CN108524478A - 山椒素在制备修复皮肤光损伤的外用制剂中的用途 - Google Patents
山椒素在制备修复皮肤光损伤的外用制剂中的用途 Download PDFInfo
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Abstract
本发明提供了山椒素或其同分异构体或含其的提取物在制备预防和/或治疗皮肤光损伤的药物或化妆品中的用途。实验结果说明，山椒素可提高成纤维细胞的增殖活性；还可抑制MMP‑1和MMP‑3的表达，减少细胞外基质的降解；并且可以显著减轻皮肤光损伤症状；可用于制备修复皮肤光损伤的化妆品或药品，具有广阔的市场应用前景。
Description
技术领域
本发明涉及山椒素制备修复皮肤光损伤的外用制剂中的用途。
背景技术
紫外线照射，特别是中波紫外线(UVB)可引起皮肤的一系列损伤，诱发皮肤出现红斑、水疱、炎症、粗糙、增厚、色素沉着、毛细血管扩张、光老化等一系列急、慢性反应。光损伤皮肤的表皮厚度不一，伴有局灶的萎缩或增生，以及不同程度的黑色素沉着。真皮层可见弹性纤维排列紊乱、粘多糖增生且成纤维细胞增生能力减弱。光损伤性皮肤病是一类由日光，特别是紫外线照射皮肤直接或间接引起的皮肤病，主要包括：①光老化；②光敏性皮肤病，如：多形性日光疹(polymorphous light eruption,PLE)、慢性光化性皮炎(chronicactinic dermatitis,CAD)；③光线加剧性皮肤病，如：痤疮(acne)、黄褐斑(chloasma)、敏感性皮肤等；④光线致癌，如：日光性角化症(actinic keratosis)、鳞状细胞癌(squamouscell carcinoma,SCC)、基底细胞癌(basal cell carcinoma,BCC)、恶性黑素瘤等(何黎.皮肤病与性病,2013,(2):78-79.)。该类疾病是一类较常见，病机复杂，临床表现多样的疾病，常发生于曝光部位，易反复、难治愈、甚至容易诱发癌变，严重危害着人民群众的身心健康，故对其研究已成为当今医学领域亟待解决的重要课题之一。目前对皮肤光损伤和光损伤性皮肤病的防护主要是避免过度日晒，使用防晒霜和防晒措施，由于多种原因，它所取得的效果非常有限。
花椒为芸香科(Rutaceae)花椒属(Zanthoxylum genus)，香料、油料和中药材，有2000多年历史，《中华人民共和国药典》历版收载，“药食同源”，现代中药学归纳其功效为：温中止痛，驱虫，外用燥湿，杀虫止痒。山椒素(sanshool)提取自花椒，于1913年首次被日本学者村山义温发现并命名，属于花椒酰胺类物质，是花椒麻味来源，近来研究证明其具有促胃动力、麻醉镇痛、驱虫、止痒、抗肿瘤、抗血小板聚集等多种作用。到目前为止还未见将山椒素用于修复皮肤光损伤的报道。
发明内容
为了解决上述技术问题，本发明提供了山椒素或其同分异构体或含其的提取物在制备预防和/或治疗皮肤光损伤的药物或化妆品中的用途。
进一步地，所述药物或化妆品是用于促进成纤维细胞增殖的物质。
进一步地，所述药物或化妆品是抑制基质金属蛋白酶MMP-1、MMP-3表达的物质。
进一步地，所述药物或化妆品是抑制细胞外基质降解的物质。
进一步地，所述药物或化妆品是增加表皮厚度，改善真皮层弹性纤维和胶原纤维排列的物质。
进一步地，所述山椒素为羟基-α-山椒素、羟基-β-山椒素、羟基-γ-山椒素、羟基-δ-山椒素、羟基-ε-山椒素、α-山椒素、β-山椒素、γ-山椒素、δ-山椒素、ε-山椒素中的一种或多种，优选为羟基-α-山椒素。
进一步地，所述含山椒素的提取物为花椒提取物。
进一步地，所述花椒提取物为除去纤维素及木质素之后的物质。
进一步地，所述皮肤光损伤是指紫外线导致的皮肤损伤。
进一步地，它是山椒素或其同分异构体或含其的提取物为活性成分，再加上药物或化妆品中可接受的辅料制备而成的制剂。
