CN1173820A - 治疗疱疹的药物组合物 - Google Patents
治疗疱疹的药物组合物 Download PDFInfo
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- CN1173820A CN1173820A CN96191807A CN96191807A CN1173820A CN 1173820 A CN1173820 A CN 1173820A CN 96191807 A CN96191807 A CN 96191807A CN 96191807 A CN96191807 A CN 96191807A CN 1173820 A CN1173820 A CN 1173820A
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Abstract
本发明涉及一种治疗单纯性疱疹病毒感染的药物组合物,它在一种药物可接受的基质中含有一种季铵化合物作第一种成分,和/或一种抗病毒剂作第二种成分,和/或一种植物提取物作第三种成分,其中三种成分彼此相容。
Description
本发明涉及一种治疗疱疹的药物组合物。
皮肤的单纯性疱疹引起表皮的疼痛性斑疹和水泡,斑疹和水泡最终破裂而导致皮肤损害。疱疹主要由单纯性疱疹病毒(HSV)1型引起,但也可由HSV2型引起,HSV2型通常引起生殖器疱疹。相反,生殖器疱疹由HSV1型引起的约占30%。
口的感染被称作唇疱疹,也可被称作感冒疮(单纯疱疹)。颜面的其它部位如眼和鼻,也可被感染。此被称作面部单纯性疱疹。感染还可出现在身体的其它部位。
基本上,大约70-90%的人感染HSV。然后这些人成为这种病毒的携带者。一个人一旦感染HSV,此病毒将在其体内潜伏。在潜伏状态下,病毒位于神经节的神经细胞体内。由于特殊的刺激如流感感染或其它呼吸疾病、胃肠感染、紧张、疲劳、行经、妊娠、变态反应、日照和发热,潜伏的病毒可被激活。从神经节出发沿着确定的神经通路到达皮肤表面,并在那里繁殖,导致症状的出现。复发形式的疱疹在约40%感染个体中发生。
本来适当无害的单纯性疱疹感染可导致非常严重的感染例如角膜炎和脑炎。因此在感染部位有效地破坏病毒病灶是很重要的。
目前最频繁应用的抗HSV感染的药物是阿昔洛韦,例如它以商品名Zovirax进行销售。阿昔洛韦是一种鸟嘌呤类似物,它干扰此病毒的DNA聚合酶,因此抑制病毒DNA的复制。虽然此病毒不能进行繁殖,但病毒本身并未被杀死。因此此病毒可退回至神经节,从而再一次进入潜伏期。
HSV-1的传播是通过直接接触唾液或皮肤上的感染灶而产生。阿昔洛韦也不能阻断这种传播。
另一个难题是继发细菌感染的发生,例如由葡萄球菌和/或链球菌引起的脓疱病。
由于这些疱疹感染难题的存在,尽管它们可能或不可能伴随出现,还是很明显地需要一种药物制剂,此制剂可减少甚至阻止潜伏及其传播和继发细菌感染的发生。
按照本发明,目前已经发现一种药物组合物可解决上述难题,此组合物由一种作为第一成分的季铵化合物和/或一种作为第二成分的抗病毒剂和/或一种作为第三成分的植物提取物组成,这三种成分在一种药物可接受的基质中是彼此相容的。
为了打破此病毒的潜伏、复发和重新潜伏的恶性循环,必须杀死病毒本身。因为死的病毒不能退回至神经节,所以在初次或复发感染的情况下由此可使潜伏较少再生,甚至没有潜伏再生。因此本发明组合物的最重要的成分是一种杀病毒物质,依靠它杀死此病毒。
抗病毒剂可细分为许多种(Colgate,S.M.和Molyneux,R.J.,生物活性的天然产物,410,CRC出版公司,(1993)),以Ia至Vb的分类组命名。现在本发明已发现:为了最大程度地处理HVS感染,IVb组中的一种或多种物质必须与Va组中的一种或多种物质结合最好。IVb组中的物质具有杀病毒活性,而Va组中的化合物具有抑制病毒和抗病毒活性。两种类型物质的结合,抑制病毒的复制并将已存在的病毒杀死。
