CN113694109A - 一种复方黄柏药物制剂、制备方法及应用 - Google Patents
一种复方黄柏药物制剂、制备方法及应用 Download PDFInfo
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- CN113694109A CN113694109A CN202110944043.5A CN202110944043A CN113694109A CN 113694109 A CN113694109 A CN 113694109A CN 202110944043 A CN202110944043 A CN 202110944043A CN 113694109 A CN113694109 A CN 113694109A
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Abstract
本发明涉及医药学技术领域,尤其涉及一种复方黄柏药物制剂、制备方法及应用。该复方黄柏药物制剂由连翘、黄柏、金银花、蒲公英、蜈蚣、薄荷脑、20%葡萄糖酸氯己定、甜菊糖苷、吐温80、丙二醇制成。该复方黄柏药物制剂在现有复方黄柏液涂剂的基础上进行组方的改良,获得了针对白塞病引起的口腔溃疡具有良好治疗效果的药物,疗效显著,解决了现有复方黄柏液涂剂味苦、难以内服且抑菌效果差的问题。
Description
技术领域
本发明涉及医药学技术领域,尤其涉及一种复方黄柏药物制剂、制备方法及应用。
背景技术
白塞病是一种以同时或先后发生口腔黏膜溃疡以及眼、生殖器、皮肤病损为主要临床特征的自身免疫性疾病,其中,口腔溃疡为最基本的病损,见于98%以上的患者,且是本病的首发症状。溃疡可以发在口腔及咽的任何部位,如上颚、颊黏膜、齿龈、舌、唇内侧及咽喉部等。该病病因及发病机制尚不十分明确,现代医学认为可能与感染、遗传、免疫等多种因素有关。局部应用糖皮质激素膏、冰硼散及锡类散等治疗。中医临床诊断中风毒湿火证较为多见,以疏风清热解毒利湿为主。
现代药理学研究表明,复方黄柏液涂剂具有抗菌、消炎、促愈合、增强局部非特异性免疫的作用。临床常用于皮肤科、外科疾病。
复方黄柏液涂剂的处方与制法如下:
【处方】连翘80g、黄柏40g、金银花40g、蒲公英40g、蜈蚣2.4g。【制法】以上五味,加水煎煮三次,第一次1小时,第二次45分钟,第三次 30分钟,合并煎液;滤过,滤液浓缩至相对密度为1.10-1.15(50℃)的清膏,加乙醇使含醇量达70%,静置24小时,滤过,滤液减压浓缩至无醇味,加水至 1000ml,搅匀,静置,冷藏24小时,滤过,灌装,灭菌,即得。本品作为非无菌多剂量包装的纯中药制剂,抑菌效力有限,口味较苦,难以内服,定位是外用制剂,常作为外用涂剂用于皮肤表面。
针对白塞病引起的口腔溃疡的治疗,现一般采用龙胆紫或锡类散等药物治疗,严重的还配合使用糖皮质激素、免疫制剂、非甾体类抗炎药等药物进行全身治疗。由于该病引起的口腔溃疡易复发,反复口腔溃疡不仅导致病情加重,且给患者的身心健康造成一定影响,治疗效果有限。
发明内容
本发明提供了一种复方黄柏药物制剂、制备方法及应用,在现有复方黄柏液涂剂的基础上进行组方的改良,获得了针对白塞病引起的口腔溃疡具有良好治疗效果的药物,疗效显著,解决了现有复方黄柏液涂剂味苦、难以内服且抑菌效果差的问题,为白塞病引起的口腔溃疡的治疗提供了新的途径。
