CN117427110B - 一种组合物及其在制备促进毛发再生的制剂中的应用 - Google Patents
一种组合物及其在制备促进毛发再生的制剂中的应用 Download PDFInfo
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Abstract
本发明涉及一种组合物及其在制备促进毛发再生的制剂中的应用，属于生物医药及化工技术领域，包括橙皮苷、黄芩提取物和黄连提取物，该组合物中将橙皮苷与多种提取物进行复配，可有效抑制皮肤炎症，明显增强其促进毛发再生的功效，针对于因iNOS基因缺陷导致的脱发后的再生障碍疗效显著。另外，本发明成分明确、疗效确切、安全可靠、稳定性好，可选择性地加入其他常用辅料进行制剂，具有广阔的应用前景。
Description
技术领域
本发明属于生物医药及化工技术领域，尤其涉及一种组合物及其在制备促进毛发再生的制剂中的应用。
背景技术
毛发生长是由毛囊驱动的循环再生过程，毛囊是皮肤附属器官，它横穿皮肤的真皮层和表皮层，包括毛干、毛球、真皮乳头、毛基质、内根鞘（IRS）、外根鞘（ORS）及皮脂腺等附属结构，其中ORS直接连接表皮基底层。毛囊干细胞（hair follicle stem cells，HFSCs），主要存在于ORS的隆突部位。毛囊在生长期、退行期和休止期不断循环再生，在这个过程中HFSCs可以动员再生新的毛囊。HFSCs可从毛囊中分离并根据其特异性细胞表面标记物体外扩增。到目前为止，已经分离鉴定出了大量的HFSCs干细胞亚群，如CD34阳性细胞等。
脱发是毛发分化过程异常的表现，最直接的表现是毛囊萎缩，头发脱落。随着社会压力的不断增大，全世界脱发人口也在增加，并且趋于年轻化。脱发最直接的原因是毛囊微环境的恶化，饮食不健康，作息不规律，情绪变化，内分泌失调，吸烟饮酒等种种原因都会导致脱发。另外，也有一些遗传因素会导致脱发症状。虽然轻微脱发对身体健康影响不大，但是严重脱发可使人失去信心，焦虑不安，甚至导致抑郁等心理疾病，严重影响患者的生活质量。
CN101172103A公开一种治疗妇女更年期综合征和骨质疏松症等多种疾病的药物，通过沙棘果油脂肪酸的信号转导作用，激活人体的内分泌系统，激活环核苷酸和特异蛋白等受体功能，十六烷酸和十六碳烯酸等脂肪酸能显著性提高机体毛发组织CAMP水平，使透明质酸酶灭活，阻断毛发细胞过快增生。CN104547449A通过引入补肝肾药物隔山撬、野料豆，补气活血药物雪灵芝、牛尾菜等来治疗因肝肾两虚、气血不足造成的脱发。CN101862374A还公开一种利用莲子心治疗脂溢性脱发的方案。但由于造成脱发的原因很多，只有对症治疗才是有效的。
因此，急需开发出更多可以治疗不同脱发原因的药物，以满足现阶段的需求。
发明内容
本发明所要解决的技术问题是提供一种组合物及其在制备促进毛发再生的制剂中的应用。
为解决上述技术问题，本发明采用的技术方案是：一种组合物，包括橙皮苷、黄芩提取物和黄连提取物。
进一步地，按重量份数计，橙皮苷0.05-1份、黄芩提取物0.05-0.8份、黄连提取物0.5-10份。
进一步地，按重量份数计，所述橙皮苷0.1-0.5份、黄芩提取物0.2-0.5份、黄连提取物1-5份。
本发明的另一目的是提供上述组合物在制备促进毛发再生的制剂中的应用。
进一步地，所述制剂为膏剂、喷剂、搽剂、贴剂中的一种（所述的制剂是采用本领域常规制备方法制备成的常用剂型）。
进一步地，所述制剂还包括药学上可接受的辅料。
进一步地，所述辅料为乙醇、丙二醇、甘油等。