为了确保HVS感染所造成损害的继发感染得到预防,此继发感染是由其它微生物如细菌引起的,建议在第一种成分和/或第二种成分中具有消毒特性。
为了减轻疼痛和炎症的相关症状,最好还使用一种植物提取物。此提取物除具有抗炎特性外,最好还具有一种润滑作用。
根据本发明,本领域的普通技术人员可用一种已知的方法从IVb组中选择具有消毒活性且因此可用于此药物组合物的产物。在此所用的方法为Colgate和Molyneux所述的终点滴定技术(EPTT)(supra.p.413),应用这种方法可检测产物的杀病毒活性。此活性用病毒滴度减小表示,这是通过在体外将疱疹病毒悬浮液与所试验产物的稀释液在37℃孵育5分钟而测定的。一个好的产物可提供的最小滴度减小为103。
根据本发明,从对已知消毒剂进行的一般性筛选中已经发现许多产物显示有很高的活性,甚至在25℃下,这些消毒剂对单纯疱疹病毒1型和2型病毒株(临床分离株)具有杀病毒作用。因为皮肤上的温度通常低于37℃,甚至低于34℃,所以这是非常有利的。已经发现浓度分别为50-200μg/ml和100-200μg/ml的季铵化合物溴棕三甲铵和氯化苯甲烃铵在25℃试验5分钟所示的滴度减小至少为103。其它已知的消毒剂,诸如醇类、酚类、过氧化物、双胍、醛、氯化物等,它们所显示的最小活性为5倍以下。仅仅汞化合物和所确定的重金属化合物具有较好的活性。然而由于这些化合物具有很高的毒性,所以它们在所需的应用中不适合。
原则上可应用所有的季铵化合物,其通式为:
其中R1、R2、R3和R4可以相同或者不同,并且可代表一个脂基或芳基,其中R1、R2、R3或R4中的至少一个为含8个或更多碳原子的脂肪链;并且
其中X为一个低分子量的无机阴离子或者为一个高分子量的有机阴离子。A.Dauphin和J.C.Darbord在“Hygi ne hospitalièrepratique”,Editions medicales internationales,巴黎(1988)中对适宜季铵化合物进行了全面评述。首选溴棕三甲铵。
季铵化合物可较好地溶解于水和乙醇中,但不能任意与其它产物相结合。因此对第二成分的一个重要要求是它必须与第一成分相容。阴离子产物、脂肪酸盐、硝酸盐、重金属、氧化产物、橡胶、蛋白质等与季铵化合物不相容。因此这些产物不适宜应用于本发明的组合物中。第二成分最好为非致畸的并且可在大剂量下没有毒性。而且第二成分最好具有较好的皮肤渗透性。
只要它们与第一成分相容,诸如阿昔洛韦、BVDU、3FT和碘苷等已知的抗病毒产物可以用作第二成分。另外还可以应用具有抗病毒活性的无毒天然产物。
还可以用本来已知的EPTT方法(Colgate和Molyneux,supra,414页)对此第二成分的适合性进行试验。在此所用的为VERO细胞。按照本发明已经发现棓酸盐在体外具有较好的抗病毒活性。这样浓度为100μg/ml的棓酸丙酯的滴度减小系数为104。浓度为25μg/ml时,在VERO细胞中的传染性颗粒的减小系数是103。浓度为100μg/ml的棓酸乙酯的滴度减小系数为104而且浓度为25μg/ml的系数为102。因此棓酸乙酯的活性略微较小。
可以通过第一和第二成分的混合物对HSV-1的试验测定这两个成分的相容性。已经发现在25℃试验5分钟以后棓酸丙酯和溴棕三甲铵(2∶1)的混合物仍具有103的杀病毒作用,在此其浓度为250μg的棓酸丙酯比125μg的溴棕三甲铵。这同样适用于棓酸乙酯和溴棕三甲铵。在体外BVDU或阿昔洛韦和溴棕三甲铵分别稀释至5μg/ml和0.1μg/ml以后,溴棕三甲铵和BVDU或阿昔洛韦的混合物仍继续显示抗病毒活性。
