CN112843113A - 一种用于治疗接触性皮炎的制剂 - Google Patents
一种用于治疗接触性皮炎的制剂 Download PDFInfo
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- CN112843113A CN112843113A CN202110306223.0A CN202110306223A CN112843113A CN 112843113 A CN112843113 A CN 112843113A CN 202110306223 A CN202110306223 A CN 202110306223A CN 112843113 A CN112843113 A CN 112843113A
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Abstract
本发明公开了一种用于治疗接触性皮炎的制剂，涉及外用药物制剂领域，包含如下质量分数的组分：芍药苷0.04～0.12wt％，白藜芦醇0.2～0.12wt％，原花青素0.1～0.9wt％，甘草酸0.02～0.14wt％，人参皂苷0.01～0.15wt％，余量为外用药物基质。本发明针对酒精接触性皮炎的病理机制，通过将芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷进行合理配比，制成护手霜，进而一方面通过GAS6‑AXL通路上调SOCS3表达发挥抗炎作用，另方一面抑制TF表达，改善慢血流，恢复循环，发挥抗炎修复作用，对酒精接触性皮炎的疗效确切，机理清晰。
Description
技术领域
本发明涉及外用药物制剂领域，特别涉及一种用于治疗接触性皮炎的制剂。
背景技术
酒精接触性皮炎，是指皮肤长时间接触酒精造成的一系列皮肤不良反应，属于刺激性接触性皮炎。常发生在身体暴露部位，轻者可产生红斑、水肿、丘疹等表现，重者皮损处可有糜烂、渗出、甚至坏死，多伴有瘙痒，属于日常生活中经常遇到的问题。部分人群如医护人员因长时间接触酒精消毒而出现“酒精手”，手部出现湿疹、脱皮。接触性皮炎通常局限于皮肤直接接触刺激物的部位，一般不会或很少超出其界限。急性接触性皮炎，去除接触物后积极处理，1-2周内可痊愈，但可遗留暂时性色素沉着。如果发生交叉过敏、多价过敏及治疗不当易导致皮损反复发作、迁延不愈或转化为亚急性和慢性皮炎。
研究发现，在接触性皮炎发生过程中，首先表皮角质形成细胞(keratineocytes，KCs)在启动和传递接触性刺激反应中起着关键作用。KC可以释放炎症细胞因子，上调主要组织相容性复合物(MHC)II类分子，诱导黏附分子对刺激物做出应答。这些介质能导致直接组织损伤，激活局部肥大细胞并促进后者释放促炎性介质，引起血管扩张并参与早期急性刺激性皮炎的发病。蛋白酶激酶受体2(protease activated receptor 2，PAR2)是肥大细胞参与皮肤炎症与超敏反应的重要分子，在接触性皮炎中发现，PAR2激活会引发多种皮肤效应，包括水肿、血浆外渗、白细胞招募、细胞黏附分子的形成以及促炎细胞因子IL-1、IL-6、TNF的增加。而针对上述病理特点进行研究发现，基质金属蛋白酶9(MMP-9)能通过使pro-IL-1裂解活化为IL-1，而基质金属蛋白酶2(MMP2)也能使IL-1裂解活化。研究发现MMP与多种皮肤病发病有密切关系。Heffler等研究显示接触性皮炎皮损中MMP9表达增加。Giannelli等研究发现接触性皮炎皮损处MMP-2及MMP-9增加，而非皮损区无变化。Wang等研究表明，MMP-9缺乏小鼠相比于野生型小鼠接触性皮炎反应时间更长。
根据《新版接触性皮炎管指南》，接触性皮炎的处理原则是保护皮肤、避免刺激。对照研究表明肥皂替代物和工作用使用护手霜可减少接触性皮炎的发病率和患病率(I级证据，A级推荐)。目前临床对于接触性皮炎主要采用外用药物涂抹进行治疗，使药物直接作用于患处，在较短时间内促进临床症状的缓解，急性期无渗液时可选用炉甘石洗剂，有少量渗液可外用氧化锌油，有明显渗液可用3％硼酸溶液冷湿敷。亚急性期可用外用糖皮质激素，有感染时应用抗生素。如若使用外用药后症状仍不能好转或病情比较严重者，医生会开一些口服药，如抗组胺药、抗生素、糖皮质激素、免疫抑制剂等。但是，糖皮质药物可能出现烧灼感、刺痛感，长期外用还可能导致皮肤变薄或颜色改变、产生斑点、毛发生长增加等副作用，抗生素也会出现耐受等副作用。