进一步地，当所述辅料为乙醇时，每ml70%乙醇溶液的中，所述橙皮苷的浓度为0.001-0.005g/ml；黄芩提取物的浓度为0.001-0.003g/ml；黄连提取物的浓度为0.03-0.05g/ml。
进一步地，所述制剂可应用于药物、化妆品、保健品及医疗器械产品中。
进一步地，所述制剂促进因iNOS基因缺陷导致的脱发后再生障碍的毛发再生。
进一步地，所述制剂通过降低Wnt信号通路关键基因、BMP信号通路关键基因以及细胞周期调控关键基因的mRNA表达水平以促进毛发再生。
进一步地，所述Wnt信号通路关键基因包括Wnt5a、Wnt11、Ctnnb1、Padi3、Hoxc13和Dlx3；所述BMP信号通路关键基因包括BMP2、BMP6和Runx1；所述细胞周期调控关键基因包括Ccnd1、Ccnd2和Ccna2。
本发明的有益效果为：
本发明的组合物中将橙皮苷与多种药物提取物进行复配使用，安全可靠，并且通过小鼠实验发现，该组合物制备的制剂可有效抑制皮肤炎症，针对于因iNOS基因缺陷导致的脱发后的再生障碍疗效显著，能够有效改善iNOS基因缺陷诱导的毛囊微环境，缓解毛囊炎症，能够修复iNOS缺失导致的休止期阻滞，使其得以向生长期转化实现毛发再生，进而改善iNOS基因缺陷导致的脱发。本发明的制剂具体是通过降低Wnt5a、Wnt11、Ctnnb1、Padi3、Hoxc13和Dlx3在内的Wnt信号通路关键基因，BMP2、BMP6和Runx1在内的BMP信号通路关键基因以及Ccnd1、Ccnd2和Ccna2在内的细胞周期调控关键基因的mRNA表达水平，促进毛发再生的，疗效确切、成分明确、稳定性好，具有广阔的应用前景。
附图说明
下面通过参考附图并结合实例具体地描述本发明，本发明的优点和实现方式将会更加明显，其中附图所示内容仅用于对本发明的解释说明，而不构成对本发明的任何意义上的限制，在附图中：
图1为本发明验证iNOS基因与毛发生长关联性实验中各组小鼠的毛发照片。
图2为本发明实施例1中各种处理方法对小鼠毛发再生影响的实验照片。
图3为本发明实施例1中iNOS基因缺失小鼠差异皮肤组织的差异表达基因。
图4为本发明实施例1中各组小鼠的Wnt信号通路关键基因的数据对比。
图5为本发明实施例1中各组小鼠的BMP信号通路关键基因的数据对比。
图6为本发明实施例1中各组小鼠的细胞周期调控关键基因的数据对比。
图7为本发明实施例2中各组小鼠的实验照片和HE染色对比。
具体实施方式
为了使本技术领域的技术人员更好地理解本发明的技术方案，下面结合附图和最佳实施例对本发明作进一步的详细说明。
1、验证iNOS基因与毛发生长的关联性：
准备两组8周龄小鼠，第一组为野生型小鼠（3只），记为WT，第二组为iNOS基因敲除型小鼠（12只），记为iNOS KO，在同一生长环境下培养8周、12周、24周、48周，然后观察其毛发变化情况。
如图1所示，可以看出，iNOS基因敲除型小鼠的毛发会逐渐脱落，具体表现为iNOS基因敲除型小鼠从第8周开始在鼻子两侧出现毛发生长抑制并伴随稍许斑秃的现象，然而野生型小鼠并未出现此现象。由此可知，iNOS基因及其信号通路的缺失可能与毛发的正常发育密切相关。
2、验证制备的制剂对小鼠毛发再生的影响：
实施例1：
（1）小鼠模型准备：
准备两组8周龄小鼠，第一组为野生型小鼠（3只），第二组为iNOS基因敲除型小鼠（12只）。使用剃毛器剔除小鼠背部毛发（动作轻微，以免伤及表皮），裸露背部皮肤。其中，野生型小鼠以“WT”表示，iNOS基因敲除型小鼠以“iNOS KO”表示。
（2）各组试剂配制：
对照试剂：70％乙醇；
橙皮苷试剂：称取0.2g橙皮苷，溶解入100mL70％的乙醇溶液中；