最好此药物组合物还含有一种植物提取物,以此可减轻疼痛和炎症反应的影响。在这里此提取物还不能影响第一和第二成分的活性。
为达到此目的,将不同的植物提取物与溴棕三甲铵和棓酸丙酯或者与氯化苯甲烃铵和棓酸丙酯一起试验,以观察杀病毒活性是否仍存在以及这些成分是否相容。已经发现春黄菊和金盏花的提取物在体外仍是可用的。芦荟、紫锥花根、三色紫罗兰、番泻叶、滇荆芥和/或山楂的提取物在杀病毒活性继续保持的同时,也能减轻炎症反应或疼痛。
然而特殊的植物提取物可造成某些季铵化合物的杀病毒活性的明显下降。例如已经发现10%北美金缕梅可使氯化苯甲烃铵(0.5%)的杀病毒和抗菌活性完全失效。洋苏草和大芒壳提取物可使0.1%氯化苯甲烃铵的抗疱疹和细菌活性减小4至8倍。但是,已发现溴棕三甲铵与第二成分和春黄菊、金盏花、洋苏草、大芒壳和番泻叶中的一种提取物的组合在体外仍保持其抗单纯疱疹病毒及细菌的活性。
因此必须提前测定所用植物提取物的相容性。这种测定为一般技术人员所掌握的。
适宜的植物提取物选自:例如,马栗树;芦荟;Anagallisarvensis L;白花春黄菊;牛蒡;铁线连马兜铃;山金车;欧水苏;金盏花;辣椒(方形);番木瓜树;Carlina acaulis L;丁香;紫草;狭叶紫锥花;紫色紫锥花;佩兰cannabinum L;汉荭鱼腥草;水杨梅urbanum L;Glechomahedracea L;北美金缕梅;金丝桃perforatum L;土木香;胡桃;桧oxycedrus L;熏衣草;散沫花;排草nummeralia L;千屈草salicariaL;锦葵;欧夏至草;德甘菊;洋薄荷;妥鲁香树;番樱桃communis L;洋橄榄树;扁桃;榅桲;橡树;肥皂草;覆盆子;洋苏草;石硷草;洋菝葜;苦茄;新疆一支黄花;越南安息香;安息香benzoides;安息香:西门肺草;胡芦巴;旱金莲;小荨麻;大荨麻;三色堇。
本发明的药物组合物由一个或多个具有杀病毒和抗菌活性的季铵化合物和/或一个与季铵化合物相容并抑制病毒复制的抗病毒产物,和/或一个同样与上述两种产物相容并可减轻疱疹感染相关影响(诸如疼痛、瘙痒、肿胀和麻刺感等)的植物提取物的组合物组成,此药物组合物对疱疹感染提供全面的治疗。此组合物的杀病毒活性杀死病毒,由此潜伏将较少发生或完全不发生。其抗病毒活性抑制病毒的复制并以此抑制病毒的繁殖。其抗菌活性阻止继发细菌感染。最后其炎症抑制活性阻止炎症发生并且减轻疼痛和瘙痒。
最好本发明组合物的成分包括在一种药物可接受的基质中。此基质的应用并不减小这三种成分的活性。为了试验基质是否适宜,可测定第一成分的杀病毒活性和消毒活性。例如可以用一种一般技术人员所掌握的方法对革兰氏阴性病菌(例如绿脓杆菌或大肠杆菌)在25℃试验5分钟以测定其消毒活性。
适宜基质的实例为不同分子大小的聚乙二醇或其混合物、脂肪酸酯类或其混合物及是否与乳化和/或护肤成分混合。混合有或无乳化和/或护肤成分的聚乙二醇和/或脂肪酸酯类的混合物也适宜。
本发明药物组合物可采用粉剂、悬浮液、溶液、喷雾剂、乳剂、软膏或霜剂并且可适用于局部应用。可以通过将以游离酸或盐形式存在的活性成分与药物可接受的中性赋形剂(诸如水或非水溶剂、稳定剂、乳化剂、洗涤剂、添加剂)结合制备此组合物,另外如果需要还可结合染色剂、香料和/或调味剂。根据治疗的性质和应用的方式,药物组合物中活性成分的浓度可在0.001%至100%(w/v)之间变化。在此推荐软膏形式。
例如本发明组合物包含10-90%的一种非水基质、1-20%的一种醇、0.1-5%的一个或多个季铵化合物、和/或0.01-2%的一个或多个抗病毒剂、和/或0.5-10%的一个或多个植物提取物。所用植物提取物的量与其活性和提取物中活性成分的浓度密切相关。
