CN101342174A - 一种酞丁安/达克罗宁的复方局部用制剂 - Google Patents
一种酞丁安/达克罗宁的复方局部用制剂 Download PDFInfo
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- CN101342174A CN101342174A CNA2008101189180A CN200810118918A CN101342174A CN 101342174 A CN101342174 A CN 101342174A CN A2008101189180 A CNA2008101189180 A CN A2008101189180A CN 200810118918 A CN200810118918 A CN 200810118918A CN 101342174 A CN101342174 A CN 101342174A
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- BZEWSEKUUPWQDQ-UHFFFAOYSA-N dyclonine Chemical compound C1=CC(OCCCC)=CC=C1C(=O)CCN1CCCCC1 BZEWSEKUUPWQDQ-UHFFFAOYSA-N 0.000 claims abstract description 34
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- OPXFZJLGAZHBMA-UHFFFAOYSA-N [[1-(carbamothioylhydrazinylidene)-3-(1,3-dioxoisoindol-2-yl)butan-2-ylidene]amino]thiourea Chemical compound C1=CC=C2C(=O)N(C(C)C(C=NNC(N)=S)=NNC(N)=S)C(=O)C2=C1 OPXFZJLGAZHBMA-UHFFFAOYSA-N 0.000 claims description 38
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 24
- -1 antiseptic Substances 0.000 claims description 24
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Abstract
本发明公开了一种治疗带状疱疹等病毒性皮肤病的酞丁安/达克罗宁复方局部用制剂，它由以下重量百分比含量的组分组成：(1)酞丁安：0.1～10重量％；(2)达克罗宁：0.1～10重量％；(3)药学上可接受的赋形剂。本发明的复方局部用制剂，用于带状疱疹的治疗，在确保抗病毒疗效、达到治疗目的基础上，并迅速止痛，可立即最大限度地减轻病患痛苦，改善病患生活质量，有助于提高患者的临床顺应性。本发明的复方局部用制剂，对带状疱疹病患疗效显著，止痛作用明显，制剂性能稳定，质量可控，疗效显著，具有对皮肤无刺激、不引起过敏反应的优点。
Description
技术领域
本发明涉及局部用药物制剂，更具体地说，涉及一种酞丁安/达克罗宁的复方局部用制剂及其制备方法，用于治疗单纯疱疹和带状疱疹皮肤病的用途。
背景技术
病毒感染一直是人们关心的一个沉重的社会话题，病毒感染引起多种疾病，严重威胁人们的身体健康，病毒性皮肤病在皮肤疾患中占有重要位置，其中带状疱疹(Herpes Zoster)是由水痘带状疱疹病毒引起的急性炎症性皮肤病，中医称为“缠腰火龙”，“缠腰火丹”，俗称“蜘蛛疮”。其主要特点为簇集水泡，沿一侧周围神经作群集带状分布，伴有明显神经痛。初次感染表现为水痘，以后病毒可长期潜伏在脊髓后根神经节，免疫功能减弱可诱发水痘带状疱疹病毒可再度活动，生长繁殖，沿周围神经波及皮肤，发生带状疱疹。病程一般为半个月左右，好发部位肋间神经及三叉神经可支配的皮肤区域，伴有神经痛，剧烈难忍。目前，西医学对带状疱疹的治疗原则是抗病毒、消炎止痛和防止继发感染，抗病毒药有阿糖腺苷、无环鸟苷及干扰素等。消炎止痛药如阿斯匹林等。