复合物A（提取物试剂）：称取黄芩提取物0.3克、黄连提取物3克，溶解入100ml70％的乙醇溶液中；
复合物B（橙皮苷+提取物的复合试剂）：称取橙皮苷0.2克、黄芩提取物0.3克、黄连提取物3克，溶解入100ml 70％的乙醇溶液中。
其中，复合物B即为本发明的制剂。
橙皮苷、黄芩、黄连均购于药店。
（3）处理方法：
WT+对照试剂组：将70％乙醇均匀涂抹至WT小鼠背部皮肤裸露部位，涂抹量为200μL，每天2次，连续涂抹10天，
iNOS KO+对照试剂组：将70％乙醇均匀涂抹至iNOS KO小鼠背部皮肤裸露部位，涂抹量为200μL，每天2次，连续涂抹10天；
iNOS KO+复合物A组：将提取物试剂均匀涂抹至iNOS KO小鼠背部皮肤裸露部位，涂抹量为200μL，每天2次，连续涂抹10天；
iNOS KO+橙皮苷组：将橙皮苷试剂均匀涂抹至iNOS KO小鼠背部皮肤裸露部位，涂抹量为200μL，每天2次，连续涂抹10天；
iNOS KO+复合物B组：将橙皮苷+提取物的复合试剂均匀涂抹至iNOS KO小鼠背部皮肤裸露部位，涂抹量为200μL，每天2次，连续涂抹10天。
每组小鼠均为3只。
（4）结果分析：
如图2所示，iNOS KO+复合物A组、iNOS KO+橙皮苷组、iNOS KO+复合物B组小鼠的背部裸露区域有黑色素形成，皮肤颜色变黑，并且在皮肤表面发现有微小的毛发生成，iNOSKO+复合物B组效果最明显。而WT+对照试剂组和iNOS KO+对照试剂组小鼠的背部裸露区域均未出现上述现象。
为了确认橙皮苷+提取物复合联用可促进毛发再生的机制，首先取3只6月龄WT小鼠和3只6月龄iNOS KO小鼠皮肤组织，进行RNA-seq（转录组测序技术）。
如图3所示，图3的左侧热图显示差异基因的变化，图中“WT1、WT2、WT3”为三只WT小鼠，“KO1、KO2、KO3”为三只iNOS KO小鼠。图3的右侧火山图显示差异基因的变化，按照变化倍数（Fold Change，FC）>1.5和p-value<0.05的标准，与WT小鼠相比，iNOS KO小鼠皮肤组织中上调基因1107个，下调基因769个。
接下来，将差异基因进行IPA（Ingenuity Pathway Analysis）分析，发现iNOS基因缺陷导致毛囊发育相关通路均表达上调，Shh信号通路、Wnt信号通路、BMP信号通路以及细胞增殖过程关键基因均表达上调。
通过qRT-PCR（实时荧光定量PCR）检测了毛囊生长发育相关通路关键基因的表达变化，如图4至图6所示，较WT+对照试剂组，iNOS KO+对照试剂组的Wnt信号通路关键基因（Wnt5a、Wnt11、Ctnnb1、Padi3、Hoxc13、Dlx3）、BMP信号通路关键基因（BMP2、BMP6、Runx1）及细胞周期调控关键基因（Ccnd1、Ccnd2、Ccna2）表皮mRNA水平均明显升高。而iNOS KO+橙皮苷组、iNOS KO+复合物A组和iNOS KO+复合物B组的上述指标均有所下降，且复合物B组效果最佳。可以确定iNOS缺失可导致毛发调控关键通路Wnt、BMP以及细胞周期调控关键基因表达升高，而橙皮苷+提取物的联合作用及橙皮苷和提取物试剂单独作用后均可逆转iNOS缺失导致的上述关键通路基因的升高，橙皮苷+提取物联合应用效果最佳。
图4至图6中，**表示KO+复合物B与KO+对照试剂相比，以及与KO+橙皮苷和KO+复合物A相比，差异均具有统计学意义，p<0.01。
实施例2：
（1）小鼠模型准备：
准备四组6周龄iNOS基因敲除型小鼠，每组三只，iNOS基因敲除型小鼠以“iNOSKO”表示。
（2）各组试剂配制：
对照试剂：70％乙醇；