基础上述的病理特点以及以往研究结果我们发现，芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷一方面可以通过抑制TLR4-MMP9炎症通路达到抑制炎症的作用，另一方面可以通过抑制PAR2-TF改善循环，但目前未有将这几种原料合用于抗炎扩张修复改善循环的药物，且对玫瑰精油、芍药苷、白藜芦醇、原花青素、甘草酸、人参皂苷通过合理配比，从而实现增强抗炎修复的功效，对酒精接触性皮炎具有很好功效。
发明内容
本发明所要解决的技术问题：通过天然活性组分合理配比后形成对酒精接触性皮炎具有治疗作用的制剂。
为解决上述技术问题，本发明提供以下的技术方案：
一种用于治疗接触性皮炎的制剂，包含如下质量分数的组分：芍药苷0.04～0.12wt％，白藜芦醇0.2～0.12wt％，原花青素0.1～0.9wt％，甘草酸0.02～0.14wt％，人参皂苷0.01～0.15wt％，余量为外用药物基质。
优选地，由如下质量分数的组分制备而成：芍药苷0.08wt％，白藜芦醇0.7wt％，原花青素0.5wt％，甘草酸0.1wt％，人参皂苷0.08wt％，余量为外用药物基质。
优选地，所述芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷中的杂质含量均小于等于1wt％。
优选地，所述外用药物基质为霜剂，凝胶剂或乳剂中的一种或多种。
一种上述用于治疗酒精接触性皮炎制剂的制备方法，具体步骤如下：
(A)按照配料表称取芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷备用；
(B)采用乳化剂制备外用药物基质，冷却至室温后备用；
(C)将芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷加入外用药物基质中，采用均质机混匀后灭菌即得制剂。
本发明获得的有益效果：
一方面，由于酒精接触性皮炎中存在预警素(HSP70)的释放，作用于TLR4受体，导致MMP9-2的升高，ROS大量增加，导致NLRP3激活，释放多种炎症因子；另一方面，酒精接触性皮炎中，组织因子(Tissue Factor,TF)升高，局部组织缺血缺氧，TF激活PAR2，PAR2激活会引发多种皮肤效应，包括水肿、血浆外渗、白细胞招募、细胞黏附分子的形成以及促炎细胞因子IL-6、IL-1β和TNF-α的增加。针对这一病理，从而通过将芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷进行合理配比，制成护手霜，进而一方面通过GAS6-AXL通路上调SOCS3表达发挥抗炎作用，另方一面抑制TF表达，改善慢血流，恢复循环，发挥抗炎修复作用。
附图说明
图1是酒精反复接触刺激诱导小鼠接触性皮炎；
图2是护手霜抑制酒精所造成的接触性皮炎中炎症细胞浸润的结果200倍对比图；
其中左图为酒精造模组，右图为护手霜组。
图3是护手霜抑制酒精所造成的接触性皮炎中炎症细胞浸润的结果400倍对比图；
其中左图为酒精造模组，右图为护手霜组。
图4是护手霜抑制酒精所造成的接触性皮炎慢血流的结果对比图；
其中，从左至右依次为空白对照组、酒精造模组、护手霜处理组。
图5为图4中局部区域的放大图；
图6是护手霜改善酒精所造成的接触性皮炎小鼠皮肤含水量和色差的结果对比图；
图7是护手霜抑制酒精所造成的接触性皮炎中HSP70的结果对比图；
图8是护手霜抑制酒精所造成的接触性皮炎中MMP9/MMP2的结果对比图；
图9是护手霜抑制酒精所造成的接触性皮炎中TF表达的结果对比图；
图10为护手霜上调酒精接触性皮炎中GAS6的Western blot图。