本发明优选组合物包含20-60%,优选52%的PEG400;10-40%,优选26%的PEG4000;2-20%,优选9%的甘油;0.5-1.8%,优选1%的溴棕三甲铵;0.2-3%,优选1%的十六烷醇;5-15%,优选8%的春黄菊提取物和0.2-1%,优选0.25%的棓酸丙酯。
本发明将通过所提交的附带实施例得到进一步地阐明,但是在此并不是要对本发明进行任何限制。实施例实施例1I.抗疱疹剂的制备应用下列组分:
A.聚乙二醇400 52%
聚乙二醇4000 26%
甘油 9%
溴棕三甲铵 1%
胆碱盐酸盐(任选) 2%
十六烷醇 1%
B.春黄菊提取物 8%
棓酸丙酯 1%通过在75℃下融化A中组分和溶解B中组分,制备一种软膏。然后,在慢慢冷却的同时,将融化后所得的A中组分的混合物混匀,并在A混合物固化前加入B混合物。继续搅拌,直至总混合物完全冷却。此混合物被命名为93J12。
聚乙二醇400和4000从市售商品名为Macrogol 400-Purna和Macrogol4000的药品中得到。甘油为p.a.品质,来自Merck(4094)。溴棕三甲铵A11936由Pharmachemic NV提供。胆碱盐酸盐(C1897)由Sigma提供。十六烷醇为Henkel KGaA的市售药品,商品名为Lanette16。液体春黄菊提取物来自Conforma。酸丙酯P3130来自Sigma。II.M-VDB培养基的制备和组成应用下列组分:氯化钠(NaCl) 6.77gD-半乳糖 0.80g丙酮酸钠 0.20g氯化钾(KCl) 0.40g氯化镁(MgCl2.6H2O) 2.0g氯化钙(CaCl2.2H2O) 0.20g磷酸二氢钠(NaH2PO4.H2O) 0.14g琥珀酸钠 1.0g琥珀酸 0.75gL-谷氨酰胺(+) 0.30g氨基酸BEM1000x 10ml维生素BEM100x 10ml酚红储液 1ml(即在一种0.05N NaOH水溶液中含1%酚红)通过将各组分溶于960ml蒸馏水,然后用NaOH(10N)调整PH值至7.4,并用一个0.2μ过滤膜过滤至无菌容器而制备一种用于细胞培养的维持培养基。然后加入2%新生牛血清(用于VERO细胞)或2%胎牛血清(用于其它细胞)。实施例2抗病毒活性1.组分的抗病毒活性
在本实施例中使用的是来自美国型培养收集液(登记号CCL26)的VERO细胞。VERO细胞在介质199(Gibco)中用Earles盐和5%小牛血清培养。使用的病毒源为在M-VDB中用100μg/ml青霉素、100μg/ml链霉素和2%小牛血清培养的单纯疱疹病毒1(HVS-1,特征临床分离菌)。
将100μl在M-VDB中HSV-1的10-1至10-6的稀释液系,排列在一个显微滴度盘(平底96井)中培养的VERO细胞的单分子层上。使病毒吸附细胞60至90分钟。然后,将在M-VDB中试验产物的稀释液系加入感染细胞中。为检查此产物的细胞毒性,用相同的方法将产物的稀释液加入未感染细胞中。在37℃的温室中孵育5天后,用显微方法评价其致细胞病变作用(CPE)。
产物的抗病毒活性用样品的最高无毒浓度的减小系数(RF)表示。减小系数(RF)是对照组中病毒浓度与产物稀释液中活病毒浓度的比。RF≥102被认为具有显著意义。用棓酸丙酯的实验结果显示于表1中。表1试验产物 试验浓度 病毒滴度减小系数溶于DMSO并用M- 100μg/ml 104VDS稀释的棓酸丙酯
同上 50μg/ml 104
同上 25μg/ml 103
同上 10μg/ml 1
从上表可以看出:棓酸丙酯对HSV-1的抗病毒活性直至25μg/ml的浓度时仍具有显著意义。
通过将含有106cfu HSV-1的病毒悬浮液与一种体积相同浓度不同的试验产物溶液混合而测定杀病毒活性。在控制温度下孵育此混合物一定时间。将每种混合物10-1至10-6的稀释液系放置在VERO的一个单分子层上。在37℃下孵育5天后评价CPE。结果用RF表示。滴度减小再次≥102被认为具有显著意义。
