CN104394867B - 含有嘌呤衍生物或其盐的用于预防或治疗过敏性皮肤炎的组合物 - Google Patents
含有嘌呤衍生物或其盐的用于预防或治疗过敏性皮肤炎的组合物 Download PDFInfo
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- CN104394867B CN104394867B CN201380019771.9A CN201380019771A CN104394867B CN 104394867 B CN104394867 B CN 104394867B CN 201380019771 A CN201380019771 A CN 201380019771A CN 104394867 B CN104394867 B CN 104394867B
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Abstract
本发明提供一种含有2‑氨基‑1,9‑二甲基嘌呤‑6‑酮或其药学上可接受的盐作为有效成分的用于预防或治疗过敏性皮肤炎的药学组合物。此外，本发明提供一种含有2‑氨基‑1,9‑二甲基嘌呤‑6‑酮或其药学上可接受的盐的用于改善过敏性皮肤炎的化妆品组合物；以及含有2‑氨基‑1,9‑二甲基嘌呤‑6‑酮或其药学上可接受的盐的用于预防或改善过敏性皮肤炎的食品(即，功能性食品)。
Description
技术领域
本发明涉及含有嘌呤衍生物或其盐的用于预防或治疗过敏性皮肤炎的组合物。更具体地，涉及含有从球孢虫草中新分离的嘌呤衍生物或其盐的用于预防或治疗过敏性皮肤炎的药学组合物。此外，本发明涉及含有所述嘌呤衍生物的用于改善过敏性皮肤炎的化妆品组合物，以及含有所述嘌呤衍生物的用于预防或改善过敏性皮肤炎的食品(即，功能性食品)。
背景技术
过敏性皮肤炎(atopic dermatitis)是伴随皮肤干燥症、角化及瘙痒症的慢性皮肤疾病，给总人口的0.5～1％，尤其是给儿童的5～10％带来痛苦，近年来呈患者数量增长更多的趋势。发生过敏性皮肤炎的患部上将大大剧增大噬细胞、肥大细胞、Th淋巴细胞等免疫相关细胞的浸润。过敏性皮炎患者血液中的IgE浓度将大大上升，其原因在于，Th2细胞数量增加而该细胞分泌的IL-6等细胞因子刺激B淋巴细胞，从而促进IgE的分泌。因此，过敏性皮肤炎被归类为与免疫体系异常相关的Th2-型皮肤疾病。过敏性皮肤炎给患者带来肉体上、精神上的痛苦的同时，导致经济上的损失，然而，至今还未发现用于该疾病的特效药。目前，将类固醇、抗阻胺类药等用作过敏性皮肤炎治疗剂，然而，长期使用此类药物会引起严重的副作用，因此，现状为需要一种能够代替此类药物的药物。
冬虫夏草是昆虫寄生真菌，属于虫草属(Cordyceps)，目前已知有300余种分布在全世界。冬虫夏草侵入到昆虫的幼虫、蛹、成虫等中，将昆虫杀死后将其作为寄主形成子实体及果实(fruit)。自古以来，冬虫夏草作为长生不老秘方药而驰名中国，并广泛地被用作用于治疗包括哮喘的呼吸器官疾病、包括黄疸的肝脏疾病的汉方药材。近年来，对冬虫夏草的免疫力增强效果方面正在广泛地进行研究。有报道称，蝙蝠蛾冬虫夏草(C.sinensis)提取物、蛹虫草(C.militaris)提取物或作为冬虫夏草主要成分的虫草素(cordycepin)不仅起到免疫调节物质的作用，而且还具有抗炎物质的作用。
球孢虫草(C.bassiana)是冬虫夏草中的一种寄生于属鳞翅目类(Order Lepidoptera)昆虫中的真菌，由中国第一次报道，在韩国也发现有球孢虫草。球孢白僵菌(Beauveria bassiana)是球孢虫草的生活周期中出现的一种形态，从很久前开始在中国和韩国(东医宝鉴)被用于神经性疾病、癌、皮肤感染、创伤等的治疗，然而，球孢虫草的子实体对人体所具有的功效完全未被公开过。