图11为护手霜上调酒精接触性皮炎中p-AXL的Western blot图。
图12为护手霜上调酒精接触性皮炎中SOCS3的Western blot图。
具体实施方式
下面通过对实施例的描述，对本发明的具体实施方式作进一步详细的说明，以帮助本领域的技术人员对本发明的发明构思、技术方案有更完整、准确和深入的理解。
实施例1：
原料的选取：芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷中的杂质含量均小于等于1wt％。
按如下方法制备护手霜：
(A)按照芍药苷0.08wt％，白藜芦醇0.7wt％，原花青素0.5wt％，甘草酸0.1wt％，人参皂苷0.08wt％，余量为外用药物基质称取原料备用；
(B)采用乳化剂制备常规霜剂，冷却至室温后备用；
(C)将芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷加入霜剂中，采用均质机混匀后灭菌即得制剂。
实施例2：原料的选取：芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷中的杂质含量均小于等于1wt％。
按如下方法制备护手霜：
(A)按照芍药苷0.04wt％，白藜芦醇0.2wt％，原花青素0.1wt％，甘草酸0.02wt％，人参皂苷0.01wt％，余量为外用药物基质称取原料备用；
(B)采用乳化剂制备常规乳剂，冷却至室温后备用；
(C)将芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷加入乳剂中，采用均质机混匀后灭菌即得制剂。
实施例3：原料的选取：芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷中的杂质含量均小于等于1wt％。
按如下方法制备护手霜：
(A)按照芍药苷0.12wt％，白藜芦醇0.12wt％，原花青素0.9wt％，甘草酸0.14wt％，人参皂苷0.15wt％，余量为外用药物基质称取原料备用；
(B)采用卡波姆粉末制备凝胶基质，冷却至室温后备用；
(C)将芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷加入凝胶基质中，采用均质机混匀后灭菌即得制剂。
各原料的药物性能如下所示：
芍药苷具有抗组织细胞氧化应激损伤、抑制星形胶质细胞的激活、增强保护神经等功效。研究发现，芍药苷是经典的细胞因子信号转导机制因子(suppressor of cytokinesignaling 3，SOCS3)激动剂。SOCS3作为SOCS家族的重要分子，目前已有大量研究表明其可抑制多种炎症因子的表达，包括IL-6、IL-1β和TNF-α的表达。我们前期工作发现，芍药苷通过上调SOCS3，抑制HSF-1-HSP70-TLR4轴来缓解神经炎症进而治疗术后痛。
白藜芦醇是一种天然的抗氧化剂，通过激活AMPK，升高NO的的生成量，扩张血管，还可以短暂升高损伤局部的MMP-9水平，进而诱发VEGF的成熟，通过改善神经组织周围的血供来促进组织修复。
原花青素(OPC)是一种新型高效抗氧化剂，是目前为止所发现的最强效的自由基清除剂，具有非常强的体内活性。研究表明，OPC可以通过降低海马区脑组织p38 MAPK信号活化，减少IL-1β的表达，减轻炎症反应，同时，OPC可以抑制吗啡耐受过程中炎症小体NLRP3的成熟和MMP-9的成熟和外排，同时，OPC是一种Akt抑制剂，可与Akt直接结合并抑制其磷酸化，研究报道，OPC剂量依赖性的抑制LPS刺激的人肝星状细胞中Akt的激活。干扰Akt可以抑制其活化并且降低HSP70的释放。
甘草酸，可以通过抑制HMGB1的磷酸化和分泌产生的抗炎作用减少脑缺血梗死面积，也可以通过抑制NF-κB和磷脂酰肌醇3激酶(phosphatidylinositol 3-kinase，PI3K)的活性抑制促炎症基因的表达，包括IL-6、IL-1β和TNF-α的表达。同时可以促进表皮生长因子的表达上升，促进成纤维细胞增殖和胶原纤维增生，促进组织愈合。甘草甜素有较强的清除自由基作用，能够显著增强SOD活性，抑制活性氧ROS的产生。