在34℃15分钟对HSV-1的杀病毒活性显示于表2中。表2试验产物 试验浓度 减小系数棓酸丙酯 500μg/ml 1溴棕三甲铵 500μg/ml 105
250μg/ml 105
125μg/ml 105
100μg/ml 105
50μg/ml 10
10μg/ml 1棓酸丙酯/溴棕三甲铵(2/1)500/250 105棓酸丙酯/溴棕三甲铵(2/1)250/125 105
从上表可以看出:棓酸丙酯不具有杀病毒活性,而溴棕三甲铵直至100μg/ml的浓度仍具有杀病毒活性。尽管棓酸丙酯过量(2/1),棓酸丙酯和溴棕三甲铵的混合物仍具有杀病毒活性。2.试验混合物的抗病毒成分
用相似的方法,测定实施例1制备的混合物的抗病毒活性。软膏2515分钟的杀病毒活性的结果显示于表3中。
表3表明:软膏在25℃直至1/100的稀释液对HSV-1仍具有杀病毒活性。因此,甚至在25℃下,溴棕三甲铵仍具有其全部活性。表3试验混合物 稀释液 RF93J12 1/2 105
1/4 105
1/8 105
1/16 105
1/32 105
1/64 105
1/128 105
1/256 1实施例3抗菌活性
用试验生物白色念珠菌(ATTC10231)、大肠杆菌(ATTC8739)、绿脓杆菌(ATTC15442)和金黄色葡萄球菌(ATTC6538)测定单独成分和最终产物的抗菌活性。所用培养基为胰大豆肉汤(TSB)、胰大豆琼脂(TSA)和无菌磷酸盐缓冲液(PBS)。I.成分和混合物的抗菌活性
37℃下在TSB中制备每一种微生物的过夜培养基,以测定最小抑制浓度(MIC)。同样在TSB中制备所用试验混合物的1/2稀释液系。将100μl每种稀释液放入一个显微滴度盘。在TSB中将此过夜培养基稀释1/1000。同样,将100μl每种细菌悬浮液加入产物稀释液中。未添加细菌的产物稀释液和未添加产物稀释液的细菌稀释液用作无菌性对照。显微滴度盘在一个37℃的湿室中孵育24小时。根据悬浮液的浊度评价细菌生长。MIC值是能够抑制微生物正常生长的最低产物浓度,即不产生任何浑浊。
结果显示于表4中。
表4
试验产物% | 白色念珠菌 | 大肠杆菌 | 绿脓杆菌 | 金黄色葡萄球菌 |
春黄菊提取物(v/v) | >25% | >25% | >25% | 12.5% |
棓酸丙酯(w/v) | >0.2% | 0.05% | 0.1% | 0.2% |
溴棕三甲铵(w/v) | 0.001% | 0.003% | 0.003% | 0.0005% |
春黄菊10%+溴棕三甲铵0.5% | - | 1/128 | - | - |
春黄菊5%+酸丙酯0.2%+溴棕三甲铵0.5% | 1/512 | 1/128 | 1/128 | 1/1024 |
以上表明:春黄菊提取物对一些微生物的抗菌活性非常有限,并且仅仅是在高浓度下。另一方面,棓酸丙酯和溴棕三甲铵则具有明显的抗菌活性。我们发现:混合物中的溴棕三甲铵保持其抗菌活性。II.试验软膏的抗菌活性
如实施例1所述,制备软膏的三个独立部分,编号为94A12、94D21和94E05。制备不添加溴棕三甲铵的相同组合物,用它作为安慰剂。此安慰剂被称作94D27。用无菌蒸馏水中1%的溴棕三甲铵作为对照。所有试验样本在室温下保存。IIa.最小抑制浓度(MIC)的测定
最小抑制浓度是在其以下细菌不再生长的试验产物的浓度。通过将1克软膏悬浮于9ml无菌蒸馏水而制备所用的最高试验浓度(1/10稀释)。将此稀释液加入细菌中,然后将细菌培养24小时。所用的试验生物为105的白色念珠菌(Ca)、106的大肠杆菌(Ec)、105的绿脓杆菌(Pa)和106的金黄色葡萄球菌(Sa)。
