CN114712375B - 一种羟基白桦酸化合物在制备皮肤病药物中的应用 - Google Patents
一种羟基白桦酸化合物在制备皮肤病药物中的应用 Download PDFInfo
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Abstract
本发明属于皮肤用药技术,具体涉及一种羟基白桦酸化合物在治疗皮肤病中的应用,尤其是湿疹、炎症性皮肤病与过敏性休克。本发明设计了多种皮肤外用给药剂型,包括溶液剂、凝胶剂、膏剂、贴剂、乳剂、喷膜剂,用于多种皮肤病的局部给药,发现其具有药效显著、毒副作用小的优势,尤其是解决了现有口服药物具有消化道毒性、用量大的问题。研究表明,使用本发明方法治疗皮肤病不仅有效、安全、治疗成本低,且在小鼠模型中,可遏制湿疹、皮炎的发展,缓解过敏性休克。
Description
技术领域
本发明属于皮肤用药技术,具体涉及一种羟基白桦酸化合物在治疗皮肤病中的应用,尤其是湿疹、炎症性皮肤病与过敏性休克。
背景技术
皮炎是人类常见的皮肤病,刺激性接触性皮炎是一种非免疫反应,由化学物质或物理制剂对皮肤的直接损害而发生,其速度快于皮肤自我修复的速度。大约80%的接触性皮炎病例是刺激性接触性皮炎。常见的刺激物包括肥皂、洗涤剂、水、溶剂和某些食品成分。目前,这些疾病最常见的治疗方法包括全身或局部应用皮质类固醇或免疫调节剂。虽然这些药物通常可以改善临床症状,但长期使用可能会出现全身或局部副作用。例如,环孢菌素A的给药会增加接触性皮炎中的调节性T细胞,导致许多不良反应,包括特异性状态下的肾功能不全,牙龈增生,帕金森综合征、白质脑病、紫外线诱导的皮肤癌和淋巴瘤。他克莫司和吡美莫司是免疫调节剂,也可有效治疗成人和儿童的接触性皮炎。然而,他克莫司治疗可导致胆固醇和血压水平升高,以及非黑色素瘤皮肤癌和淋巴瘤。此外,外用他克莫司会损害表皮通透性屏障功能,从而导致病情反弹。糖皮质激素也常用于治疗急性过敏性接触性皮炎和刺激性接触性皮炎,但持续使用这些药物可诱发重要的全身和皮肤副作用,如皮肤萎缩、通透性屏障功能障碍和皮肤感染风险增加。此外,肿瘤坏死因子TNF-α抑制剂,如英夫利昔单抗,虽然最近被证明可有效治疗皮炎,但也可引起严重的不良反应,包括脑膜炎,牛皮癣样和扁平苔藓样病变,以及增加淋巴瘤的患病风险。因此寻求经济、副作用较少的药物对临床治疗皮炎有重要意义。
几个世纪以来,中草药一直被用作皮肤病的全身治疗,包括过敏性接触性皮炎、刺激性接触性皮炎,既便宜又广泛可用。近年对一些中药及从中药分离到的活性成分进行研究发现,具有清热凉血、活血化瘀、养血润燥为主,兼以健脾利湿、解毒散结的中药方剂及单味中药均有不同程度的改善皮炎作用。例如丁香酚可显著降低PMA诱导的细胞释放的MPO量,从而抑制人类嗜中性粒细胞的促炎机制,控制皮炎等多种炎症性疾病。刺槐的根茎主要成分柳叶菊A通过抑制蛋白激酶C和NF-κB活化而表现出抗炎作用,进而抑制了TPA诱导的耳厚度增加和表皮增生。菊花提取物的主要成分芹菜素抑制TNF-α基因表达外以及TNF-α的分泌,改善皮肤病。此外,很多中药中提出来的活性成分,多糖、多酚、皂苷等类成分也具有改善皮肤通透性的作用。临床使用中草药全身治疗皮肤病,然而,与局部治疗相比,使用中草药进行全身治疗时,所需中药提取物剂量更高,因而增加给药成本和毒性。关于中草药局部应用在过敏性皮肤病如湿疹和接触性皮炎中的疗效的研究很少。