实验结果说明，山椒素可提高成纤维细胞的增殖活性；还可抑制MMP-1和MMP-3的表达，减少细胞外基质的降解；并且可以显著减轻皮肤光损伤症状；可用于制备修复皮肤光损伤的化妆品或药品，具有广阔的市场应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为小鼠皮肤的HE染色图，其中，1所指为表皮，2所指为真皮层纤维。
具体实施方式
实施例1、含山椒素的花椒提取物的制备
取干燥花椒果皮2kg破碎，用16kg体积分数为85％的乙醇水溶液对花椒果皮粉末进行冷浸提取，提取时间为48h，提取3次，合并浸提液，弃药渣，浸提液减压浓缩得浓缩液，浓缩液的体积为浸提液的1/5～1/4，得到羟基山椒素混合物；将所得的羟基山椒素混合物用水稀释到乙醇溶液体积分数为20％，通过HP-20型大孔吸附树脂柱层析进行分离纯化，干燥花椒果实重量与大孔吸附树脂体积比例为1Kg：0.7L，动态吸附上样，吸附速度控制在每小时2.5BV，吸附完毕后，先分别用2.5BV的水和55％的乙醇溶液洗脱除杂，再用3BV的85％的乙醇溶液洗脱，收集洗脱液，减压浓缩得羟基山椒素混合物浸膏。浓缩的山椒素混合提取物可以直接使用，也可以通过有机溶剂进一步分离纯化后使用。
实施例2、
一种修复皮肤光损伤的化妆品，它是有下述重量配比的原料组成：去离子水73％、1，3-丙二醇8％、戊二醇3.5％、环五聚二甲基硅氧烷3％、聚二甲基硅氧烷3％、含山椒素的花椒提取物2％、麦芽寡糖葡糖苷2％、甘油三酯2％、季戊四醇四酯2％、辛甘醇/甘油/聚丙烯酸共聚物1.5％。
制备方法：将配方量的去离子水、1，3-丙二醇、戊二醇和麦芽寡糖葡糖苷混合搅拌加热至85-90℃；加入配方量的环五聚二甲基硅氧烷、聚二甲基硅氧烷、甘油三酯、季戊四醇四酯和辛甘醇/甘油/聚丙烯酸共聚物继续加热搅拌，冷却至室温后加入配方量的含山椒素的花椒提取物搅拌混匀。
使用方法：取适量直接外用涂抹于皮肤，一天一次，无需清洗，使用前可涂抹保湿霜。
实施例3、
一种修复皮肤光损伤的化妆品，它是有下述重量配比的原料组成：去离子水74％、1，3-丙二醇8％、戊二醇3.5％、环五聚二甲基硅氧烷3％、聚二甲基硅氧烷3％、含山椒素的花椒提取物1％、麦芽寡糖葡糖苷2％、甘油三酯2％、季戊四醇四酯2％、辛甘醇/甘油/聚丙烯酸共聚物1.5％。
制备方法：将配方量的去离子水、1，3-丙二醇、戊二醇和麦芽寡糖葡糖苷混合搅拌加热至85-90℃；加入配方量的环五聚二甲基硅氧烷、聚二甲基硅氧烷、甘油三酯、季戊四醇四酯和辛甘醇/甘油/聚丙烯酸共聚物继续加热搅拌，冷却至室温后加入配方量的含山椒素的花椒提取物搅拌混匀。
使用方法：取适量直接外用涂抹于皮肤，一天一次，无需清洗，使用前可涂抹保湿霜。
以下通过试验例来说明本发明的有益效果。
试验例1、山椒素修复光损伤的细胞实验
(1)建立细胞光损伤模型
取小儿***，采用常规方法分离成纤维细胞培养，传代至3-5代后冻存，细胞复苏后接种于培养皿，培养基中加入50mg/L的8-甲氧沙林(8-MOP)，照射时弃培养基，以含50mg/L的8-MOP的PBS漂洗2次后行UVA辐照，照射一次剂量为9J/cm2，连续照射21天。显微镜下观察细胞均出现损伤的特征改变：即细胞变大，胞内颗粒增加，胞质空泡化及增殖延缓。
(2)实验药物：羟基-α-山椒素
(3)促进成纤维细胞的增值活性(％)
实验方法：将UVA照射后的成纤维细胞按6×103个/孔接种于96孔板中，培养24小时后加入10μL浓度分别为0.01％，0.02％和0.04％的山椒素，继续培养24小时后加入10μL/孔的CCK-8试剂，孵育3小时后用酶联免疫检测仪测定450nm的吸光度(A)值。重复3次。
细胞活力(％)＝[A(试验组)-A(0)]/[A(空白对照)-A(0)]×100％