人参皂苷在抗肿瘤、提高免疫力、改善肺功能、抗炎、降血压方面有大量报道。人参皂苷通过抑制NF-КB活性来下调炎性介质，减少急性肺损伤时的肺水肿，从而改善脓毒血症引起急性肺损伤时的炎症反应，保护肺的功能。同时，人参皂苷的多种活性形式可以抑制NLRP3的激活，在神经退行性疾病中发挥重要作用。
为了测定本发明的治疗效果和治疗机理，将实施例1中制备的护手霜进行如下实验：
实验一：
取SPF级ICR雄性健康小鼠(体重为20-22g)，进行酒精造模。实验前一天剃毛，暴露背部皮肤。酒精造模组，连续两天涂抹酒精(每天涂抹6次)。
实验结果如图1所示，酒精造模后，小鼠背部皮肤出现明显的红斑、丘疹、水肿等现象。
实验二：
取SPF级ICR雄性健康小鼠(体重为20-22g)，随机分为三组，空白组，酒精造模组，涂抹护手霜组，每组6只小鼠。实验前一天剃毛，暴露背部皮肤。酒精造模组，连续两天涂抹酒精(每天涂抹6次)，护手霜干预组于第三天涂抹酒精，间隔两小时涂抹护手霜(每天涂抹酒精六次，护手霜涂抹3次)，连续7天进行酒精和护手霜的涂抹。实验最后一天取皮肤组织进行HE染色。
实验结果如图2和图3所示，酒精造模组，炎症细胞浸润区域面积大，炎症细胞数量多；涂抹护手霜组，炎症细胞浸润区域面积明显减少，炎症细胞数量明显减少。
实验三：
取SPF级ICR雄性健康小鼠(体重为20-22g)，随机分为三组，空白组，酒精造模组，涂抹护手霜组，每组6只小鼠。实验前一天剃毛，暴露背部皮肤。酒精造模组，连续两天涂抹酒精(每天涂抹6次)，护手霜干预组于第三天涂抹酒精，间隔两小时涂抹护手霜(每天涂抹酒精六次，护手霜涂抹3次)，连续7天进行酒精和护手霜的涂抹。实验最后一天拍摄皮肤激光多普勒血流图。
实验结果如图4和图5所示，空白对照组，小鼠背部皮肤血流量丰富；酒精造模组，小鼠背部血流量明显下降；涂抹护手霜组，小鼠背部皮肤血流量有了明显的改善。
实验四：
取SPF级ICR雄性健康小鼠(体重为20-22g)，随机分为三组，空白组，酒精造模组，涂抹护手霜组，每组6只小鼠。实验前一天剃毛，暴露背部皮肤。酒精造模组，连续两天涂抹酒精(每天涂抹6次)，护手霜干预组于第三天涂抹酒精，间隔两小时涂抹护手霜(每天涂抹酒精六次，护手霜涂抹3次)，连续7天进行酒精和护手霜的涂抹。每天进行背部皮肤含水量测试。
实验结果如图6所示，酒精造模组，小鼠背部皮肤的含水量明显下降；涂抹护手霜组，随着涂抹时间的延长，其背部皮肤的含水量有了明显的升高。
实验五：
取SPF级ICR雄性健康小鼠(体重为20-22g)，随机分为三组，空白组，酒精造模组，涂抹护手霜组，每组6只小鼠。实验前一天剃毛，暴露背部皮肤。酒精造模组，连续两天涂抹酒精(每天涂抹6次)，护手霜干预组于第三天涂抹酒精，间隔两小时涂抹护手霜(每天涂抹酒精六次，护手霜涂抹3次)，连续7天进行酒精和护手霜的涂抹。最后一天，取皮肤组织进行western blot实验。
实验结果如图7所示，与空白对照组相比，酒精刺激皮肤组织中HSP70的表达，HSP70作为TLR4的配基，可以激活TLR4-NF-kB-MMP9通路诱导炎症的发展，与LPS刺激组相比，给予护手霜组可以不同程度的降低HSP70的高表达，达到抑制炎症的作用。
实验六：
取SPF级ICR雄性健康小鼠(体重为20-22g)，随机分为三组，空白组，酒精造模组，涂抹护手霜组，每组6只小鼠。实验前一天剃毛，暴露背部皮肤。酒精造模组，连续两天涂抹酒精(每天涂抹6次)，护手霜干预组于第三天涂抹酒精，间隔两小时涂抹护手霜(每天涂抹酒精六次，护手霜涂抹3次)，连续7天进行酒精和护手霜的涂抹。最后一天，取皮肤组织进行基质金属蛋白酶实验。
实验结果如图8所示，与空白对照组相比，酒精刺激可显著增加皮肤组织中MMP9/MMP2的表达，诱导炎症的发生；与酒精刺激组相比，给予护手霜可以不同程度的降低酒精刺激导致的MMP9/2的高表达，达到抑制炎症的作用。
实验七：