发明内容
本发明评估了局部使用羟基白桦酸化合物在佛波酯(TPA)诱导的急性接触性皮炎或2,4-二硝基氯苯(DNCB)诱导的湿疹和过敏性休克小鼠模型中的预防/治疗益处。
一种羟基白桦酸化合物在制备治疗过敏性皮肤病或者炎症性皮肤病药物中的应用。
一种羟基白桦酸化合物在制备治疗湿疹、过敏性休克药物中的应用。
本发明中,羟基白桦酸化合物的化学结构式如下:
本发明公开了一种治疗过敏性皮肤病或者炎症性皮肤病药物,其活性成分为上述羟基白桦酸化合物;还可以包括常规药物辅料,包括稀释剂、分散剂、粘接剂、润滑剂、促渗透剂中的一种或几种。
本发明公开了一种治疗湿疹、过敏性休克药物,其活性成分为上述羟基白桦酸化合物;还可以包括常规药物辅料,包括稀释剂、分散剂、粘接剂、润滑剂、促渗透剂中的一种或几种。
本发明公开了上述治疗过敏性皮肤病或者炎症性皮肤病药物的制备方法,将上述羟基白桦酸化合物与常规药物辅料混合,得到治疗过敏性皮肤病或者炎症性皮肤病药物。
本发明公开了上述治疗湿疹、过敏性休克药物的制备方法,将上述羟基白桦酸化合物与常规药物辅料混合,得到治疗湿疹和过敏性休克药物。
本发明中,治疗过敏性皮肤病或者炎症性皮肤病药物为外用药物,治疗湿疹和过敏性休克药物为外用药物,优选为皮肤外用药物。本发明的羟基白桦酸化合物为中药白头翁提取物,常规称为白头翁皂苷B4,分子量大,结构中含有5分子糖,传统上认为难以透过皮肤屏障,不适合于透皮给药,故未见任何经皮给药的文献报道。本发明中,外用药物剂型包括溶液剂、凝胶剂、膏剂、贴剂、乳剂、喷膜剂等;炎症性皮肤病包括皮炎等;过敏性皮肤病包括湿疹等;过敏性休克为过敏源导致的过敏性休克。本发明设计了多种皮肤外用给药剂型,用于多种皮肤病的局部给药,发现其具有药效显著、毒副作用小的优势,尤其是解决了现有口服药物具有消化道毒性、用量大的问题。
本发明中,溶液剂可以为羟基白桦酸化合物水溶液,也可为添加辅料的羟基白桦酸化合物水溶液,辅料为常规物质,比如甘油、苯甲酸钠、香精等;凝胶剂除了羟基白桦酸化合物外,还包括常规辅料,比如卡波姆、甘油、丙二醇、水等;软膏剂除了羟基白桦酸化合物外,还包括常规辅料,比如硬脂酸、单硬脂酸甘油酯、液状石蜡、白凡士林、水等;皮肤贴剂除了羟基白桦酸化合物外,还包括常规辅料,比如聚丙烯酸钠、传明酸、甘羟铝、EDTA(乙二胺四乙酸)、水等;微乳剂除了羟基白桦酸化合物外,还包括常规辅料,比如油酸、吐温、助乳化剂、水等;皮肤用喷膜剂除了羟基白桦酸化合物外,还包括常规辅料,比如聚乙酰吡咯烷酮、羟丙基甲基纤维素、水等。各剂型中,辅料及用量为常规技术,符合一般外用药物要求即可。
本发明的羟基白桦酸化合物提取自中药白头翁,与常规汤剂以及口服药不同,其作为活性成分制备为外用药物剂型,实现了病灶部位局部用药,尤其是解决了内服药物导致的毒性。本发明设计了多种皮肤外用给药剂型,用于多种皮肤病的局部给药,发现其具有药效显著、毒副作用小的优势,尤其是解决了现有口服药物具有消化道毒性、用量大的问题。
附图说明
图1为给药七天内的小鼠左右耳廓皮肤照片。
图2为给药七天内的小鼠左右耳皮肤照片。
图3为给药6天内的小鼠左右耳厚度差。
图4为给药第6天内的小鼠左右耳重量差。
图5为给药7天内各个给药组的生存率。
图6为给药第七天的小鼠左右耳廓皮肤照片。
图7为给药第8天的小鼠左右耳厚度差。