其中，A(试验组)表示有细胞、CCK-8溶液和山椒素的孔的吸光度；A(0)表示有CCK-8溶液，而无细胞和山椒素的孔的吸光度；A(空白对照)有细胞、CCK-8溶液，而无山椒素的孔的吸光度。
表1.不同浓度山椒素对成纤维细胞增殖的影响
由表1可知，山椒素作用于成纤维细胞后，可显著提高细胞增殖活性。
(4)抑制基质金属蛋白酶(MMP-1、MMP-3)的表达
试验分为四组，分别为未处理组(未予山椒素和UVA辐照处理的正常对照组)、山椒素处理组(成纤维细胞+0.01％山椒素)、UVA处理组、UVA+山椒素处理组(UVA辐照后予以0.01％山椒素处理)，培养48小时后取细胞上清液，提取后按照ELISA试剂盒说明加样、温育、洗涤后加酶、温育、洗涤，最后用酶标仪在450nm波长下测定吸光度(OD值)，通过标准曲线计算样品中人MMP-1、MMP-3浓度。
表2.山椒素对MMP-1和MMP-3表达的影响
由表2可知，山椒素可抑制MMP-1和MMP-3的表达，而MMP-1和MMP-3是分解细胞外基质成分的重要酶：其中MMP-1主要水解I，II和III型胶原；MMP-3水解底物则比较广泛，包括胶原、蛋白多糖和明胶等。因此抑制二者活性可减少细胞外基质的降解。
试验例2、山椒素修复光损伤的动物实验
(1)建立动物光损伤模型
先用剪刀和电动剃须刀剔除小鼠背部毛发，充分暴露其背部皮肤后进行UVB(300mJ/cm2)辐照小鼠，每天一次，连续3天，造模结束，造模成功的小鼠背部皮肤出现明显红斑鳞屑改变。
(2)实验分组
建模成功后的小鼠共20只，对照组和试验组各10只。对照组不予处理，试验组隔日局部给予浓度为2％的羟基-α-山椒素，共给药2周。
(3)对小鼠背部UVB照射区域进行皮肤损伤状况评分(评分细则见表3)，结果如表4所示：
表3.小鼠背部UVB照射区域皮肤损伤状况评分标准
表4.山椒素对光损伤小鼠背部皮肤损伤状况评分的影响
由表4可知，山椒素治疗4次后可以显著减轻皮肤光损伤。
(4)将小鼠处死后取材，进行HE染色显示实验组小鼠表皮厚度增加，真皮层纤维排列整齐(图1)。
综上，山椒素可提高成纤维细胞的增殖活性；还可抑制MMP-1和MMP-3的表达，减少细胞外基质的降解；并且可以显著减轻皮肤光损伤症状；可用于制备修复皮肤光损伤的化妆品，具有广阔的市场应用前景。
Claims (10)
1.山椒素或其同分异构体或含其的提取物在制备预防和/或治疗皮肤光损伤的药物或化妆品中的用途。
2.根据权利要求1所述的用途，其特征在于：所述药物或化妆品是用于促进成纤维细胞增殖的物质。
3.根据权利要求1所述的用途，其特征在于：所述药物或化妆品是抑制基质金属蛋白酶MMP-1、MMP-3表达的物质。
4.根据权利要求3所述的用途，其特征在于：所述药物或化妆品是抑制细胞外基质降解的物质。
5.根据权利要求1所述的用途，其特征在于：所述药物或化妆品是增加表皮厚度，改善真皮层弹性纤维和胶原纤维排列的物质。
6.根据权利要求1～5任一项所述的用途，其特征在于：所述山椒素为羟基-α-山椒素、羟基-β-山椒素、羟基-γ-山椒素、羟基-δ-山椒素、羟基-ε-山椒素、α-山椒素、β-山椒素、γ-山椒素、δ-山椒素、ε-山椒素中的一种或多种，优选为羟基-α-山椒素。
7.根据权利要求1～6任一项所述的用途，其特征在于：所述含山椒素的提取物为花椒提取物。
8.根据权利要求7所述的用途，其特征在于：所述花椒提取物为除去纤维素及木质素之后的物质。
9.根据权利要求1～8任一项所述的用途，其特征在于：所述皮肤光损伤是指紫外线导致的皮肤损伤。
10.一种预防和/或治疗皮肤光损伤的外用制剂，其特征在于：它是山椒素或其同分异构或含其的提取物为活性成分，再加上药物或化妆品中可接受的辅料制备而成的制剂。
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