CN105816594A - 一种用于治疗痤疮的药物组合物及其制备方法和用途 - Google Patents
一种用于治疗痤疮的药物组合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明提供了一种用于治疗痤疮的药物组合物，由丹参、紫草、芦荟和冰片四味药物组成；本发明提供了一种用于治疗痤疮的组合药物及其乳膏制剂，本制剂提供的药物组合具有止痒消炎的良好活性，优于目前常用市售红霉素软膏。
Description
技术领域
本发明涉及一种外用药物制剂，更具体的说涉及一种用于治疗痤疮的药物组合物及其制剂。
技术背景
痤疮是一种常见病、多发病，除与内分泌、免疫等因素有关外，皮脂分泌过多和毛囊角质化过度也参与发病，痤疮丙酸杆菌等厌氧菌和金黄色葡萄球菌、表皮葡萄球菌等需氧菌的混合感染亦与其密切相关。痤疮患者皮损区，上述菌群都比健康入增加，痤疮丙酸杆菌是人体皮肤的优势菌种，由于皮脂腺发育快速、皮脂分泌过量、毛囊皮脂腺导管异常角化、皮脂排出受阻，痤疮丙酸杆菌在局部厌氧环境下得以生长繁殖，导致毛囊、皮脂腺继发感染。痤疮丙酸杆菌突出的致病性已被证实，不仅能诱导机体的免疫反应和局部炎症，还与毛囊导管上皮细胞角化过度过快相关。由于皮脂排泄不畅又可促使痤疮丙酸杆菌和金黄色葡萄球菌、表皮葡萄球菌等部分需氧菌生长繁殖，引发炎性丘疹、脓疱。从中医理论上讲，痤疮的发生与外感秽浊湿邪、嗜食肥甘厚味、饮食不节或情志内伤等因素相关，加之素体阳热偏盛，恣食辛辣肥甘之品，脾胃失健，滋生湿浊，久蕴化为湿热浊毒，郁结头面而成痤疮。
丹参性微寒、味苦，有活血通络、凉血消肿的功效。有研究认为，丹参酮有抗菌作用，可以显著抑制致病菌的生长繁殖。其中隐丹参酮对革兰阳性细菌抗菌作用强，能抑制急性及亚急性炎症反应，并可明显抑制痤疮丙酸杆菌数量。有研究证实，活血化瘀也是丹参酮的重要功能，可以改善面部的血液循环，促使面部皮肤的新陈代谢增加。因此丹参常被作为治疗痤疮的主要中药成分。
在市售的痤疮外用制剂中，复方丹参酮祛痘胶含有的中药主要成分是丹参；青痤乳膏由大黄、丹参、赤芍、白芷、僵蚕、冰片等组成。在现有技术中多采用丹参为君药的药物组合治疗痤疮，
如中国专利申请“一种快速治疗痤疮的中药擦剂(CN00123396.3)”就提供了一种主要配方由蛇床子、芦荟、丹参、生地、虫草、灵芝、甘草、金银花等配成。用于治疗痤疮的中药组合药物。在该配方中，蛇床子、芦荟、丹参和生地作为君药,共同发挥杀菌消炎的活性作用。
中国专利申请“一种防治痤疮皮肤病的外用中药擦剂及其制备方法(CN201110374815.2)”提供了一种由苦参、丹参、黄芩、雪胆、芦荟、甘草和冰片组成的外用药物制剂，在该制剂中苦参和丹参作为君药是主要活性成分。中国专利“丹参酮ⅡA在制备抑制痤疮丙酸杆菌的药物或化妆品中的用途(CN201310023814.2)”开了丹参酮IIA在用于制备预防或治疗由痤疮丙酸杆菌繁殖引起的粉刺的药物或化妆品中的用途。
体外抑菌试验是国内外检验抗生素效价的通用方法，也是各国药典规定的方法。待检菌对测定药物的敏感程度通过抑菌圈的大小反应，抑菌圈越大，MIC越小，药物的抑菌效果也就越强。本实验证明，复方丹参酮祛痘胶对痤疮主要致病菌群有很好的抑制作用，对痤丙酸杆菌的MIC为7.82，对表皮葡萄球菌、柠檬葡萄球菌的MIC为15.63～62.5。治疗痤疮药物的疗效需多方面综合评价，通过本临床疗效观察和体外抑菌实验证实，复方丹参酮祛痘胶对痤疮患者皮损症状改善明显，且疗效显著、可靠，对于其作用机理的探讨为临床用药提供了可靠的依据。
发明内容
为解决上述问题，本发明提供了一种用于治疗痤疮的药物组合物，由丹参、紫草、芦荟和冰片四味药物组成。