此外，公开有球孢虫草的提取物有助于皮肤瘙痒及过敏性皮肤炎的预防及治疗(韩国专利授权第10-1013061号)，并且，还公开有包括球孢虫草热水提取步骤的球孢虫草提取物的改善的制备方法(韩国专利授权第10-1079221号)。另外，还公开有抗过敏功能性化妆香皂组合物、抗过敏功能性化妆品组合物、抗过敏功能性食品组合物、抗过敏功能性冰淇淋组合物等(韩国授权专利第10-1104408号，10-2010-0122356，韩国专利公开第10-2010-0122357号及专利公开第10-2010-0122359号)。
发明内容
本发明要解决的技术问题
本发明人为了从球孢虫草的提取物中分离出显示过敏性皮肤炎的活性的单一物质，进行了多种研究。尤其，本发明人对诸多提取馏分进行了分析及活性评价，其结果，惊讶地发现之前从未被报道过的作为球孢虫草成分的嘌呤衍生物对过敏性皮肤炎具有优异的抑制活性。
因此，本发明的目的在于，提供一种含有所述嘌呤衍生物作为有效成份的用于预防或治疗过敏性皮肤炎的药学组合物。
此外，本发明的目的在于，提供一种含有所述嘌呤衍生物的用于改善过敏性皮肤炎的化妆品组合物。
此外，本发明的目的在于，提供一种含有所述嘌呤衍生物的用于预防或改善过敏性皮肤炎的食品(即，功能性食品)。
解决技术问题的技术手段
根据本发明提供一种含有下述化学式1的化合物或其药学上可接受的盐作为有效成分的用于预防或治疗过敏性皮肤炎的药学组合物。
〈化学式1〉
根据本发明的药学组合物可以为用于皮肤给药的剂型，例如，可以为选自由溶液、凝胶、乳液、悬浮液、微乳液、微胶囊、脂质体、霜剂(cream)、洗剂、软膏、气雾剂、喷雾剂、糊剂、贴剂组成的组。根据本发明的药学组合物，以组合物总重量计，所述化学式1的化合物的含量为0.005～0.5重量％。
而且，根据本发明，提供一种含有所述化学式1的化合物或其药学上可接受的盐的用于改善过敏性皮肤炎的化妆品组合物。根据本发明的化妆品组合物中，以组合物总重量计，所述化学式1的化合物的含量为0.005～0.5重量％。。
此外，根据本发明，提供一种含有所述化学式1的化合物或其药学上可接受的盐的用于预防或改善过敏性皮肤炎的功能性食品。所述功能性食品可以具有粉末、颗粒、片剂、胶囊、糖浆或饮料的形态。
有益效果
通过本发明揭示了从球孢虫草中新分离的嘌呤衍生物，即化学式1的化合物对过敏性皮肤炎具有优异的抑制活性。因此，含有所述化学式1的化合物的本发明的药学组合物可有效地用于预防或治疗过敏性皮肤炎。此外，含有所述化学式1的化合物的本发明的化妆品组合物作为用于改善过敏性皮肤炎的化妆品，即，可以有效地用作抗过敏功能性化妆品。
附图说明
图1示出将化学式1的化合物对过敏性皮肤炎动物模型NC/Nga小鼠给药10天后的各组小鼠的外形(NC：正常对照组，AC：过敏对照组，0.03％：将化学式1的化合物以0.03重量％的浓度处理的实验组，0.1％：将化学式1的化合物以0.01重量％的浓度处理的实验组)。
图2示出将化学式1的化合物对过敏性皮肤炎动物模型NC/Nga小鼠给药10天后，通过苏木精—伊红(hematoxylin-eosin(H&E))法对从各组小鼠的患部组织中得到的组织切片进行染色的结果(NC：正常对照组，AC：过敏对照组，0.03％：将化学式1的化合物以0.03重量％的浓度处理的实验组，0.1％：将化学式1的化合物以0.01重量％的浓度处理的实验组)。