图8为给药第8天的小鼠脾指数。
图9为给药七天内的小鼠背部皮肤照片。
图10为给药7天的小鼠EASI评分。
具体实施方式
本发明中,羟基白桦酸化合物的化学结构式如下:
本发明羟基白桦酸化合物(B4)以及常规药物辅料都是常规市售产品,动物实验符合苏州大学要求,具体实验方法为常规技术。本发明以所述羟基白桦酸化合物为活性成分与常规辅料组成溶液剂、凝胶剂、膏剂、贴剂、乳剂、喷膜剂等,作为外用药物,实现皮肤外给药。作为示例,本发明给出几种剂型制备方法,如无特殊说明,浓度为质量浓度。皮肤用凝胶剂:称取卡波姆940撒于蒸馏水中,静置,过夜,使其充分溶胀。将甘油、丙二醇溶于适量蒸馏水中,倒入已溶胀充分的卡波姆940中,作为凝胶基质备用;另精密称取处方量羟基白桦酸化合物粉末,加蒸馏水混匀,在水溶温热的条件下,将药物溶液溶解于凝胶基质中,充分搅拌;然后加入10%氢氧化钠溶液调pH值至6.1-6.5内,加入蒸馏水定量至100 g,即得羟基白桦酸化合物凝胶剂;各成分最终浓度为羟基白桦酸化合物 0.1%-2%、卡波姆940 0.2%-2%、甘油0.5%-2%、丙二醇0.5%-2%。皮肤用软膏剂:称取硬脂酸、单硬脂酸甘油酯、液状石蜡、白凡士林,在70℃水浴下加热融化后作为油相,再精密称取羟基白桦酸化合物粉末及甘油和蒸馏水,在70℃水浴下加热融化后作为水相;然后在搅拌下,将水相倒入到油相中,使其成软膏状,即得羟基白桦酸化合物 W/O型软膏透皮制剂;各成分最终浓度为羟基白桦酸化合物 0.5%-1.5%、硬脂酸2%-8%、单硬脂酸甘油酯5%-20%、液体石蜡5%-20%、白凡士林5%-20%、甘油5%-15%。皮肤贴剂:称取聚丙烯酸钠、传明酸、甘羟铝、EDTA加入到甘油中,搅拌均匀,再加入水溶解,再精密称取羟基白桦酸化合物粉末,充分搅拌后制成药物层,再将药物层涂布到背衬层上,以防粘离型膜作为表面覆盖层,切分,即得羟基白桦酸化合物贴剂;各成分最终浓度为羟基白桦酸化合物 0.5%-1.5%、聚丙烯酸钠20%-30%、传明酸2%-8%、甘羟铝2%-5%、EDTA 0.1%-0.5%、甘油40%-50%。皮肤用微乳剂:分别取油酸和吐温-80混匀作为油相,精密称取适量的羟基白桦酸化合物溶于蒸馏水中作为水相,室温下将水相滴加到油相中,同时逐滴加入助乳化剂乙醇,磁力搅拌15 min,超声除去气泡,直至溶液呈澄明稠状液体,即得微乳;各成分最终浓度为羟基白桦酸化合物 0.2%-1%、油酸50%-60%、吐温-80 15%-20%、乙醇15%-20%。皮肤用溶液剂:精密称取羟基白桦酸化合物粉末,加入蒸馏水溶解,再加入甘油、苯甲酸钠、适量玫瑰香精混匀,补加水至1000mL,即得羟基白桦酸化合物溶液剂;各成分最终浓度为羟基白桦酸化合物 0.5%-1%、甘油5%-10%、苯甲酸钠0.05%-0.5%、玫瑰精油适量;可供皮肤上涂抹或喷雾给药。皮肤用喷膜剂:精密称取羟基白桦酸化合物粉末,加入蒸馏水溶解,再加入聚乙酰吡咯烷酮K30和羟丙基甲基纤维素混匀,补加水至1000mL,即得羟基白桦酸化合物喷膜剂;各成分最终浓度为羟基白桦酸化合物 0.5%-2%、聚乙酰吡咯烷酮K30 2%-6%、羟丙基甲基纤维素 0.1%-0.6%。
实施例一 软膏剂对皮炎的治疗作用