由丹参和紫草的乙醇提取物、芦荟的水提物以及冰片组成。
所述丹参、紫草、芦荟和冰片的重量比为5-50:5-50:5-50:1-5。
所述丹参、紫草、芦荟和冰片的重量比为16:16:10:2。
一种用于治疗痤疮的药物组合物乳膏的制备方法，包括以下步骤：
1)丹参、紫草粉碎成粗粉，以乙醇作为溶剂，进行渗漉，浓缩，得到丹参紫草醇提物；
2)将丹参紫草醇提物与冰片粉末一起加入油相基质；
3)混合水相基质和油相基质，得到用于治疗痤疮的组合药物半成品乳膏；
4)芦荟干品粉碎成粒径小于75μm的超微粉，加入半成品乳膏中，继续搅拌均匀，冷却形成组合物乳膏。
步骤1)所述的用乙醇浓度为70-90％。
步骤2)所述的油相为硬脂酸、硬脂酸甘油酯、白凡士林、羊毛脂、蜂腊、高级醇(如十八醇和十六醇等)等一种或几种形成的混合物。
步骤3)所述的水相基质为在水中加入甘油、水、乳化剂(三乙醇胺、十二烷基硫酸钠等)透皮促进剂和防腐剂形成的混合物。
上述所述的的用于治疗痤疮的药物组合物在制备治疗痤疮药物中的应用。
本发明的有益技术效果是：本发明提供了一种用于治疗痤疮的组合药物及其乳膏制剂，本制剂提供的药物组合具有止痒消炎的良好活性，优于目前常用市售红霉素软膏。
具体实施方式
实施例1不同丹参药物组合的抑菌活性研究
菌种：
菌株痤疮丙酸杆菌标准菌株ATCC1l827、金黄色葡萄球菌标准菌株ATCC100817。
试剂：
痤疮丙酸杆菌培养基；脑心浸液培养基；金黄色葡萄球菌：牛肉膏培养基。
培养基按常规方法配制，调pH值为7.1～7.2。将培养基于锥形瓶中密封好后，放入灭菌锅中于121℃下灭菌30min，待冷却后，置于4℃冰箱中保存备用。
菌悬液的制备将标准菌株分别接种培养增菌，在常规培养条件下培养24h(痤疮丙酸杆菌用厌氧手套箱培养48h)，吸取菌液用培养基稀释调整为0.5个麦氏比浊单位(约为1.5×108CFU/mL)，将菌悬液用培养基继续稀释，用麦氏比浊仪将调整为1×105～106CFU/mL，备用。
供试液制备
称取丹参药材，用90％的乙醇渗漉提取，渗漉溶媒的量为药材5倍重量，回收提取液，浓缩制备得到丹参提取物，提取物中丹参酮ⅡA的转移率高于70％，给名为实验组A；
称取芦荟干品，芦荟干品粉碎成粒径小于75μm的超微粉，给名为实验组B；
称取紫草药材，用90％的乙醇渗漉提取，渗漉溶媒的量为药材5倍重量，回收提取液，浓缩制备得到紫草提取物，给名为实验组C；
按重量比1:1称取丹参和紫草，用90％的乙醇渗漉提取，渗漉溶媒的量为药材5倍重量，回收提取液，浓缩制备得到丹参和紫草提取物；给名为实验组D；
将上组得到的实验组B与实验组C混合，混合的比例为丹参、紫草和芦荟重量比1:1:1；给名为实验组E；
将实验组B与冰片粉末混合，混合的比例为丹参、紫草、芦荟和冰片重量比为10:10:10:1；得到实验组F。
抑菌圈测定
在无菌操作条件下，分别取上述菌悬液，用涂布棒均匀涂抹在培养基上。再用无菌镊将牛津杯轻放在凝固的培养基表面，轻压牛津杯使接触良好。用一次性注射针吸取供试液于牛津杯中，37℃培养箱培养24h后取出(痤疮丙酸杆菌用厌氧手套箱培养48h)，用卡尺准确测量各培养皿中供试液有效抑菌圈的直径。各样品重复3次。另外配制对照组：空白对照组(培养基)、阴性对照组(培养基、菌悬液、无菌水)、阳性对照组(培养基、菌悬液、红霉素)，来观察细菌的生长情况、培养基和中草药对细菌生长的影响。具体如表1所示。
表1各种提取物对痤疮致病菌的抑制圈(n＝3)
注：为重复3次实验的的平均结果，“-”表示无明显抑菌圈