本发明所采用的技术方案是:
一种复方黄柏药物制剂,由以下重量份的组分制成:
连翘5-10份,黄柏2-10份,金银花2-10份,蒲公英2-10份,蜈蚣0.1-0.5 份,薄荷脑0.2-0.5份,20%葡萄糖酸氯己定2-10份,甜菊糖苷0.1-0.5份, 0.5-5份吐温80,丙二醇5-15份。
进一步地,所述的一种复方黄柏药物制剂由以下重量份的组分制成:
连翘8份,黄柏4份,金银花4份,蒲公英4份,蜈蚣0.24份,薄荷脑 0.3份,20%葡萄糖酸氯己定2.5份,甜菊糖苷0.1份,2份吐温80,丙二醇 10份。
上述复方黄柏药物制剂的制备方法,采用如下步骤制备:
(1)薄荷脑丙二醇溶液配制:按前述重量份数,取丙二醇加入薄荷脑, 50-80℃加热搅拌溶解,冷却至常温,备用;
(2)按前述重量份数,取以上五味组分,加水煎煮,滤过,滤液浓缩至清膏,醇提,得提取液;
(3)向提取液中加入前述重量份数的吐温80和甜菊糖苷,搅拌溶解,依次加入葡萄糖酸氯己定溶液、步骤(1)制备的薄荷脑丙二醇溶液,混匀,过滤,灌装,即得。
进一步地,步骤(2)加水煎煮次数为三次,第一次加入10倍重量的水煎煮1h,第二次加入8倍重量的水继续煎煮45min,第三次加入6倍重量的水煎煮30min;合并滤液,滤过,浓缩至清膏;
醇提采用乙醇进行,加入乙醇量使含醇量达70%,静置,滤过,减压浓缩至无醇味,加入适量水,搅拌、静置,冷藏,滤过,即得提取液。
上述复方黄柏药物制剂的制备方法制得的复方黄柏药物制剂在制备治疗白塞病引起的口腔溃疡药物中的应用。
进一步地,所述药物制剂为喷雾剂;所述喷雾剂的使用剂量为喷涂2-3次 /日
本发明的有益效果:
该复方黄柏药物制剂通过对现有复方黄柏液涂剂处方及工艺优化、药理药效、临床观察研究,开发出本发明复方药物制剂并用于治疗白塞病引起的口腔溃疡。本发明复方药物制剂疗效显著,解决了味苦且抑菌效果差的问题;使用剂量小。
本发明复方药物制剂中的薄荷脑在发挥清爽矫味的同时,作为全处方的“佐使药”定位,也拥有“清利疏透”之功,疏风、清热、解毒、消肿的作用,与其他几味药共用协同增效;相比原复方黄柏液涂剂,大大降低了用药量。经验证对比其他矫味剂或促透剂,均难以达到口感、疗效与本发明药物制剂中薄荷脑相似的作用。本发明复方药物制剂中的葡萄糖酸氯己定作为防腐剂,拥有广谱抑菌杀菌能力,同时其带正电荷吸附于粘膜表面而不被吸收,相比使用其他防腐剂,葡萄糖酸氯己定使本品可长效抑菌,防止免疫力低下患者的口腔内细菌感染。
本发明通过配方调整及制备过程优化,增强了药物制剂的清热解毒、愈合疮疡的疗效,显著减少了用药量,同时疗效显著、无副作用,扩大了适应症,为临床治疗白塞病提供了更优的选择。
附图说明
图1为本发明各实施例及空白组的黏膜组织TNF-α,I L-2,I L-6蛋白相对表达量统计图。
具体实施方式
为能清楚说明本方案的技术特点,下面通过具体实施方式,对本发明进行详细阐述。
实施例1
一种复方黄柏药物制剂,由以下重量的组分制成:
连翘8g,黄柏4g,金银花4g,蒲公英4g,蜈蚣0.24g,薄荷脑0.3g, 20%葡萄糖酸氯己定2.5g,甜菊糖苷0.1g,2g吐温80,丙二醇10g。
上述复方黄柏药物制剂的制备方法,采用如下步骤制备:
(1)薄荷脑丙二醇溶液配制:按前述重量,取丙二醇加入薄荷脑,50-80℃加热搅拌溶解,冷却至常温,备用;
(2)按前述重量,取以上五味组分,加水煎煮三次,第一次加总药物重量的10倍量水煎煮1小时,第二次加8倍量水煎煮45分钟,第三次加6倍量水煎煮30分钟,合并煎液;滤过,滤液浓缩至相对密度为1.10-1.15(50℃) 的清膏,加乙醇使含醇量达70%,静置24小时,滤过,滤液减压浓缩至无醇味,加水至适量,搅匀,静置,冷藏24小时,滤过,得提取液,备用;
(3)向提取液中加入前述重量的吐温80和甜菊糖苷,搅拌溶解,依次加入葡萄糖酸氯己定溶液、步骤(1)制备的薄荷脑丙二醇溶液,混匀,过滤,灌装,即得。
本发明复方黄柏药物制剂制成喷雾剂使用。
实施例2
该复方黄柏药物制剂由以下重量的组分制成:
连翘5g,黄柏2g,金银花2g,蒲公英2g,蜈蚣0.1g,薄荷脑0.2g,20%葡萄糖酸氯己定2g,甜菊糖苷0.1g,0.5g吐温80,丙二醇5g。
制备方法同实施例1的制备步骤,此处不再详述。
实施例3
该复方黄柏药物制剂由以下重量的组分制成:
连翘10g,黄柏10g,金银花10g,蒲公英10g,蜈蚣0.5g,薄荷脑0.5g, 20%葡萄糖酸氯己定10g,甜菊糖苷0.5g,5g吐温80,丙二醇15g。
制备方法同实施例1的制备步骤,此处不再详述。
实施例4
一种复方黄柏药物制剂,同实施例1的复方黄柏药物制剂,所不同的是,将薄荷脑替换为冰片。
实施例5
一种复方黄柏药物制剂,同实施例1的复方黄柏药物制剂,所不同的是,将薄荷脑替换为月桂氮酮。
实施例6
一种复方黄柏药物制剂,采用现有复方黄柏液涂剂,由山东汉方制药有限公司生产,批号:20101522。组分组成为:连翘8g、黄柏4g、金银花4g、蒲公英4g、蜈蚣0.24g。
一、药理试验
1.1、实验材料:SPF级雄性大鼠
1.2、药物:薄荷脑组(实施案例一方法制备)、冰片组(实施案例一方法制备,冰片替换薄荷脑)、月桂氮酮组(实施案例一方法制备,月桂氮酮替换薄荷脑)、复方黄柏液涂剂(山东汉方制药有限公司生产,批号20101522);
1.3、主要试剂及仪器:TNF-α,IL-2,IL-6酶联免疫试剂盒(武汉默沙克生物科技有限公司),全自动酶标仪(Thermo)、电泳仪(Bio-Rad公司)。
1.4、模型建立及分组
鉴于白塞病为自身免疫性疾病,选择免疫方法,使用完全弗氏佐剂(内包含免疫原及结核分枝杆菌的细胞壁)构建,更符合白塞病特点。
取70只大鼠脊柱两侧剃毛后消毒,两侧皮内注射完全弗氏佐剂0.1ml,7 天注射1次,共3次。定期观察大鼠口腔黏膜变化,最后一次给药7天后70 只大鼠均出现口腔溃疡,模型建立成功。
将70只口腔溃疡大鼠模型随机分为7组。每组10只。空白组用无菌生理盐水10ml,观察组(实施例1-5)用样品溶液10ml,对照组(实施例6)用复方黄柏液涂剂10ml,冲洗口腔,每天冲洗3次,每次间隔4h,连续给药7天。各组自由饮水进食。
1.5、黏膜组织TNF-α,IL-2,IL-6蛋白相对表达量测定