由于带状疱疹发病时伴有明显的神经痛，剧痛难忍，因此其对症治疗的原则在抗病毒的基础上，还要求止痛，如果有一种药物能够在抗病毒的基础上，同时还能兼顾最大限度地降低患者的疼痛程度，必将起到“双管齐下，疗效更佳”的效果。
酞丁安(Ftibamzone)，又名增光素，是我国首创的抗病毒药物，其作用机制主要是明显抑制病毒DNA和早期蛋白质合成，而对正常细胞DNA合成影响甚微，具有抗沙眼衣原体及抗疱疹病毒活性并且具有较好的抗真菌作用及止痒作用。其化学结构为：
分子式：C14H15N17O2S2分子量：377.45
由于该药物理化学性质不稳定，既不溶于水，而且对光和热均较敏感给该药的生产和临床应用带来了一定的困难，酞丁安搽剂(CN89108540.8)通过一种对酞丁安溶解度好、而且稳定的溶剂，能保持该药对病毒性皮肤病的疗效，该剂型收载于《中华人民共和国药典》05版二部。目前临床上使用的酞丁安制剂有酞丁安乳膏，酞丁安搽剂，酞丁安滴眼液。
达克罗宁(Dyclonine)，通常为盐酸盐，其结构为：
分子式：C18H27NO2·HCl分子量：325.87
达克罗宁为局部麻醉药，对粘膜穿透能力强，局部麻醉作用见效快(2-10min)，作用时间持久(2-4小时)，止痛止痒又杀菌。目前临床上使用的剂型为1％软膏，乳膏，0.5％，1％水溶液，胶浆剂以及凝胶剂，广泛用于烧伤，擦伤，痒疹，溃疡等，局部用药后很少有吸收，大鼠经皮给药的LD50接近于1.6g/kg。
目前，还未见关于酞丁安和达克罗宁联合用药以及用于治疗带状疱疹等病毒性皮肤病的报道。
发明内容
发明人进行了大量的研究和试验，令人惊奇地发现酞丁安与达克罗宁联合应用的协同作用，可有效地治疗单纯性疱疹和带状疱疹。
本发明目的在于提供一种既能抗疱疹病毒，同时还能止痛的复方局部用药物制剂。
本发明的另一个目的是提供上述复方局部用药物制剂的制备方法。
本发明的另一个目的是提供上述复方局部用药物制剂的用途。
本发明的技术解决方案是：一种酞丁安、达克罗宁复方局部用制剂。具体来说是克服现有酞丁安搽剂的不足，在发挥酞丁安搽剂抗病毒作用的基础上，增加主药达克罗宁，开发出一种含有局部麻醉药达克罗宁的局部用酞丁安复方制剂。
本发明提供了一种局部用制剂，包括酞丁安、达克罗宁或其可接受的药用盐、以及药学上可接受的赋形剂。
本发明所提供的酞丁安达克罗宁的复方局部用制剂，是由以下重量百分比的组分组成：
酞丁安：0.1～10重量％
达克罗宁：0.1～10重量％
药学上可接受的赋形剂：80～99.8重量％
这里，达克罗宁任选地是以游离碱或盐酸盐的形式。
所述酞丁安和达克罗宁的重量比为1∶0.5～1∶10，优选为1∶0.5～1∶5，更优选为1∶0.5～1∶2。
所述酞丁安的重量百分比含量为0.1～10重量％，优选为0.1～5重量％，更优选为0.1～1重量％。
所述达克罗宁的重量百分比含量为0.1～10重量％，优选为0.1～5重量％，更优选为0.1～1重量％。
本发明的复方局部用制剂，任选地为药学上所能接受的液体制剂、软膏剂、凝胶剂、或乳剂等所有局部用剂型。
所述药学上可接受的赋形剂选自以溶剂，助溶剂，软膏基质，凝胶基质，乳剂基质，透皮吸收促进剂，防腐剂，稳定剂，以及香料等所组成的组，任选地，为其中的一种或两种以上的组合。