图3至图6分别示出将化学式1的化合物对过敏性皮肤炎动物模型NC/Nga小鼠给药10天后，对各组小鼠的皮肤炎指数(图3)、表皮层的厚度(图4)、左右耳厚度的差异(图5)及血清LgE浓度(图6)进行测定的结果(NC：正常对照组，AC：过敏对照组，0.03％：将化学式1的化合物以0.03重量％的浓度处理的实验组，0.1％：将化学式1的化合物以0.01重量％的浓度处理的实验组)。
图7及图8分别示出将化学式1的化合物对过敏性皮肤炎动物模型NC/Nga小鼠给药10天后，对各组小鼠的肥大细胞分布(图7)及肥大细胞的数量(图8)进行测定的结果(NC：正常对照组，AC：过敏对照组，0.03％：将化学式1的化合物以0.03重量％的浓度处理的实验组，0.1％：将化学式1的化合物以0.01重量％的浓度处理的实验组)。
图9示出使用化学式1的化合物对由脂多糖(lipopolysaccharide)诱发炎症的Raw264.7细胞进行处理时，对已知为炎性细胞因子的IL-6、IL-10、IL-12p40及COX-2的mRNA的表达进行测定的结果。
具体实施方式
本说明书中所述的“过敏性皮肤炎(atopic dermatitis)，”亦被称为过敏性皮肤疾病，包括伴随过敏性皮肤炎的疾病，即包括皮肤干燥症、皮肤角化、皮肤瘙痒症等。
本发明提供一种含有下述化学式1的化合物或其药学上可接受的盐作为有效成分的用于预防或治疗过敏性皮肤炎的药学组合物。
〈化学式1〉
本申请人根据本申请人的在先发明(专利授权第10-1079221号)中公开的方法得到球孢虫草提取物(CBW-Es)。用甲醇等醇类溶解所述提取物后，对通过硅胶柱色谱法得到的馏分物实施Prep-HPLC法，从而分离出多种物质，并对在结构上与糖及其它嘌呤类化合物具有结构类似性的各种化合物，通过重结晶方法及结构-活性分析方法等过程分离出显示明显活性的单一物质。
对得到的物质通过UV、IR、H-NMR、C-NMR及EI-MS等能谱数据进行结构分析的结果，惊讶地发现该物质为以前未被报道过的球孢虫草中的嘌呤衍生物，即具有所述化学式1的结构的2-氨基-1,9-二甲基嘌呤-6-酮。虽然化学式1的化合物被证实为已知物质(CAS42484-34-4)，但是对包括过敏性皮肤炎的其药理活性还未被报道过。所述化学式1的化合物可以通过已知方法合成。(R.LeBreton，XuYang，ShigeyukUrano，Sharon Fetzer，Min Yu，Nelson J，Leonardk Shiv Kumar，J.Am.Chem.Soc.,1990，112，2138-2147)。所述化学式1的化合物的盐可具有以氮原子为介质的多种酸加成盐形状，例如盐酸、硝酸、硫酸等的无机酸加成盐；以及醋酸、樟脑磺酸、柠檬酸等的有机酸加成盐。
本发明的药学组合物可以包括药学上可接受的载体，例如，乳糖、玉米淀粉等赋形剂，硬脂酸镁等润滑剂，还可以包括已知可使用的乳化剂、悬浮剂、缓冲剂、等张剂等。本发明的药学组合物可制备成经口或非经口的给药形态，优选制备成非经口给药形状，更优选制备成用于皮肤给药的剂型，例如，可以制备成选自由溶液、凝胶、乳液、悬浮液、微乳液、微胶囊、脂质体、霜剂、洗剂、软膏、气雾剂、喷雾剂、糊剂及贴剂组成的组中的剂型。而且，本发明的药学组合物可以为包括诸如pH为7.4的盐水的药学上可接受的载体的水溶液剂的形态，可以以溶液、悬浮液、乳液、半固态剂等形态局部地涂抹于皮肤。例如，可以根据需要将美白剂、保湿剂、抗氧化剂、紫外线吸收剂、表面活性剂、增稠剂、水性介质(例如，水，酒精等)、皮肤营养剂适当地混合制成制剂。所述药学组合物中，以组合物总重量计，化学式1的化合物的含量为0.005～0.5重量％，优选为0.03～0.3重量％，但不限定于此。