各组分别在给药后7天,采血后二氧化碳处死,取口腔黏膜组织置于离心管,加入1*PBS进行匀浆,按照蛋白提取试剂盒说明书提取总蛋白,BCA进行蛋白定量测定后,各泳道进样20μl,进行SDS-PAGE电泳分离,电转2h后蛋白转入硝酸纤维素膜。封闭液孵育2h,加入一抗(1:500),4℃摇床过夜,加入二抗(1:10000),常温孵育1.5h,暗室中曝光、显影及定影。采用凝胶成像软件系统扫描拍照,使用ImageJ软件对图片进行灰度值分析,分别用 TNF-α,IL-2,IL-6灰度值与内参β-action灰度值比值表示蛋白相对表达量。
表1黏膜组织TNF-α,IL-2,IL-6蛋白相对表达量数据
1.6、结果:
各组大鼠给药7天后口腔溃疡黏膜组织中TNF-α,IL-2,IL-6蛋白相对表达量比较,差异均有统计学意义。
实施例6的对照组复方黄柏液涂剂,和实施例1-5的样品溶液皆可有效减少大鼠血清及口腔黏膜组织中炎症因子TNF-α,IL-6表达量,有效缓解炎症反应。IL-2口腔溃疡黏膜组织中蛋白相对表达量均显著高于对照组实施例6, IL-2主要由活化的T淋巴细胞产生,是重要的免疫调控及监视因子,组织中 IL-2水平显著增加,提高机体免疫应答速度,最终可使创面加速愈合。TNF-α, IL-6表达量越低,IL-2表达量越高,意味着药效越好。
数据统计分析采用SPSS软件,计量资料采用均数±标准差进行描述;各组大鼠造模后各指标的均衡性检验及给药7天后蛋白相关表达量的比较采用完全随机设计单因素方差分析进行比较,若差别有统计学意义,采用T检验进行组间两两比较;P<0.05为差异有统计学意义。图1各项指标显示疗效,本发明薄荷脑组(实施例1-3)具有显著优势。具体疗效趋势为:薄荷脑组(实施例1-3)>月桂氮酮组(实施例5)>冰片组(实施例4)>复方黄柏液涂剂组 (实施例6)>空白对照组。各组间不同细胞因子水平存在显著差异(P<0.05)。薄荷脑组内,即实施例1-3之间各细胞因子水平无统计学差异(P>0.05)。
二、药物制剂口味评价
2.1、志愿者筛选,公司内部选择20名健康志愿者(男性10名,女性10 名),对样品进行了苦味筛选,实验前均签署知情同意书。
2.2、口味评价
采用排序法,取25℃下不同溶液:薄荷脑组(实施例1)、月桂氮酮组(实施例5)、冰片组(实施例4)、复方黄柏液涂剂组(实施例6),各20mL于口尝杯中,由志愿者含于口中,计时15s,此间口腔作漱口动作,吐出,漱口 5次至口腔内无味,15min后同法测定另一溶液。志愿者根据自己的口尝感受排序。
2.3、评价结果
感官评价:薄荷脑组>月桂氮酮组>复方黄柏液涂剂组>冰片组;
相比其他各组,本发明的薄荷脑组在疗效明显的基础上,很好的消除了现有复方黄柏液涂剂的苦味,更容易接受,且更有利于产品疗效的发挥。
三、临床观察
3.1一般资料:
符合白塞病口腔溃疡诊断标准;将100例患者随机分为对照组和观察组,各50例。对照组中,男性患者22例,女性患者28例;年龄20~60岁,平均年龄为(39.5±5.34)岁;平均患病时间为(2.47±1.55)年。观察组中,男性26 例,女性24例;年龄21~59岁,平均年龄为(36.7±3.65)岁;平均患病时间为(2.64±1.54)年。对照组与观察组患者年龄、患病时间均无差异,具有可比性。
3.2纳入与排除标准纳入标准:
本次研究通过了伦理委员会的同意;所有患者均在研究前自愿签署了知情同意书;均符合医学组织所制定的白塞病诊断标准,病程均大于一年;患者停止使用其他免疫抑制剂或者糖皮质激素一年以上。排除标准:精神障碍患者;合并心脑血管、肝、肾等系统严重原发性疾病者;合并有其他自身免疫疾病患者;妊娠以及哺乳期患者;药物过敏患者;依从性较差患者。