表5显示抑制细菌生长的稀释液。表5
此表表明:所有试验软膏均保持抗菌活性。这些软膏的MIC值与水中1%溴棕三甲铵的MIC值相类似。试验浓度下的安慰剂不具有抗菌活性。IIb.杀细菌和杀真菌活性的测定
试验混合物 | Ca | Ec | Pa | Sa |
94A12 | 1/80 | 1/160 | 1/40 | 1/5120 |
94D21 | 1/80 | 1/160 | 1/40 | 1/5120 |
94D27 | >1/20 | >1/20 | >1/20 | >1/20 |
94E05 | 1/80 | 1/160 | 1/40 | 1/5120 |
溴棕三甲铵1% | 1/80 | 1/320 | 1/40 | 1/5120 |
用白色念珠菌(105)、大肠杆菌(106)、绿脓杆菌(105)和金黄色葡萄球菌(106)试验其杀细菌活性。依据欧洲药典的规定测定其杀细菌活性。这些规定要求所试验的产物与微生物混合并孵育一段时间,然后稀释此混合物并且测定哪一种稀释液中仍发生细菌生长。
将每一种微生物的稀释液终末浓度制备至106-107cfu。以未稀释的和在无菌蒸馏水中的1/2和1/10稀释液试验此软膏。将100μl稀释接种物加入1g软膏或其稀释液中并且混合。在25℃孵育15分钟后,从100mg的此混合物中于TSB(胰大豆肉汤(Gibco))中制备1/10稀释液系。将每个稀释液平铺于TSA(胰大豆琼脂(Gibco))上。在37℃将此平皿孵育24小时。未处理的微生物培养基和蒸馏水中1%溴棕三甲铵作为对照。孵育后评价所有平皿细菌的生长。将以减小系数(Rf)表示的此试验进行三次。结果显示于表6中。
表6
上表显示所有的试验软膏在稀释液中仍保持其杀细菌活性。所有的细菌都被杀死。并发现安慰剂的杀细菌活性非常有限。IIc.杀真菌活性
试验混合物 | Ca(106) | Ec(106) | Pa(105) | Ba(105) |
1/194A121/21/10 | -105-105-105 | -106-106-106 | -105-105-105 | -106-106-106 |
1/194D211/21/10 | -105-105-105 | -106-106-106 | -105-105-105 | -106-106-106 |
1/194D271/21/10 | -105-105-1 | -103-103-1 | 111 | -10-101 |
1/194E051/21/10 | -105-105-105 | -106-106-106 | -105-105-105 | -106-106-106 |
1/1溴棕三甲铵1%1/21/10 | -105-105 | -106-106 | -105-105 | -106-106 |
为测定其杀真菌活性,应用试验生物絮状表皮癣菌(RV69635)和红毛癣菌(RV58124)。
应用杀细菌活性同样的方法测定杀真菌活性。
为达到此目的,将每种微生物稀释液的终末浓度制备至104-105cfu。以未稀释的和在无菌蒸馏水中的1/2和1/10稀释液试验此软膏。将100μl稀释接种物加入1g软膏或其稀释液中并且混合。在25℃孵育15分钟后,从100mg的此混合物中于SAB(萨布罗肉汤(Gibco))中制备1/10稀释液系。将每个稀释液平铺于SABA(萨布罗琼脂(Gibco))上。在25℃将此平皿孵育5天。未处理的微生物培养基和蒸馏水中1%溴棕三甲铵作为对照。孵育后评价所有平皿细菌的生长。将此试验进行三次。以减小系数(Rf)表示的结果显示于表7中。表7
试验混合物 | 絮状表皮癣菌(103) | 红毛癣菌(104) |
94A12 | 102 | 104 |
94D21 | 102 | 104 |