从表1中的统计结论可以发现，紫草的提物多痤疮丙酸杆菌不具备活性，而有丹参、紫草、芦荟和冰片组成的混合抑菌效果最为理想；其中在对痤疮丙酸杆菌的活性上接近红霉素的活性。
最小抑菌浓度(MIC)测定
采用试管2倍稀释法，测定将上述各组供试液最小抑菌浓度(MIC)。在上述抑菌圈测定中对两种致病菌均有抑菌效果的中药供试液用液体培养基依次稀释l0、20、40、80、160、320、640、1280和2560倍。即最终药液(原药材含量)的浓度分别为lOOmg/mL、50mg/mL、25mg/mL、12.5mg/mL、6.25mg/mL、3.125mg/mL、1.5625mg/mL、0.7825mg/mL、0.3913mg/mL。在lmL的稀释液中加入0.1mL的菌悬液。并设无药菌液对照管、纯中药对照管和阳性对照管。37℃培养24h(痤疮丙酸杆菌用厌氧手套箱培养48h)，观察结果。从无菌生长的各管中找出最低稀释液浓度的实验管，确定MIC；具体见表2所示。
表2各组提取物对痤疮致病菌的MIC(mg/mL)(±s)
注：为3次重复实验的平均值。
实施例2治疗痤疮的丹参组合药物乳膏在药效学考察
称取丹参160g、紫草160g、芦荟96g、冰片16g；以上四味，取芦荟粉碎成粒径小于75μm的超微粉；冰片研细；取丹参、紫草粉碎成粗粉，以90％乙醇作为溶剂，浸渍24小时后，进行渗漉，收集渗漉液，减压回收乙醇至无醇味，与冰片细粉一起加入油相基质(硬脂酸9g、单双硬脂酸甘油酯36g、白凡士林90g、羊毛脂72g、十六醇72g)充分搅匀，于80℃保温，备用；另取甘油117g、十二烷基酸钠18g、羟苯乙酯1.8g、氮酮20g和适量水作为水相，于80℃保温，备用。将上述油相基质缓慢加入水相基质中，采用后加法加入芦荟细粉，边加边搅拌(1000r/min),80℃保持15min，降至室温，制成1000g乳膏，分装，即得药物组Ⅰ；
称取丹参500g、紫草50g、芦荟50g、冰片10g；采用上述方法制备得到药物组Ⅱ；
称取丹参50g、紫草500g、芦荟500g、冰片50g；采用上述方法制备得到药物组Ⅲ。
称取丹参500g，以90％乙醇作为溶剂，进行渗漉，收集3800ml渗漉液，减压回收乙醇至稠膏(密度为不低于1.2)，和打成细粉的冰片一起加入油相基质(硬脂酸9g、单双硬脂酸甘油酯36g、白凡士林90g、羊毛脂72g、十六醇72g)充分搅匀，于80℃保温，备用；制备水相基质(适量水中加入甘油117g、十二烷基酸钠18g、羟苯乙酯1.8g、氮酮20g)溶解，于80℃保温，备用。将上述油相基质缓慢加入水相基质中，边加边搅拌1000r/min,80℃保持15min，制成1000g乳膏，降至室温，即得玄参对照组。
抗炎试验：采用小鼠耳肿胀法，选取SD大白鼠60只，雌雄各半，体重180-220g。将6O只鼠随机分为6组，每组10只，即空白对照组，药物组Ⅰ、药物组Ⅱ、药物组Ⅲ、玄参对照组和阳性药物对照组。药物组Ⅰ、药物组Ⅱ、药物组Ⅲ、玄参对照组分别给小鼠右耳生药量1.5g的制剂，阳性对照组在小鼠右耳涂抹市售红霉素软膏0.2g；空白对照组不作处理，30min后用二甲苯(0.03mL/只)涂于各组小鼠右耳致炎，15min后脱颈椎处死小鼠，用8mm直径打孔器分别在左右两耳同一部位打下圆耳片。于电子分析天平称量，每鼠右耳片重量减去左耳片重量即为该鼠炎症组织肿胀度，药物组耳肿胀度与空白对照组比较。
各组小鼠抗炎试验的结果，见表3所示；各组小鼠二甲苯致炎耳肿胀度明显小于空白对照组，且差异具有高度显著性(P<0.01)，说明治疗痤疮的丹参组合药物乳膏各组具有抗炎作用。
表3治疗痤疮的丹参组合药物乳膏对小鼠肿胀度的影响
注：与空白组比较，*P﹤0.01；