本发明的复方局部用制剂为液体制剂时，其包含的药学上可接受的赋形剂为溶剂，助溶剂，增溶剂，透皮吸收促进剂，防腐剂，稳定剂，芳香剂等。这里，所述的溶剂为水，不同浓度的醇，非水性溶剂，如丙二醇，甘油，二甲基亚砜，植物油，三醋酸甘油酯，以及上述溶剂两种或两种以上混合物。所述的增溶剂为肥皂类，硫酸化物，磺酸化物类阴离子型表面活性剂，吐温类，卖泽类，聚氧乙烯脂肪醇醚类非离子型表面活性剂，所述的助溶剂为苯甲酸、水杨酸及其钠盐、甘草酸等有机酸及其盐，烟酰胺、乙酰胺、二乙胺、乙醇胺等酰胺或胺类化合物，及无机盐、多聚物、酯类、多元醇等。
本发明的复方局部用制剂为软膏制剂时，其包含的药学上可接受的赋形剂为软膏基质，透皮吸收促进剂，防腐剂，稳定剂，芳香剂等。这里，所述的软膏基质为烃类基质，类脂类基质，有机硅氧化物的聚合物等油性基质，由油相、水相、乳化剂组成的乳剂型基质，聚乙二醇、纤维素衍生物、甘油明胶等水溶性基质。
本发明的复方局部用制剂为凝胶剂时，其包含的药学上可接受的赋形剂为基质，透皮吸收促进剂，防腐剂，稳定剂，芳香剂等。这里，所述的基质为明胶、琼脂、海藻酸盐、桃胶、黄原胶、铺路蓝、预胶化淀粉等天然凝胶材料；羟丙甲纤维素、甲基纤维素、羟丙基纤维素钠、脱-酰甲壳素等半合成凝胶材料；聚丙烯酰胺、聚甲基丙烯酸羟乙酯、聚丙烯酸甘油脂、聚丙烯酸羟丙酯、聚羧乙烯、丙烯酸钠、聚乙烯吡咯烷酮、聚乙二醇、聚乙烯醇、透明质酸钠等合成凝胶材料。
本发明的复方局部用制剂为乳剂时，其包含的药学上可接受的赋形剂为水相、油相、透皮吸收促进剂、防腐剂、稳定剂、芳香剂等。这里，所述的油相为油脂性基质、高级脂肪醇、酸、酯。所述的水相主要为水，任选地含有多元醇类保湿剂、水溶性乳化剂等。
所述的透皮吸收促进剂为：(1)醇类，如乙醇，丙二醇，异丙醇，油醇，月桂醇，十六醇等，(2)高级脂肪酸类，如油酸，月桂酸，亚麻油酸，(3)高级脂肪酸酯类，如硬脂酸单甘油酯，(3)萜烯类，如薄荷醇，(4)内酰胺类，如十二烷氮酮(或氮酮)类等，(5)大环酮类，如樟脑，(6)亚砜类，如二甲基亚砜，十二烷基甲基亚砜，(7)离子型或非离子表面活性剂类，如甜菜碱、月桂醇硫酸钠，吐温-80等，或它们的两种及两种以上混合物。
其中所述防腐剂为对羟基苯甲酸类，苯甲酸钠及其盐类，山梨酸及其盐，三氯叔丁醇、苯甲醇、苯乙醇、醋酸洗必泰、尼泊金乙酯以及季胺化合物类等阳离子表面活性剂。
其中所述的稳定剂选自抗氧剂，如亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠、抗坏血酸、异抗坏血酸、硫代甘油、硫代山梨酸等；pH调节剂，如不同浓度的盐酸、磷酸、酒石酸、柠檬酸、顺丁烯二酸、乳酸、氢氧化钠等，或者β-CD，HP-β-CD等特殊稳定剂。
其中所述的芳香剂为薄荷水、橙皮酊、桂皮油等天然芳香油，香蕉香精、桔子香精、柠檬香精等由醇、醛、酮、酸、胺、酯、萜、醚、缩醛等香料组成的各种香型的香精。
利用酞丁安和达克罗宁制备所需药物的各种剂型时，可以按照药剂学领域的常规生产方法制备，将酞丁安、达克罗宁以及药学上可接受的赋形剂相混合，具体的制备方法参照实施例进行。
本发明将酞丁安以及达克罗宁制成复方局部用制剂，用于带状疱疹等病毒性皮肤病的治疗，与目前临床上使用的酞丁安搽剂相比，本发明的复方局部用制剂在发挥酞丁安的抗病毒作用的基础上，增加了达克罗宁的止痛作用，更符合带状疱疹的治疗原则(止痛，抗病毒，抗炎，保护局部，防止感染)，从而在保证疗效、达到治疗目的基础上，最大限度地减轻病患疼痛之苦，在一定程度上缓解病患压力，改善病患生活质量，提高病患免疫力，从而能够达到加速治愈，缩短病程的作用，有助于提高患者的临床顺应性，提供了酞丁安的新复方剂型用药选择，丰富了临床用药。
具体实施方式
下面结合具体实施方式对本发明作进一步说明，并非对本发明的限定，依照本领域公知的现有技术，本发明的实施方式并不限于此，因此凡依照本发明公开内容所做出的本领域的等同替换，均属本发明的保护范围。
实施例1酞丁安/达克罗宁软膏
酞丁安 2g
达克罗宁 1g
二甲基甲酰胺 5ml
十六醇 3g
十八醇 3g，
十二烷基硫酸钠 0.5g