取SPF级ICR雄性健康小鼠(体重为20-22g)，随机分为三组，空白组，酒精造模组，涂抹护手霜组，每组6只小鼠。实验前一天剃毛，暴露背部皮肤。酒精造模组，连续两天涂抹酒精(每天涂抹6次)，护手霜干预组于第三天涂抹酒精，间隔两小时涂抹护手霜(每天涂抹酒精六次，护手霜涂抹3次)，连续7天进行酒精和护手霜的涂抹。最后一天，取皮肤组织进行western blot实验。
实验结果如图9所示，与酒精刺激组相比，给予护手霜组可以不同程度的降低酒精刺激导致的TF的高表达，达到提升皮肤血流，改善循环的作用。
实验八：
取SPF级ICR雄性健康小鼠(体重为20-22g)，随机分为三组，空白组，酒精造模组，涂抹护手霜组，每组6只小鼠。实验前一天剃毛，暴露背部皮肤。酒精造模组，连续两天涂抹酒精(每天涂抹6次)，护手霜干预组于第三天涂抹酒精，间隔两小时涂抹护手霜(每天涂抹酒精六次，护手霜涂抹3次)，连续7天进行酒精和护手霜的涂抹。最后一天，取皮肤组织进行western blot实验。
实验结果如图10～12所示，与酒精刺激造模组相比，给予护手霜可以不同程度的升高GAS6、AXL、SOCS3的表达，达到抑制炎症的作用。
综上所述，本发明针对酒精接触性皮炎的病理机制，通过将芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷进行合理配比，制成护手霜，进而一方面通过GAS6-AXL通路上调SOCS3表达发挥抗炎作用，另方一面抑制TF表达，改善慢血流，恢复循环，发挥抗炎修复作用，对酒精接触性皮炎的疗效确切，机理清晰。
以上实施例仅为说明本发明的技术思想，不能以此限定本发明的保护范围，凡是按照本发明提出的技术思想，在技术方案基础上所做的任何改动，均落入本发明保护范围之内；本发明未涉及的技术均可通过现有技术加以实现。
Claims (5)
1.一种用于治疗接触性皮炎的制剂，其特征在于，包含如下质量分数的组分：芍药苷0.04～0.12wt％，白藜芦醇0.2～0.12wt％，原花青素0.1～0.9wt％，甘草酸0.02～0.14wt％，人参皂苷0.01～0.15wt％，余量为外用药物基质。
2.根据权利要求1中所述的一种用于治疗接触性皮炎的制剂，其特征在于：由如下质量分数的组分制备而成：芍药苷0.08wt％，白藜芦醇0.7wt％，原花青素0.5wt％，甘草酸0.1wt％，人参皂苷0.08wt％，余量为外用药物基质。
3.根据权利要求1中所述的一种用于治疗接触性皮炎的制剂，其特征在于：所述芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷中的杂质含量均小于等于1wt％。
4.根据权利要求1～3中任一项所述的一种用于治疗接触性皮炎的制剂，其特征在于：所述外用药物基质为霜剂，凝胶剂或乳剂中的一种或多种。
5.一种如权利要求4中所述用于治疗酒精接触性皮炎制剂的制备方法，其特征在于：具体步骤如下：
(A)按照配料表称取芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷备用；
(B)采用乳化剂制备外用药物基质，冷却至室温后备用；
(C)将芍药苷、白藜芦醇、原花青素、甘草酸和人参皂苷加入外用药物基质中，采用均质机混匀后灭菌即得制剂。
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Application publication date: 20210528 Assignee: Suzhou Nanyi University Innovation Center Assignor: NANJING MEDICAL University Contract record no.: X2024980000191 Denomination of invention: A preparation for treating contact dermatitis Granted publication date: 20220201 License type: Common License Record date: 20240109 |
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