本发明的药学组合物，可以以一天约0.01至10mg/kg的用量对患有各种过敏性皮肤炎的患者给药。通常可以根据患者的年龄、体重及症状而适当地改变给药量。
本发明还提供一种含有所述化学式1的化合物或其药学上可接受的盐的用于改善过敏性皮炎的化妆品组合物。
本发明的化妆品组合物为含有化学式1的化合物或其药学上可接受的盐的组合物，对其形态没有限定。即，本发明的化妆品组合物的形态可以为霜剂、面膜、洗剂、精华素、化妆水、粉底及隔离霜等常用的化妆品组合物的形态，所述化妆品组合物可以通过常用的方法与化妆品领域中常用的载体一起被制剂化。关于所述化学式1的化合物或其药学上可接受的盐的含量，例如，在每单位化妆品组合物中的含量可以为0.005～0.5重量％，优选为0.03～0.3重量％。当然，所述含量可以根据需改善的过敏性皮炎的程度等而有所不同。
本发明还提供一种含有所述化学式1的化合物或其药学上可接受的盐的用于预防或改善过敏性皮肤炎的功能性食品。
本发明的功能性食品可用作健康功能食品。所述“健康功能食品”是表示使用根据健康功能食品相关法律第6727号的对人体有利的功能性原料或成分进行制备或加工的食品，所述“功能性”是表示对人体结构及功能能够获得调节营养素或对诸如生理学作用等的保健用途有利的效果，并以获得上述效果为目的而进行摄取。
本发明的食品组合物可以包括常用的食品添加物，在对“食品添加物”的合适与否没有其他规定的情况下，将根据食品医药品安全局承认的食品添加物规程及一般实验法对相应品目相关规格及标准进行判定。在所述“食品添加物规程”中记载的品目中，可以例举酮类、甘氨酸、柠檬酸钾、烟酸、桂皮酸等化学合成物；柿子色素、甘草提取物、结晶纤维素、高粱色素、瓜尔豆胶等天然添加物；L-谷氨酸钠制剂、面类碱性添加剂、防腐剂、焦油色素制剂等混合制剂类等。
本发明的功能性食品以预防及/或改善过敏性皮肤炎为目的，以组合物总重量计，可以以0.01～95％，优选以1～80％重量％的重量百分率含有所述化学式1的化合物。并且，以预防及/或改善过敏性皮肤炎为目的，可以制备及加工成粉末、颗粒、片剂、胶囊、糖浆或饮料等形态。
例如，所述片剂形状的健康功能性食品可以通过常用的方法将化学式1的化合物、赋形剂、粘合剂、崩解剂及其他添加剂的混合物颗粒化后，加入润滑剂等压缩成型；或者可以将所述混合物直接压缩成型。此外，所述片剂形态的健康功能食品根据需要可以含有甜味剂等，根据需要可以以适当的包衣剂进行包衣处理。胶囊形态的健康功能性食品中硬质胶囊剂可以通过在常用的硬质胶囊中填充所述化学式1的化合物及赋形剂等添加剂的混合物或其粒状物或进行了包衣的粒状物而制备，软胶囊剂可以通过将化学式1的化合物及赋形剂等添加剂的混合物填充于明胶等胶囊基材而制备。所述软胶囊剂根据需要可以含有甘油或山梨醇等可塑剂、着色剂、保存剂等。颗粒形态的健康功能性食品可以通过适当的方法将所述化学式1的化合物、赋形剂、粘合剂、崩解剂等混合物制备为颗粒状，根据需要可以含有矫味剂、甜味剂等。对所述赋形剂、粘合剂、崩解剂、润滑剂、甜味剂、矫味剂等的术语定义记载在本领域的公知的文献中，包括与其功能相同或类似的添加剂(大韩药典解说篇，文成祠，韩国药学大学协议会，第5修订版，p33-48,1989)。
下面，将通过实施例对本发明进行更详细的说明。然而，这些实施例只是为了例示本发明，本发明的范围不限定于这些实施例。
实施例1：对过敏性皮肤炎的化学式1的化合物的生物体内(invivo)的抑制活性评价
1.试验方法
(1)过敏性皮肤炎的诱发