单硬脂酸甘油脂 7g
蒸馏水 68ml
甘油 10ml
制备方法：取十六醇、十八醇、单硬脂酸甘油脂加热，90度保温，另取十二烷基硫酸钠、甘油、水加热与上述液体搅拌混匀，制成基质，再取酞丁安，达克罗宁原料溶于二甲基甲酰胺，加入到配好的基质当中，搅拌混匀即可。
实施例2酞丁安/达克罗宁凝胶
酞丁安 2g
达克罗宁 1g
羧甲基纤维素钠 3g
丙二醇 10g
二甲基甲酰胺 适量
尼伯金乙酯 0.1g
蒸馏水加至 100g
制备方法：将羧甲基纤维素钠用60ml水浸泡24小时备用，另将酞丁安，达克罗宁用适量的二甲基甲酰胺溶解，加入用水浸泡的羧甲基纤维素钠中，加入丙二醇，尼泊金乙酯，蒸馏水加至全量，搅拌均匀即可。
实施例3酞丁安/达克罗宁搽剂
酞丁安 0.5g
达克罗宁 1g
丙二醇 20ml
氮酮 1ml
三醋酸甘油酯 加至100ml
制备方法：将上述酞丁安，达克罗宁，丙二醇，氮酮，适量三醋酸甘油酯混合，加热，使溶解，三醋酸甘油酯加至全量，搅拌混匀即可。
同理，以下实施例均以活性成分以及活性成分比例表示，具体剂型以及相应的非活性成分参照实施例1，或2，或3。
试验例
下面为酞丁安/达克罗宁复方制剂用于治疗带状疱疹的疗效报告
目的：观察酞丁安/达克罗宁复方制剂对带状疱疹的临床疗效
材料与方法
1.药品来源
0.5％酞丁安搽剂：本品为对照品，由北京四环药厂提供。
0.5％酞丁安/达克罗宁复方搽剂(按实施例8制备，以下简称复方搽剂)：由北京天川军威医药技术有限公司提供。
2.临床资料
依照病例选择标准，按各病种病人就诊时间的先后，以随机数字表分组进行治疗观察，分为酞丁安搽剂组61例，复方搽剂组67例，两组患者例数、性别、年龄及病期分布均无统计学差异。
4.用药，用量和疗程设置
两药剂均局部涂抹，每日3次，其用量视患病面积而定；以一周为一疗程，一般用药一至四疗程，每疗程结束后，记录其疗效及反应。
5.观察项目
皮损消退情况：包括止疱、脱痂、皮疹数、炎症等。
自觉症状：包括疼痛瘙痒等。
毒副作用：包括刺激、过敏等。
6.对带状疱疹的治疗结果
对带状疱疹各种症状疗效时间的比较
对带状疱疹神经痛的镇痛疗效
以上的试验结果表明，两组总有效率无显著差异，但是与酞丁安搽剂组比较，复方搽剂组的镇痛效果，止痛、止疱、脱痂、痊愈时间的等指标明显优于酞丁安搽剂组。
酞丁安/达克罗宁复方搽剂组由于止痛效果明显，减轻了带状疱疹病患的痛苦，在一定程度上能够缓解病患压力，改善病患生活质量，提高病患免疫力，从而能够达到加速治愈，缩短病程的作用。
7.副作用观察结果
复方搽剂组：在67例患者中，有66例用药后无刺激性，反映良好，均无其它副作用，仅有1例主诉有轻微刺激感，总发生率为1.49％。
酞丁安搽剂组：在61例患者中，有60例用药后无刺激性，仅有1例表现出轻微刺激性症状，总发生率为1.64％。
上述两种药剂的副作用发生率，无统计学意义。
Claims (16)
1.一种局部用制剂，包括酞丁安，达克罗宁或其可接受的药用盐，以及药学上可接受的赋形剂。
2.根据权利要求1所述的局部用制剂，由以下组分组成：
(1)酞丁安：0.1～10重量％
(2)达克罗宁：0.1～10重量％
(3)药学上可接受的赋形剂：80～99.8重量％。
3.根据权利要求2所述的局部用制剂，其中所含酞丁安和达克罗宁的剂量比为1∶0.5～1∶10；优选为1∶0.5～1∶5，更优选为1∶0.5～1∶2。
4.根据权利要求2所述的局部用制剂，其中所含酞丁安的重量百分比为0.1～10重量％，优选为0.1～5重量％，更优选为0.1～1重量％。
5.根据权利要求2所述的局部用制剂，其中所含达克罗宁的重量百分比为0.1～10重量％，优选为0.1～5重量％，更优选为0.1～1重量％。
6.根据权利要求2所述的复方局部用制剂，任选地为药学上所能接受的液体制剂，软膏剂，凝胶剂，或乳剂。