止痒试验：将豚鼠按体重、性别随机分成给药组和对照组。随机分为6组，每组10只，雌雄各半，即空白对照组，药物组Ⅰ、药物组Ⅱ、药物组Ⅲ、玄参对照组和阳性药物对照组。药物组Ⅰ、药物组Ⅱ、药物组Ⅲ、玄参对照组分别在豚鼠右耳耳廓均匀涂抹上述得到的药物组Ⅰ、药物组Ⅱ、药物组Ⅲ1.5(生药)g·kg-1，阳性对照组在豚鼠右耳耳廓均匀涂抹红霉素乳膏2.0g·kg-1，玄参对照组在豚鼠右耳耳廓均匀涂抹得到的玄参对照组2.0g·kg-1,空白对照组在豚鼠右耳耳廓均匀涂抹空白基质2.0g·kg-1，2次/d，实验前1d，给各组豚鼠右后足背剃毛，并涂药1次。实验当Et，用0号砂纸擦伤动物右后足背剃毛处，以少量渗血为度，面积为1cm2，局部再涂药一次。末次给药后10min。开始在创面处滴以0.O1％磷酸组织胺0.05mL/只，每次间隔时间为3min，直至出现豚鼠回头舔右后足，以开始出现豚鼠回头舔右后足时所给予的磷酸组织胺总量最为致痒阈。记录并比较各组致痒闽，进行组间t检验.结果见表4。从表4可见，药物组Ⅰ、Ⅱ、Ⅲ药物组与空白对照组比较，差异有统计学意义(P<0.05或P<0.01)。药物组Ⅰ、Ⅱ对提高磷酸组胺致痒阈的作用比较明显，说明治疗痤疮的丹参组合药物乳膏可显著提高磷酸组胺对豚鼠的致痒阈。
表4治疗痤疮的丹参组合药物乳膏对磷酸组胺致足瘙痒的影响(±SD，n＝10)
注：与空白组比较，*P<O.05，#P<O.O1。
Claims (9)
1.一种用于治疗痤疮的药物组合物，其特征在于：由丹参、紫草、芦荟和冰片四味药物组成。
2.根据权利要求1所述的用于治疗痤疮的药物组合物，其特征在于：由丹参和紫草的乙醇提取物、芦荟干品超微粉以及冰片组成。
3.根据权利要求2所述的用于治疗痤疮的药物组合物，其特征在于：所述丹参、紫草、芦荟和冰片原药材的重量比为5-50:5-50:5-50:1-5。
4.根据权利要求2所述的用于治疗痤疮的药物组合物，其特征在于：所述丹参、紫草、芦荟和冰片原药材的重量比为16:16:10:2。
5.一种用于治疗痤疮的药物组合物乳膏的制备方法，其特征在于：包括以下步骤：
1）丹参、紫草粉碎成粗粉，以乙醇作为溶剂，浸渍24小时后，进行渗漉，浓缩，得到丹参紫草醇提物；
2）将丹参紫草醇提物与冰片粉末一起加入油相基质；
3）芦荟干品粉碎成粒径小于75μm的超微粉，得到芦荟细粉；
4)混合水相基质和油相基质后添加芦荟细粉，得到用于治疗痤疮的药物组合物乳膏。
6.根据权利要求5所述的用于治疗痤疮的药物组合物乳膏的制备方法，其特征在于：步骤1）所述的用乙醇浓度为90%。
7.根据权利要求5所述的用于治疗痤疮的药物组合物乳膏的制备方法，其特征在于：步骤2）所述的油相为硬脂酸、单双硬脂酸甘油酯、白凡士林、羊毛脂和十六醇的混合物。
8.根据权利要求5所述的用于治疗痤疮的药物组合物乳膏的制备方法，其特征在于：步骤3）所述的水相基质为在水中加入甘油、十二烷基酸钠、羟苯乙酯和氮酮的混合溶液。
9.权利要求1-4所述的的用于治疗痤疮的药物组合物在制备治疗痤疮药物中的应用。
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| CN106974995A (zh) * | 2017-04-26 | 2017-07-25 | 重庆市中药研究院 | 一种用于日本医蛭外用组合药物、制剂及其应用 |
| CN111529440A (zh) * | 2020-04-22 | 2020-08-14 | 重庆市中药研究院 | 祛痘乳剂的制备方法 |
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