3.3治疗方法
对照组使用口腔炎喷雾剂治疗,用法用量为:口腔喷雾用。每次向口腔挤喷药液适量,一日3次。观察组由实施例1方法制备的药物制剂治疗,同对照组方法使用。持续治疗3个月。
3.4疗效评价标准
经过治疗后,比较分析2组患者的疗效及平均间歇时间。
3.5统计学方法
本次研究中进行数据统计分析和处理的是SPSS19.0,计数资料以(%)表示,采取χ2检验;计量资料以(x±s)表示,采取t检验,对比以P<0.05表示研究有统计学意义。
3.6结果
表1疗效观察对比统计表
疗效比较观察组治疗总有效率高于对照组,P<0.05。
表2平均间歇时间对比统计表
由表1结果可知,本发明的复方黄柏药物制剂相比现有口腔炎喷雾剂,在用药剂量相当的条件下,治疗总有效率显著提升,高达98%,无效数量少,为白塞病引起的口腔溃疡提供了新的有效的治疗药物。表2结果显示,治疗后,观察组平均间歇时间比对照组长(P<0.05),即本品对于症状复发的控制效果优于口腔炎喷雾剂。
上述具体实施方式不能作为对本发明保护范围的限制,对于本技术领域的技术人员来说,对本发明实施方式所做出的任何替代改进或变换均落在本发明的保护范围内。
本发明未详述之处,均为本技术领域技术人员的公知技术。
Claims (6)
1.一种复方黄柏药物制剂,其特征在于,由以下重量份的组分制成:
连翘5-10份,黄柏2-10份,金银花2-10份,蒲公英2-10份,蜈蚣0.1-0.5份,薄荷脑0.2-0.5份,20%葡萄糖酸氯己定2-10份,甜菊糖苷0.1-0.5份,0.5-5份吐温80,丙二醇5-15份。
2.根据权利要求1所述的一种复方黄柏药物制剂,其特征在于,由以下重量份的组分制成:
连翘8份,黄柏4份,金银花4份,蒲公英4份,蜈蚣0.24份,薄荷脑0.3份,20%葡萄糖酸氯己定2.5份,甜菊糖苷0.1份,2份吐温80,丙二醇10份。
3.如权利要求1或2所述的一种复方黄柏药物制剂的制备方法,其特征在于,采用如下步骤制备:
(1)薄荷脑丙二醇溶液配制:按前述重量份数,取丙二醇加入薄荷脑,50-80℃加热搅拌溶解,冷却至常温,备用;
(2)按前述重量份数,取以上五味组分,加水煎煮,滤过,滤液浓缩至清膏,醇提,得提取液;
(3)向提取液中加入前述重量份数的吐温80和甜菊糖苷,搅拌溶解,依次加入葡萄糖酸氯己定溶液、步骤(1)制备的薄荷脑丙二醇溶液,混匀,过滤,灌装,即得。
4.根据权利要求3所述的复方黄柏药物制剂的制备方法,其特征在于,步骤(2)加水煎煮次数为三次,第一次加入10倍重量的水煎煮1h,第二次加入8倍重量的水继续煎煮45min,第三次加入6倍重量的水煎煮30min;合并滤液,滤过,浓缩至清膏;
醇提采用乙醇进行,加入乙醇量使含醇量达70%,静置,滤过,减压浓缩至无醇味,加入适量水,搅拌、静置,冷藏,滤过,即得提取液。
5.如权利要求3或4所述的复方黄柏药物制剂的制备方法制得的复方黄柏药物制剂在制备治疗白塞病引起的口腔溃疡药物中的应用。
6.根据权利要求5所述的应用,其特征在于,所述药物制剂为喷雾剂;所述喷雾剂的使用剂量为喷涂2-3次/日。
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