聚合物本身可降解和可溶性实现微针针体和基底快速脱离,避免了针体拔出对皮肤的二次损伤。进一步由于壳聚糖自身酸响应和聚合物胶束在体液中的稀释裂解最终实现在痤疮的炎症偏酸性部位实现pH刺激响应可控释药,避免了药物突然释放造成的局部药物浓度过高引起的皮肤刺激性。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为实施例1纸杯的天然水凝胶的场发射环境扫描电镜图。
图2为实施例1制备的天然水凝胶的拉伸应力-应变曲线。
图3为实施例1制备的天然水凝胶的循环拉伸加载-卸载曲线。
图4为实施例1、2、3制备的水凝胶祛痘微针的扫描电镜图。
图5为对四棱锥水凝胶祛痘微针施加0-500g重量后形变图像。
图6为实施例2制备的水凝胶祛痘微针对金黄色葡萄球菌抗菌情况。
图7为实施例2制备的水凝胶祛痘微针对和痤疮丙酸杆菌的抗菌情况。
图8为实施例3制备的水凝胶和水凝胶祛痘微针在体外的渗透实验。
图9为实施例3制备的水凝胶祛痘微针在猪皮的溶解实验。
图10为实施例3制备的水凝胶在不同pH的释放介质中的药物释放速率图。
具体实施方式
下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有付出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
本实施例的自组装凝胶祛痘微针贴片的制备方法,步骤如下:
(1)称取600mg的壳聚糖粉末溶于29.4g浓度为10mg/mL的醋酸溶液,得到2wt%的壳聚糖醋酸溶液;称取500mg的透明质酸钠粉末溶于49.5g的蒸馏水中,得到1wt%的透明质酸钠水溶液;
(2)称取300mg苯甲醛修饰的三嵌段共聚物普朗尼克F127(BAF127)和5mg阿达帕林(ADP)溶解在6mL的四氢呋喃中,搅拌均匀形成混合透明溶液,将有机溶剂旋转蒸发,制备BAF127-ADP薄膜,将薄膜在55oC水浴中溶胀15min,之后加入同温度的水9mL,搅拌溶解30min,形成澄清的载药胶束,经过0.22μm过滤膜过滤,经过冷冻干燥得到载药胶束粉末。
(3)吸取5g步骤(1)得到的2wt%的壳聚糖醋酸溶液,加入0.3g的β-甘油磷酸钠溶液,室温搅拌10min,之后缓慢滴加5g的1wt%的透明质酸钠水溶液,搅拌30min,加入0.3g的载药胶束粉末于混合溶液中,静置自组装形成载药复合水凝胶。将载药凝胶注入到高度为500μm的四棱锥微针模具中,干燥后脱模制得水凝胶祛痘微针贴片。
本实施例实施的结果如图1、2、3、4、5所示。
将所得的天然水凝胶的形貌进行场发射环境扫描电子显微镜观察,图1为天然水凝胶的微观形貌,可以看出呈现三维网络结构,并且交联密度大。
将所得的天然水凝胶进行万能试验机测试。图2为天然水凝胶的拉伸应力-应变曲线,当达到最大段裂伸长率为1000%时,段裂拉伸强度为0.55MPa。图3为天然水凝胶的循环加载-卸载实验,在整个应变范围内,结果表现出有明显的滞后环,网络结构发生能量耗散,随着加载次数增多,该天然水凝胶表现出良好的抗疲劳性能。
将所得的水凝胶祛痘微针贴片进行形貌观察以及抗压性能测试。图4分别为四棱锥水凝胶祛痘微针的场发射环境扫描电子显微镜图像。将20 g、100 g、200 g 和500 g 的砝码分别放置在微针贴片顶部的平面上,图5为通过场发射电子显微镜观察微针针体的形变情况。
实施例2
本实施例的自组装凝胶祛痘微针贴片的制备方法,步骤如下:
(1)称取900mg的壳聚糖粉末溶于29.1g浓度为10mg/mL的醋酸溶液,得到3wt%的壳聚糖醋酸溶液;称取600mg的透明质酸钠粉末溶于49.4g的蒸馏水中,得到1.2wt%的透明质酸钠水溶液;
(2)称取150mg苯甲醛修饰的三嵌段共聚物普朗尼克F127(BAF127)和5mg阿达帕林(ADP)溶解在4mL的四氢呋喃中,搅拌均匀形成混合透明溶液,将有机溶剂旋转蒸发,制备BAF127-ADP薄膜,将薄膜在55oC水浴中溶胀15min,之后加入同温度的水12mL,搅拌溶解30min,形成澄清的载药胶束,冷冻干燥得到载药胶束粉末。