称取硬脂酸、单硬脂酸甘油酯、液状石蜡、白凡士林,在70℃水浴下加热融化后作为油相,称取羟基白桦酸化合物粉末及甘油和蒸馏水,在70℃水浴下加热融化后作为水相。然后在搅拌下,将水相倒入到油相中,使其成软膏状,即得羟基白桦酸化合物 W/O型软膏透皮制剂。各成分最终浓度为羟基白桦酸化合物 1%、硬脂酸5%、单硬脂酸甘油酯10%、液体石蜡10%、白凡士林10%、甘油9%。
将35只Balb/c小鼠按体重随机分为正常对照组、模型组、地塞米松阳性药组(7.5mg/kg)、羟基白桦酸化合物软膏低剂量组(6.6mg/kg)、羟基白桦酸化合物软膏高剂量组(13.2 mg/kg),每组7只。在每次TPA应用前,使用数字卡尺在第0、2、4和6天测量耳厚。第1-4天,除正常对照组以外,每天中午2点将TPA的丙酮溶液(12.5µg/ml)涂抹于小鼠右耳前后表面各50µl,正常对照组右耳涂抹等体积的丙酮;第1-5天,地塞米松组下午6点于右耳前后表面共涂抹地塞米松乳膏,6.4mg/kg·d;给药组上午10点分别于右耳前后表面共涂抹软膏,下午6点再同剂量涂抹一次,分别达到6.6mg/kg·d、13.2 mg/kg·d;模型组上午10点于右耳前后表面共涂抹200µl不含药物的空白软膏,下午6点涂抹一次;对照组分别于上午10点、下午6点涂抹等量的不含药物的空白软膏。连续处理5d。第6天不经任何药物处理,拍照记录测量耳厚度后处死。用打孔器获得直径为7mm的耳组织检查。称取耳活检并进行组织病理学分析。
当局部组织受到TPA刺激后,细胞的组织胺等介质被释放,通过H1和H2受体使耳部皮肤、粘膜毛细血管扩张及毛细血管壁通透性增高,导致水肿。实验结果表明,第一天涂抹TPA后,与正常对照组相比,模型组耳阔皮肤微微发红,随着药物的持续作用,模型组从第 2天开始红肿日益严重,出现细微鳞屑,皮肤浸润明显,且小鼠抓挠次数显著增加,对照组与模型组左右耳厚度差结果第2、4、6天(P<0.01)均有统计学意义,表明皮炎小鼠模型建立成功。
软膏高剂量组皮肤与模型组相比同期的耳肿胀症状明显减轻,耳朵仅轻微发红,浸润很轻;阳性药组皮肤微微泛红,几乎无鳞屑和肿胀(图1和图2),其中高剂量组与模型组左右耳厚度差结果在第2、4、6天(P<0.01)均有统计学意义;阳性药组与模型组厚度差结果在第2、4、6天(P<0.01)均有统计学意义;软膏低剂量组与模型组厚度差结果在第2、4、6天(P<0.01)均有统计学意义;高剂量组与阳性药组厚度差结果在第6天(P<0.05)有统计学意义(图3)。第6天处死实验动物,测量左右耳重量差值,结果表明模型组和对照组的左右耳重量差值有统计学意义(P<0.0001),软膏高剂量组、低剂量组与模型组左右耳重量差值有统计学意义(P<0.01,P<0.001)(图4)。实验结果提示本发明羟基白桦酸化合物软膏对TPA引起的接触性皮炎改变具有保护作用,效果几乎与糖皮质激素效果相当。
实施例二 皮肤用凝胶剂对过敏性休克的治疗作用
称取卡波姆940撒于蒸馏水中,静置过夜;将甘油、丙二醇溶于蒸馏水中,倒入已溶胀充分的卡波姆940中,作为凝胶基质备用。将羟基白桦酸化合物粉末加蒸馏水混匀,在40℃的条件下,将药物溶液溶解于凝胶基质中,搅拌,然后加入10%氢氧化钠溶液调pH值至6.2,加入蒸馏水定量至100 g,即得羟基白桦酸化合物凝胶剂;各成分最终浓度为羟基白桦酸化合物 1%、卡波姆940 1%、甘油1%、丙二醇1.1%。