将作为过敏性皮肤炎的模型动物的NC/Nga小鼠(雄性，6周龄)的背部的毛去除干净，并放置24小时以使皮肤的细微伤口愈合，然后诱发过敏性皮肤炎。过敏性皮肤炎是通过对去除了毛的部位以150μl的量,每周涂抹两次，共涂抹四周下述溶液诱发的，所述溶液是在丙酮/橄榄油(3:1，v/v)溶液中，使2,4-DNFB(2,4-二硝基氟苯)的浓度为0.2％而制得。
(2)试验物质的给药
对正常对照组(NC)只实施了背部除毛；对过敏对照组(AC)，诱发过敏性皮肤炎，并在除毛的部位仅涂抹凡士林。对试验组，诱发过敏性皮肤炎，并将化学式1的化合物以0.03重量％及0.1重量％的比例与凡士林混合并涂抹于患部，并且涂抹10天，每天涂抹两次。各组分别使用了8只。
(3)过敏性皮肤炎治疗活性评价
分别测定皮肤炎指数(dermatitis score)、表皮层厚度、左右耳厚度、血清IgE浓度及肥大细胞的数量来评价对过敏性皮肤炎的治疗活性。
皮肤炎指数是通过在试验物质的处理结束时，观察患部，并将红斑、出血、疱痂等肉眼观察到的变化分为1-10个阶段进行评价，从而计算出皮肤炎指数。与过敏性对照组(AC)进行对比计算出试验组的减少率。
在患部的中央部截取1cm×1cm大小的皮肤组织，并固定于10％的甲醛溶液中后，用石蜡包埋制成4μm的切片。通过苏木精—伊红(hematoxylin-eosin)法将组织切片进行染色后，使用光学显微镜放大200倍并选择5视野而进行表皮层厚度的计量。
对于左右耳厚度，在试验开始时和试验结束时，利用数字游标卡尺进行测定。
对于血清IgE浓度，从各组的小鼠的心脏采血并通过ELISA(酶联免疫吸附测定)法进行测定。
对于肥大细胞的数量，以0.5cm×1cm的大小截取老鼠患部中央部位的皮肤组织并固定于免疫组化非福尔马林锌固定(IHC zinc fixativeformalin-free)溶液中。并使用石蜡包埋皮肤组织后，连续制成4μm厚度的切片，并将各切片粘贴于由多聚-L-赖氨酸(poly-L-lysine)涂覆的幻灯片上。经过除石蜡与水化过程后用甲苯胺蓝(toluidine blue)染色，然后用光学显微镜放大200倍并选取3视野测定肥大细胞的数量。
在上面得到的所有测定值通过平均±标准偏差来算出，统计显著性鉴定是利用分散分析法(ANOVA)进行的。显著性水平定为，5％以下。
2.试验结果
用试验物质进行10天的处理时，各组的小鼠如图1所示，对从患部的皮肤组织中得到的组织切片，通过苏木精—伊红(H&E)方法进行染色的结果如图2所示。皮肤炎指数、表皮层的厚度、左右耳厚度差及血清IgE浓度的测定结果分别如图3至图6所示。此外，肥大细胞分布程度如图7所示，据此，肥大细胞数量的测定结果如图8所示。
对图3至图8的结果进行归纳如下述表1所示。表1示出对过敏性对照组(AC)的各评价项目的减少率(％)。
表1
| 减少率(％) | 试验组1 | 试验组2 |
| 皮肤炎指数 | 8.96* | 24.00*** |
| 表皮层厚度 | 36.13*** | 52.63*** |
| 耳厚度差异 | 7.69 | 38.46 |
| 血清IgE | 51.76 | 56.46** |
| 肥大细胞的数量 | 7.7 | 24.9** |
*p<0.05,**p<0.01,***p<0.001(与过敏对照组对比)
通过图1至图8的结果及所述表1可知，经过4周诱发过敏性皮肤炎，将化学式1的化合物分别以0.03％(试验组1)及0.1％(试验组2)的浓度对患部涂抹10天的结果，根据过敏性皮肤炎增加的皮肤炎指数、表皮层厚度、耳厚度差异、血清IgE的浓度及肥大细胞的数量均显著减少。
实施例2：炎症性细胞因子表达抑制活性评价
