CN111249472B - 一种可经皮给药的透明质酸纳米凝胶及其制备方法 - Google Patents
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Abstract
本发明涉及一种可经皮给药的透明质酸纳米凝胶及其制备方法，所述透明质酸通过硫醇长链连接药物分子。本发明可用于经皮给药以治疗多种皮肤疾病，可以长时间、持续性在皮肤病灶部位提供有效活性的药物浓度，提高临床治疗效果。
Description
技术领域
本发明属于透皮给药领域，特别涉及一种可经皮给药的透明质酸纳米凝胶及其制备方法。
背景技术
透皮给药是指药物涂布或贴于皮肤表面的一种给药方法，成为口服、注射后的第三大给药途径，使药物以恒定速率(或接近恒定速率)通过皮肤，进入体循环产生全身或局部治疗作用。相比于传统用药方式，透皮给药系统的优势是市场快速发展的主要原因。除有效避免肝脏首过效应，透皮给药可以减少口服药物给肠胃造成的刺激以及减少药效流失，采取注射用药的方式则也会带来非常的不便及身体上的二次伤害，降低患者依存性。然而，皮肤是药物进入体内的主要屏障，研究发现只有少数药物具有优良的皮肤透过性，且主要是小分子药物。而对于水溶性差的药物在透皮给药时存在药物利用度较低的问题，因此，开发合适的经皮给药体系，是实现透皮给药产业化发展的必由之路。
近年来，透明质酸(HA)因其具有良好的生物相容性、理化特性和特异的配体-受体生理功能，在药物递送方面发挥着越来越重要的作用。首先，透明质酸是一种糖胺聚糖，天然存在于皮肤细胞外基质中，具有良好的生物相容性。其次，透明质酸具有特殊的吸水性能和亲疏水两性结构域，可通过水化作用降低角质层屏障功能，有效促进药物穿透角质层进行经皮渗透。而且，透明质酸凝胶在一定浓度下呈空间网格结构，可包载和固定药物，吸水后网格结构降解而释放药物，实现药物控释。目前在经皮给药方面，已有研究证实皮肤中的成纤维细胞表面具有大量的透明质酸受体，因此透明质酸能主动聚集于成纤维细胞表面，实现药物的靶向运输。
发明内容
本发明所要解决的技术问题是提供一种可经皮给药的透明质酸纳米凝胶及其制备方法，可通过经皮给药方式显著提高药物在皮肤中的有效浓度。
本发明提供了一种可经皮给药的透明质酸纳米凝胶，所述透明质酸通过硫醇长链连接药物分子。
所述透明质酸的分子量为10-100kD；所述透明质酸与硫醇长链的摩尔比为1:3-1:1。
所述药物分子与硫醇长链的摩尔比为1:2-2:1。
所述纳米凝胶为囊泡结构，囊泡大小为40-200nm。
本发明还提供了一种可经皮给药的透明质酸纳米凝胶的制备方法，包括以下步骤：
(1)将透明质酸溶于水中，加入EDC(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)和NHS(N-羟基琥珀酰亚胺)活化，在室温下反应4-12h；
(2)将硫醇长链化合物与药物分子加入到乙醇中，并在室温条件下反应4-16h；
(3)将步骤(1)和(2)的产物混合，室温反应8-20h，产物经透析、超声得到囊泡结构的透明质酸；
(4)将步骤(3)得到的透明质酸进行超滤，除去多余的水分，即得可经皮给药的透明质酸纳米凝胶。
所述步骤(1)中的透明质酸、EDC和NHS的质量比为90-170:14-45:22-68。
所述步骤(2)中的药物分子与硫醇长链化合物的摩尔比为1:2-2:1。
所述步骤(2)中的硫醇长链化合物为正十八硫醇或正十六硫醇。
所述步骤(3)中的超声功率为200-400W，超声时间为0.4-2h。
有益效果