7.根据权利要求6所述的复方局部用制剂，其中所述液体制剂包含的药学上可接受的赋形剂为溶剂，助溶剂，增溶剂，透皮吸收促进剂，防腐剂，稳定剂，芳香剂。
8.根据权利要求6所述的复方局部用制剂，其中所述软膏剂包含的药学上可接受的赋形剂为软膏基质，透皮吸收促进剂，防腐剂，稳定剂，芳香剂。
9.根据权利要求6所述的复方局部用制剂，其中所述凝胶剂包含的药学上可接受的赋形剂为基质，透皮吸收促进剂，防腐剂，稳定剂，芳香剂。
10.权利要求6所述的复方局部用制剂，其中所述乳剂包含的药学上可接受的赋形剂为水相，油相，透皮吸收促进剂，防腐剂，稳定剂，芳香剂。
11.根据权利要求7所述的复方局部用制剂，其中所述的溶剂为水，不同浓度的醇，非水性溶剂，如丙二醇，甘油，二甲基亚砜，植物油，三醋酸甘油酯，以及上述两种或两种以上混合物；所述的增溶剂为肥皂类，硫酸化物，磺酸化物类阴离子型表面活性剂，吐温类，卖泽类，聚氧乙烯脂肪醇醚类非离子型表面活性剂；所述的助溶剂为苯甲酸、水杨酸及其钠盐、甘草酸等有机酸及其盐，烟酰胺、乙酰胺、二乙胺、乙醇胺等酰胺或胺类化合物，及无机盐、多聚物、酯类、多元醇。
12.根据权利要求8所述的复方局部周制剂，其中所述的软膏基质为油性基质，选自烃类基质，类脂类基质，有机硅氧化物的聚合物；乳剂型基质，选自由油相、水相、乳化剂组成的基质；或水溶性基质，选自聚乙二醇、纤维素衍生物、或甘油明胶。
13.根据权利要求9所述的复方局部用制剂，其中所述的基质为天然凝胶材料，选自明胶、琼脂、海藻酸盐、桃胶、黄原胶、铺路蓝、预胶化淀粉；半合成凝胶材料，选自羟丙甲纤维素、甲基纤维素、羟丙基纤维素钠、脱-酰甲壳素；或合成凝胶材料，选自聚丙烯酰胺、聚甲基丙烯酸羟乙酯、聚丙烯酸甘油脂、聚丙烯酸羟丙酯、聚羧乙烯、丙烯酸钠、聚乙烯吡咯烷酮、聚乙二醇、聚乙烯醇、透明质酸钠。
14.根据权利要求10所述的复方局部用制剂，其中所述的油相为油脂性基质、高级脂肪醇、酸、酯；所述的水相主要为水，含有多元醇类保湿剂、水溶性乳化剂。
15.根据权利要求7、8或9中任一权利要求所述的复方局部用制剂，其中所所述的透皮吸收促进剂为：醇类，选自乙醇，丙二醇，异丙醇，油醇，月桂醇，十六醇；或高级脂肪酸类，选自油酸，月桂酸，亚麻油酸；或高级脂肪酸酯类；或萜烯类，选自薄荷醇；或内酰胺类选自十二烷氮
酮酮类；或大环酮类，选自樟脑；或亚砜类，选自二甲基亚砜，十二烷基甲基亚砜；或离子型及非离子表面活性剂类，选自月桂醇硫酸钠，吐温-80，或它们的两种及两种以上混合物；
其中，所述防腐剂为对羟基苯甲酸类、苯甲酸钠及其盐类，山梨酸及其盐、山梨酸及其盐，三氯叔丁醇、苯甲醇、苯乙醇、醋酸洗必泰、尼泊金乙酯或季胺化合物类阳离子表面活性剂；
其中，所述的稳定剂为抗氧剂，选自亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠、抗坏血酸、异抗坏血酸、硫代甘油、硫代山梨酸；或pH调节剂，选自不同浓度的盐酸、磷酸、酒石酸、柠檬酸、顺丁烯二酸、乳酸、氢氧化钠；或者特殊稳定剂，选自β-CD、HP-β-CD；
其中所述的芳香剂为天然芳香油，选自薄荷水、橙皮酊、桂皮油；或者香精，选自香蕉香精、桔子香精、柠檬香精等由醇、醛、酮、酸、胺、酯、萜、醚、缩醛等香料组成的各种香型的香精。
16.权利要求1至15中任一权利要求所述的复方局部用制剂在制备治疗单纯疱疹或带状疱疹皮肤病药品中的应用。
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| CN114767624A (zh) * | 2022-05-10 | 2022-07-22 | 南京唯创远医药科技有限公司 | 一种含4－丁氧基－β－哌啶基苯丙酮类化合物的药物组合物及其制备方法和应用 |
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