对已知为炎性细胞因子的IL-6、IL-10、IL-12p40及COX-2的表达的化学式1的化合物的抑制活性进行评价。即，将Raw264.7小鼠巨噬细胞系(ATCCTIB-71)的约1×106细胞涂抹于12孔板(12-well plate)中的各孔中，并在包括100U/ml青霉素、100μg/ml链霉素及10％胎牛血清(fetal bovine serum)的RPMI培养基中培养后，用400uM化学式1的化合物及1μg/ml的LPS进行处理，并在37℃,5％CO2的条件下培养24小时。从各组的培养液中分离细胞后用取试剂(Trizolreagent)进行处理而提取出总RNA。用第一链cDNA合成试剂盒(Firststrand cDNA synthesis kit，Fermentas)，根据制造公司的指南制备cDNA后，将同量的cDNA进行PCR扩增。这时所使用的目标蛋白质的正向(sense)及反向(antisense)引物根据文献(Zhi-Qiang Changet al.，J.Nutr.Sci.Vitaminol.，2011，27，p118-122，JiYeon Lee et al.，Biol.Pharm.Bull.，2007，30(11)，p2043-2051，E.V.Maryukhnichet al.，Biol.Sci.，2007，414，p242-245.)中公开的方法制备。PCR扩增是使用i-Master PCR试剂盒(i-Master PCR kit)，在包括各试验组cDNA和目标蛋白质(IL-6、IL-10及IL-12p40，COX-2)的正向/反向引物、对照组磷酸甘油醛脱氢酶(GAPDH)引物及250uM的dNTP、10mM的三羟甲基氨基甲烷盐酸盐(Tris-HCL)(pH8.3)、50mM的KCl、1.5mM的NgCl2的20μl的HiPi溶液(HiPi solution)中进行。
PCR以在94℃下进行30秒变性(denaturing)处理，在55～58℃下进行30秒退火处理(annealing)，以及在72℃进行1分钟拉伸(extension)处理的条件下进行，对各个引物的退火处理温度(annealing temperature)和周期数分别如下。GAPDH为在55℃下实施25周期；IL-6为在55℃下实施25周期，IL-10为在55℃下实施25周期，以及IL-12p40为在58℃下实施30周期；COX-2为在55℃下实施25周期。通过所述RT-PCR测定的各炎性细胞因子的mRNA的表达量如图9所示。
根据图9的结果可知，在用LPS诱发炎症的Raw264.7细胞中，化学式1的化合物能够有效地抑制已知为炎性细胞因子的COX-2、IL-6、IL-10及IL-12p40的mRNA的表达。因此，可知化学式1的化合物能够在转录水平上抑制过敏性皮肤炎。
Claims (5)
1.一种药学组合物，所述药学组合物含有化学式1的化合物或其药学上可接受的盐作为有效成分，并用于预防或治疗过敏性皮肤炎：
所述药学组合物具有用于皮肤给药的剂型。
2.根据权利要求1所述的药学组合物，其特征在于，所述用于皮肤给药的剂型选自由溶液、凝胶、乳液、悬浮液、微乳液、微胶囊、脂质体、霜剂、洗剂、软膏、气雾剂、喷雾剂、糊剂及贴剂组成的组。
3.根据权利要求1或2所述的药学组合物，其特征在于，以组合物总重量计，所述化学式1的化合物的含量为0.005～0.5重量％。
4.一种化妆品组合物，所述化妆品组合物含有化学式1的化合物或其药学上可接受的盐，并用于改善过敏性皮肤炎，
5.根据权利要求4所述的化妆品组合物，其特征在于，以组合物总重量计，所述化学式1的化合物的含量为0.005～0.5重量％。
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