研究上述凝胶剂对过量DNCB(2,4-二硝基氯苯)诱导的小鼠死亡模型的改善作用,设计如下实验。将35只Balb/c小鼠按体重随机分为正常对照组、模型组、地塞米松阳性药组、凝胶低剂量组(2mg/kg)、凝胶高剂量组(6.6mg/kg),每组7只。实验前1天,用一次性备皮刀给小鼠背部皮肤刮毛,均选取约3cmx3cm范围备用。第1天,除正常对照组以外,以7%DNCB200µl溶液外涂小鼠背部、1%DNCB 100µl溶液致敏,第2天同法强化涂抹1次。第1-7天,地塞米松组下午6点于背部和右耳壳内外涂抹地塞米松乳膏,7.5mg/kg·d;给药组上午10点分别背部和右耳壳内外涂抹凝胶剂,下午6点同剂量涂抹一次,分别达到6.6mg/kg·d、2mg/kg·d;模型组上午10点背部和右耳壳内外共涂抹200µl不含药物的空白凝胶,下午6点涂抹一次,对照组分别于上午10点、下午6点涂抹等量的不含药物的空白凝胶。连续处理7d。实验期间,每天观察小鼠背部皮损变化,并拍照记录。实验第一天涂抹造模药后,除对照组以外,各组小鼠背部出现糜烂、水肿、发红,同时小鼠躁动不安,搔抓次数显著增加。第二天再次给予造模药4小时以后,模型组小鼠开始出现抽搐、昏迷等休克症状,24h 内出现4只小鼠死亡;阳性药组出现3只小鼠死亡;凝胶剂2mg/kg组出现1只小鼠死亡、凝胶剂6.6mg/kg组无小鼠死亡。第三天模型组小鼠背部出现大片血痂,几乎丧失行动能力,24 h内模型组小鼠全部死亡,阳性药组出现2只小鼠死亡;凝胶剂2mg/kg组出现2只小鼠死亡、凝胶剂6.6mg/kg组出现1只小鼠死亡。第五天至第七天凝胶剂2mg/kg组、凝胶剂6.6mg/kg组小鼠皮肤无小鼠死亡(见图5)。实验结果提示本发明对过量DNCB引起的小鼠死亡具有保护作用,效果比糖皮质激素效果更优。
实施例三 溶液喷雾剂对湿疹的治疗作用
称取羟基白桦酸化合物粉末,加入蒸馏水溶解,再加入甘油、苯甲酸钠、玫瑰香精混匀,补加水至1000mL,即得羟基白桦酸化合物溶液剂。各成分最终浓度为羟基白桦酸化合物 0.7%、甘油7%、苯甲酸钠0.25%、玫瑰精油0.5%。可供皮肤上涂抹或喷雾给药。
研究药物对DNCB(2,4-二硝基氯苯)诱导的小鼠湿疹模型的改善作用,设计如下实验。将35只Balb/c小鼠按体重随机分为正常对照组、模型组、地塞米松阳性药组(7.5mg/kg)、溶液喷雾剂低剂量组(6.6mg/kg)、溶液喷雾剂高剂量组(13.2 mg/kg),每组7只。实验前1天,用一次性备皮刀给小鼠背部皮肤刮毛,均选取约3cm×3cm范围备用。第1天,除正常对照组以外,以5%DNCB 50µl溶液外涂小鼠背部致敏;第2天同法强化涂抹1次,再次致敏;第3天在小鼠右耳壳内、外用移液枪外涂1%DNCB丙酮酸溶液 50µl的激发,第4天、第5天继续激发,连续激发三天,左耳壳内涂抹等量的丙酮。模型成功的标准为DNCB溶液反复刺激小鼠右耳部及背部皮肤后出现不同程度的潮红、丘疹、水疱、糜烂、渗出、结痂、脱屑的表现。第1-7天,地塞米松组下午6点于背部和右耳壳内外涂抹地塞米松乳膏,7.5mg/kg·d;给药组上午10点分别背部和右耳壳内外喷涂药物喷雾剂,下午6点同剂量涂抹一次,分别达到6.6mg/kg·d、13.2 mg/kg·d。模型组上午10点背部和右耳壳内外共涂抹200µl不含药物的空白喷雾剂,下午6点涂抹一次;对照组分别于上午10点、下午6点涂抹等量的不含药物的空白喷雾剂。连续处理7d。