(3)吸取3g步骤(1)得到的2wt%的壳聚糖醋酸溶液,加入0.6g的30wt%的β-甘油磷酸钠,室温搅拌20min,之后缓慢滴加5g的1wt%的透明质酸钠水溶液,搅拌30min,加入0.1g的载药胶束粉末于混合溶液中,静置自组装形成载药复合水凝胶。将载药凝胶注入到圆锥体微针模具中,干燥后脱模制得水凝胶祛痘微针贴片。
本实施例实施的结果如图6、7所示。
将所得的水凝胶祛痘微针贴片进行金黄色葡萄球菌的抗菌测试。具体为:将活化好的106 CFU的金黄色葡萄球菌取1mL放入微针中进行培养6h,然后取100μL细菌培养液在LB琼脂板上涂布,孵育12h,计录菌落数,计算杀菌率。图6为原始细菌涂板情况和微针抗菌后的细菌涂板情况,可知水凝胶祛痘微针贴片对金黄色葡萄球菌的杀菌率可以达到98%以上。
将所得的水凝胶祛痘微针贴片进行痤疮丙酸杆菌的抗菌测试。具体为:将活化好的106 CFU的痤疮丙酸杆菌球菌取1mL放入微针中进行培养6h,然后取200μL细菌培养液在哥伦比亚血平板上涂布,孵育72h,记录菌落数,计算杀菌率。图7为原始细菌涂板情况和微针抗菌后的细菌涂板情况,可知水凝胶祛痘微针贴片对痤疮丙酸杆菌的杀菌率可以达到96%以上。
实施例3
本实施例的自组装凝胶祛痘微针贴片的制备方法,步骤如下:
(1)称取750mg的壳聚糖粉末溶于29.25g浓度为10mg/mL的醋酸溶液,得到2.5wt%的壳聚糖醋酸溶液;称取500mg的透明质酸钠粉末溶于49.5g的蒸馏水中,得到1wt%的透明质酸钠水溶液;
(2)称取200mg苯甲醛修饰的三嵌段共聚物普朗尼克F127(BAF127)和5mg阿达帕林(ADP)溶解在6mL的二甲亚砜中,搅拌均匀形成混合透明溶液,将有机溶剂旋转蒸发,制备BAF127-ADP薄膜,将薄膜在55oC水浴中溶胀15min,之后加入同温度的水8mL,搅拌溶解30min,形成澄清的载药胶束,冷冻干燥得到载药胶束粉末。
(3)吸取4g步骤(1)得到的2wt%的壳聚糖醋酸溶液,加入0.5g的β-甘油磷酸钠溶液,室温搅拌10min,之后缓慢滴加5g的1wt%的聚γ-谷氨酸钠水溶液,搅拌30min,加入0.3g的载药胶束粉末于混合溶液中,静置自组装形成载药复合水凝胶。将载药凝胶注入到蚊子针形微针模具中,干燥后脱模制得水凝胶祛痘微针贴片。
本实施例实施的结果如图8、9、10所示。
将所得的天然水凝胶和凝胶祛痘微针进行猪皮体外渗透实验,经过猪皮切片,在荧光显微镜下观察复合水凝胶和水凝胶祛痘微针的渗透实验,可以看出凝胶的渗透效果远低于微针的渗透效果。
将所得的凝胶祛痘微针进行体外猪皮溶解实验,将制备的微针用手指按压至猪皮表面30min、60min、120min,分别在场发射环境扫描电子显微镜下观察微针的溶解情况。
将所得的凝胶祛痘微针在37oC,pH分别为5.0、5.5、6.0、6.5、7.0、7.5的释放介质中进行药物释放,通过累计释放率的计算和数据处理,得知凝胶祛痘微针在pH=5.5时释放速率最高,表明有一定的pH刺激响应性。
实施例4
本实施例的自组装凝胶祛痘微针贴片的制备方法,步骤如下:
(1)称取750mg的壳聚糖粉末溶于29.25g浓度为10mg/mL的醋酸溶液,得到2wt%的壳聚糖醋酸溶液;称取500mg的透明质酸钠粉末溶于49.5g的蒸馏水中,得到1wt%的透明质酸钠水溶液;
(2)称取200mg泊洛沙姆188和5mg他扎罗汀溶解在6mL的二甲亚砜中,搅拌均匀形成混合透明溶液,将有机溶剂旋转蒸发,制备泊洛沙姆188-他扎罗汀薄膜,将薄膜在45℃水浴中溶胀15min,之后加入同温度的水8mL,搅拌溶解30min,形成澄清的载药胶束,冷冻干燥得到载药胶束粉末。
(3)吸取4.5g步骤(1)得到的2wt%的壳聚糖醋酸溶液,加入0.5g的β-甘油磷酸钠溶液,室温搅拌10min,之后缓慢滴加4.5g的1wt%的羧甲基纤维素钠水溶液,搅拌30min,加入0.3g的载药胶束粉末于混合溶液中,静置自组装形成载药复合水凝胶。将载药凝胶注入到蚊子针形微针模具中,干燥后脱模制得水凝胶祛痘微针贴片。
实施例5
本实施例的自组装凝胶祛痘微针贴片的制备方法,步骤如下:
(1)称取750mg的壳聚糖粉末溶于29.25g浓度为10mg/mL的醋酸溶液,得到2wt%的壳聚糖醋酸溶液;称取500mg的透明质酸钠粉末溶于50mL的蒸馏水中,得到1wt%的透明质酸钠水溶液;
(2)称取100mg泊洛沙姆338和5mg他扎罗汀溶解在6mL的二甲亚砜中,搅拌均匀形成混合透明溶液,将有机溶剂旋转蒸发,制备泊洛沙姆338-他扎罗汀薄膜,将薄膜在45℃水浴中溶胀15min,之后加入同温度的水8mL,搅拌溶解30min,形成澄清的载药胶束,冷冻干燥得到载药胶束粉末。
(3)吸取4.5g步骤(1)得到的2wt%的壳聚糖醋酸溶液,加入0.5g的α-甘油磷酸钠溶液,室温搅拌10min,之后缓慢滴加4.5g的1wt%的藻酸钠水溶液,搅拌30min,加入0.3g的载药胶束粉末于混合溶液中,静置自组装形成载药复合水凝胶。将载药凝胶注入到蚊子针形微针模具中,干燥后脱模制得水凝胶祛痘微针贴片。
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、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种自组装凝胶祛痘微针贴片的制备方法,其特征在于,步骤如下:
(1)将壳聚糖溶于醋酸溶液中,室温搅拌得壳聚糖醋酸溶液,将天然阴离子聚合物粉末溶于蒸馏水中,配制天然阴离子聚合物水溶液;
(2)将两亲性三嵌段共聚物与疏水药物按比例溶解于有机溶剂中,形成混合溶液,然后旋蒸去除有机溶剂,得疏水药物薄膜,疏水药物薄膜经溶胀水化、冷冻干燥后得包埋疏水药物的聚合物胶束;
(3)向步骤(1)的壳聚糖醋酸溶液中加入小分子调节剂,搅拌至溶液由粘稠变澄清透明,再加入步骤(1)的天然阴离子聚合物水溶液,搅拌至溶液由澄清变浑浊,最后加入步骤(2)的聚合物胶束,搅拌至溶液由澄清变浑浊,静置自组装得高强度的天然水凝胶;
(4)将步骤(3)的天然水凝胶真空注入微针模板,使得针体和基底全部注满,待微针自然干燥脱模即得自组装水凝胶祛痘微针贴片。
2.根据权利要求1所述的制备方法,其特征在于:所述步骤(1)中壳聚糖脱乙酰度>90%,醋酸溶液的质量浓度为1wt%,壳聚糖在醋酸溶液中的浓度为2wt%-3wt%。
3.根据权利要求1所述的制备方法,其特征在于:所述天然阴离子聚合物为透明质酸钠、藻酸钠、果胶、羧甲基纤维素钠、黄原胶、卡拉胶、聚γ-谷氨酸钠中的一种或多种,其平均分子量达到100kDa-2000kDa,浓度为0.8wt%-1.2wt%。
4.根据权利要求1所述的制备方法,其特征在于:所述步骤(2)中两亲性三嵌段共聚物为泊洛沙姆188、泊洛沙姆237、泊洛沙姆338、普朗尼克F127中的一种或几种;疏水药物为阿达帕林、他扎罗汀或水杨酸中的任一种;两亲性三嵌段共聚物与疏水药物的质量比为(100-300):5;有机溶剂为四氢呋喃或二甲基亚砜。
5.根据权利要求4所述的制备方法,其特征在于:所述溶胀水化的操作为将疏水药物薄膜于45-65℃水浴溶胀15min,然后加入等温的蒸馏水进行水化得胶束溶液,再过0.22μm的过滤膜,过滤物进行后续操作。
6.根据权利要求1所述的制备方法,其特征在于:所述步骤(3)中小分子调节剂为α-甘油磷酸钠、β-甘油磷酸钠及它们的水合物中的一种或几种;所述天然水凝胶中壳聚糖醋酸溶液、小分子调节剂、天然阴离子聚合物溶液、聚合物胶束的质量比为(3-5):(0.3-1.5):(3-5):(0.15-0.35);静置自组装的时间为10-15h。
7.根据权利要求1所述的制备方法,其特征在于:所述步骤(4)中真空注入的操作为在-0.8kPa、37℃的真空作用下注入25min,去除基底气泡后反复重新注入,直至气泡不再出现。
8.根据权利要求1所述的制备方法,其特征在于:所述微针的结构为四棱锥形、圆锥体形或蚊子针形,微针针体高度为300-800μm,微针针体底面边长为100-500μm,针尖直径为5-10μm。
9.权利要求1-8任一项所述的方法制备的自组装凝胶祛痘微针贴片。
10.权利要求9所述的自组装凝胶祛痘微针贴片在制备治疗痤疮的药剂中的应用。
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