本发明采用透明质酸钠为原料，通过化学修饰及物理交联两步法，制备得到一种可经皮给药的透明质酸纳米凝胶。本发明具有较好的粘性，可直接附着于皮肤表面，包含大量粒径在50-100nm的纳米颗粒。可用于经皮给药来治疗多种皮肤疾病(瘢痕、黑色素瘤等)，在长时间、持续性在皮肤病灶部位提供有效活性的药物浓度，提高临床治疗效果。
附图说明
图1为实施例1透射电镜下的可经皮给药的透明质酸纳米凝胶；
图2为实施例1可经皮给药的透明质酸纳米凝胶(左)与IR780水溶液(右)在人体皮肤中的渗透情况；放大倍数40倍，从上往下渗透时间为1、2和3h；
图3为实施例2透射电镜下的可经皮给药的透明质酸纳米凝胶；
图4为实施例2可经皮给药的透明质酸纳米凝胶(左)与IR780水溶液(右)在人体皮肤中的渗透情况；放大倍数40倍，从上往下渗透时间为1、2和3h。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
(1)将90mg透明质酸加入到4mL水中，加入活化试剂25mg EDC和20mg NHS，室温搅拌反应8h。
(2)将40mg邻氨基苯硫醇与20mg吲哚菁绿(ICG)共同溶解于2ml乙醇中，室温搅拌反应10h。
(3)将步骤(1)和(2)的产物混合，室温再反应10h。产物用超纯水透析1天后，在功率为300w的超声环境中超声0.5h，使得透明质酸形成囊泡结构。
(4)利用50kd的超滤管对步骤(3)所得溶液进行过滤，除去多余的水分，即得到具有一定粘性的可经皮给药的透明质酸纳米凝胶。
所得可经皮给药的透明质酸纳米凝胶经透射电镜观察，如图1所示,该凝胶含有大量的50nm左右囊泡。
将所得可经皮给药的透明质酸纳米凝胶涂抹于离体人皮，分别进行渗透1、2、3小时后，制备成垂直于表皮的冰冻切片。利用共聚焦电镜发现，该可经皮给药的透明质酸纳米凝胶比IGC水溶液具有优异的渗透性能(如图2所示)。
实施例2
(1)将140mg透明质酸加入到4mL的水中，加入活化试剂40mg EDC和40NHS，室温搅拌反应12h，
(2)将30mg邻氨基苯1-dodecanethiol与20mg花菁染料IR780共同溶解于3ml乙醇中，室温搅拌反应12h。
(3)将步骤(1)和(2)的产物混合，室温再反应15h。产物用超纯水透析1天后，在功率为200w的超声环境中超声1h，使得透明质酸形成囊泡结构。
(4)利用50kd的超滤管对步骤(3)所得溶液进行过滤，除去多余的水分，即得到具有一定粘性的可经皮给药的透明质酸纳米凝胶。
所得可经皮给药的透明质酸纳米凝胶经透射电镜观察，如图3所示，该凝胶含有大量的60nm左右囊泡。
将所得可经皮给药的透明质酸纳米凝胶涂抹于离体人皮，分别进行渗透1、2、3小时后，制备成垂直于表皮的冰冻切片。利用共聚焦电镜发现，该可经皮给药的透明质酸纳米凝胶比IR780水醇溶液具有优异的渗透性能(如图4所示)。
Claims (3)
1.一种可经皮给药的透明质酸纳米凝胶的制备方法，包括以下步骤：
（1）将透明质酸溶于水中，加入EDC和NHS活化，在室温下反应4-12 h；
（2）将邻氨基苯硫醇与吲哚菁绿加入到乙醇中，并在室温条件下反应4-16h；
（3）将步骤（1）和（2）的产物混合，室温反应8-20h，产物经透析、超声得到囊泡结构的透明质酸；
（4）将步骤（3）得到的透明质酸进行超滤，除去多余的水分，即得可经皮给药的透明质酸纳米凝胶。
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）中的透明质酸、EDC和NHS的质量比为90-170:14-45:22-68。
3. 根据权利要求1所述的制备方法，其特征在于：所述步骤（3）中的超声功率为200-400 W，超声时间为0.4-2h。
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