试验期间,每天观察每组小鼠背部皮肤的湿疹情况(皮肤上明显的红肿、斑疹、糜烂和渗出)并拍照,参考各组小鼠皮肤临床症状采用湿疹面积及严重指数(EASI)评分标准,从红斑、丘疹/脓疱、鳞屑、结痂4项指标进行评价,以0~3分进行记分:0分=无症状,1分=轻度,2分=中度,3分=重度,将各指标积分相加得到总积分。由两名观察者采取盲法的方式分别在干预第1、3、5和第7天进行评分,并采用数码照相的方法进行记录。末次给药后24h。用游标卡尺测量双耳厚度(取3个点测量后取均值),计算厚度差:厚度差=右耳厚度-左耳厚度;每天称量体重并记录。
当局部组织受到DNCB刺激后,细胞的组织胺等介质被释放,通过H1和H2受体使耳部皮肤、粘膜毛细血管扩张及毛细血管壁通透性增高,导致水肿。实验结果表明,第三天首次涂抹DNCB后,与空白组相比,模型组耳阔皮肤微微发红,随着药物的持续作用,模型组从第 4天开始红肿日益严重,出现脱屑,第五天开始出现渗出,溃烂并开始结痂。对照组与模型组左右耳厚度差结果第7天(P<0.0001)有统计学意义,表明湿疹小鼠模型建立成功。溶液剂高剂量组耳廓与模型组相比同期的耳肿胀症状明显减轻,耳朵几乎无溃烂;阳性药组溃烂严重,有明显的渗出和结痂(图6),其中高剂量组与模型组左右耳厚度差结果在第7天(P<0.0001)有统计学意义;阳性药组与模型组厚度差结果在第7天(P<0.0001)均有统计学意义;溶液剂低剂量组与模型组厚度差结果在第7天(P<0.0001)有统计学意义(图7)。实验结果发现给DNCB 7天后,模型组小鼠的脾指数明显升高,药物组脾指数明显降低,但高于正常对照组;地塞米松组脾指数明显低于正常对照组,提示本发明对免疫系统的毒副作用明显低于地塞米松(图8)。背部皮肤涂抹DNCB后,与空白组相比,模型组皮肤出现渗出、糜烂及结痂,产生类似湿疹样皮损。随着DNCB的持续作用,模型组从第 2天开始皮损日益严重,出现明显的红斑,皮肤浸润、结痂明显,对照组与模型组EASI综合评分结果第3、5、7天(P<0.0001)均有统计学意义,表明湿疹小鼠模型建立成功。高剂量组皮肤与模型组相比同期的皮损症状明显减轻,皮肤较光滑,渗出较少,结痂轻微或脱落最早;阳性药组皮肤结痂较严重,痂皮几乎无脱落,有明显的鳞屑和丘疹(图9),其中高剂量组与模型组EASI综合评分差异结果第3天(P<0.001)、5天(P<0.0001)、7天(P<0.001)均有统计学意义;阳性药组与模型组EASI综合评分差异在第3天(P<0.001)有统计学意义,低剂量组与模型组EASI综合评分差异在第3天(P<0.0001)、5天(P<0.0001)有统计学意义;高剂量组与地塞米松阳性药组EASI综合评分在第5(P<0.0001)、第7天(P<0.001)均有统计学意义(图10)。实验结果提示本发明对DNCB引起的湿疹皮损改变具有保护作用,效果比糖皮质激素效果更优,而安全性更高。
Claims (3)
1.一种羟基白桦酸化合物在制备治疗过敏性休克药物中的应用,其特征在于,所述药物为外用药物;所述羟基白桦酸化合物的化学结构式如下:
。
2.根据权利要求1所述的应用,其特征在于,外用药物剂型包括溶液剂、凝胶剂、膏剂、贴剂、乳剂、喷膜剂。
3.根据权利要求1所述的应用,其特征在于,DNCB诱导过敏性休克。
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