橙皮苷试剂：称取0.2g橙皮苷，溶解入100mL70％的乙醇溶液中；
复合物A（提取物试剂）：称取黄芩提取物0.3克、黄连提取物3克，溶解入100ml70％的乙醇溶液中；
复合物B（橙皮苷+提取物的复合试剂）：称取0.2g橙皮苷、黄芩提取物0.3克、黄连提取物3克，溶解入100ml70％的乙醇溶液中。
（3）处理方法：
iNOS KO+对照试剂组：将70％乙醇均匀涂抹至iNOS KO小鼠背部无毛区域，涂抹量为200μL，每天2次；
iNOS KO+橙皮苷组：将橙皮苷试剂均匀涂抹至iNOS KO小鼠背部无毛区域，涂抹量为200μL，每天2次；
iNOS KO+复合物A组：将提取物试剂均匀涂抹至iNOS KO小鼠背部无毛区域，涂抹量为200μL，每天2次；
iNOS KO+复合物B组：将橙皮苷+提取物的复合试剂均匀涂抹至iNOS KO小鼠背部无毛区域，涂抹量为200μL，每天2次。
（4）结果分析：
如图7所示，iNOS KO+橙皮苷组、iNOS KO+复合物A组和iNOS KO+复合物B组小鼠的头背部无毛区域在涂抹药物第32天时有毛发形成，而iNOS KO+对照试剂组的背部裸露区域均未出现毛发生长现象，说明橙皮苷和提取物复合试剂可促进iNOS缺陷小鼠脱发部位的毛发再生，并且橙皮苷和提取物复合试剂联合使用效果明显优于橙皮苷和提取物单独使用。
通过苏木素-伊红（HE）染色发现，iNOS KO+橙皮苷组、iNOS KO+复合物A组呈现休止期向生长期的转化，iNOS KO+复合物B组也呈现出异常休止期向正常休止期的转化，而iNOS KO+对照试剂组无此现象。此外，HE染色结果显示：iNOS KO+对照试剂组，表皮增生明显，表皮及真皮层均存在明显炎细胞浸润、大量炎性介质以及组织水肿，iNOS KO+橙皮苷以及iNOS KO+复合物A组上述情况有所缓解，iNOS KO+复合物B组表皮增生以及炎细胞浸润和组织水肿现象明显改善（如图7箭头所示）。
可见，橙皮苷联合提取物能够明显抑制炎性介质的释放、缓解皮肤炎症，抑制表皮增生。
以上对本发明的实施例进行了详细说明，但所述内容仅为本发明的较佳实施例，不能被认为用于限定本发明的实施范围。凡依本发明范围所作的均等变化与改进等，均应仍归属于本专利涵盖范围之内。
Claims (5)
1.一种组合物在制备促进毛发再生的制剂中的应用，其特征在于：组合物由0.2g橙皮苷、0.3g黄芩提取物和3g黄连提取物组成。
2.根据权利要求1所述的组合物在制备促进毛发再生的制剂中的应用，其特征在于：所述制剂为喷剂、搽剂、贴剂中的一种。
3. 根据权利要求1所述的组合物在制备促进毛发再生的制剂中的应用，其特征在于：所述制剂还包括乙醇，每ml 70%乙醇溶液中，所述橙皮苷的浓度为0.002g/ml；黄芩提取物的浓度为0.003g/ml；黄连提取物的浓度为0.03g/ml。
4.根据权利要求1所述的组合物在制备促进毛发再生的制剂中的应用，其特征在于：所述制剂促进因iNOS基因缺陷导致的脱发后再生障碍的毛发再生。
5.根据权利要求1所述的组合物在制备促进毛发再生的制剂中的应用，其特征在于：所述制剂通过降低Wnt信号通路关键基因、BMP信号通路关键基因以及细胞周期调控关键基因的mRNA表达水平以促进毛发再生，所述Wnt信号通路关键基因包括Wnt5a、Wnt11、Ctnnb1、Padi3、Hoxc13和Dlx3；所述BMP信号通路关键基因包括BMP2、BMP6和Runx1；所述细胞周期调控关键基因包括Ccnd1、Ccnd2和Ccna2。
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