94D27 | 10 | 102 |
94E05 | 102 | 104 |
溴棕三甲铵1% | 102 | 104 |
上表显示试验软膏保持其抗真菌活性,此活性与在蒸馏水中1%溴棕三甲铵的活性相似。安慰剂的抗真菌活性有限。IId.杀病毒活性
按照D.Vanden Berghe等在“植物生物化学中的方法”,第6卷“生物活性分析”,49-67页,Academic Press Limited1991中所述的微量法测定杀病毒活性。将300μl未稀释病毒悬浮液加入300μl产物稀释液中。在34℃孵育这些混合物15分钟。向稀释试管中提供0.9ml冷却的病毒培养基,并将其置于冰浴器中。将100μl孵育混合物置于此稀释试管中。由此制备1/10稀释液系。将200μl的这些稀释液置于VERO细胞上。对照为未处理病毒(=病毒对照)和未处理细胞(=细胞对照)。在湿性培养器中于37℃孵育此平皿5至7天。用微观方法评价这些细胞的细胞毒性和致细胞病变效应(CPE)。结果用减小系数(Rf)表示。减小系数为剩余病毒浓度与原始病毒浓度的比率。将此试验进行三次。以Rf表示的结果显示于表8中。表8
试验混合物 | 1/2 | 1/5 | 1/10 | 1/20 | 1/50 |
94A12 | 105 | 105 | 105 | 105 | 105 |
94D21 | 105 | 105 | 105 | 105 | 105 |
94D27 | 1 | 1 | 1 | 1 | 1 |
94E05 | 105 | 105 | 105 | 105 | 105 |
溴棕三甲铵1% | 105 | 105 | 105 | 105 | 105 |
上表显示试验软膏稀释至1/50仍具有杀病毒活性。其杀病毒活性与1%溴棕三甲铵的活性相似。安慰剂没有杀病毒活性。实施例4体内活性试验
试验组由15个口唇上有唇疱疹的病人组成。用含下面成分的软膏对他们进行治疗:
PEG400 52%
PEG4000 26%
甘油 9%
溴棕三甲铵 1%
胆碱(任选) 2%
十六烷醇 1%
春黄菊提取物 8%
棓酸丙酯 0.25%试验结果显示于表9中。表9:试验软膏体内抗-HSV活性的临床评价
病人 | 治疗 | 结果 | 早期治疗 | 评价 | |||
频率 | 持续时间 | 起效 | 何种效果 | 副作用 | |||
1 | 3x/天 | 1天 | 是 | 水泡未发展 | 无 | 阿昔洛韦 | 开始应用时有麻刺感 |
2 | 2x/天 | 1天 | 是 | 未蔓延/迅速愈合 | 麻刺感 | 阿昔洛韦 | -- |
3 | 4-5x/天 | 3天 | 是 | 迅速愈合 | 无 | pate hime | -- |
4 | 6/天 | 7天 | 是 | 水泡干燥较前增快 | 无 | 阿昔洛韦 | -- |
5 | 4-5/天 | 3天 | 是 | 迅速愈合 | 无 | 阿昔洛韦 | 味道差 |
6 | 5/天 | 4-6天 | 是 | 快速恢复 | 无 | 阿昔洛韦 | -- |
7 | 2/天 | 2天 | 是 | 水泡未发展 | 无 | 未知 | 若冷则预防性应用 |
8 | 2/天 | 3天 | 是 | 迅速愈合 | 有:干燥 | 未知 | 以后症状不再复发/过去>1x/月 |
9 | 3/天 | 4天 | 是 | 快速恢复 | 无 | 未知 | 以后症状复发频率减小/4月内不再复发 |
10 | 1/天 | 30天 | 是 | 12个月内症状未复发 | 无 | 未知 | 过去频率>1x/月 |
11 | 2/天 | 4-5天 | 是 | 迅速愈合 | 无 | 凡士林 | 症状复发频率减小 |
12 | 2-3/天 | 4天 | 是 | 迅速愈合 | 无 | 阿昔洛韦 | -- |
13 | 3/天 | 4天 | 是 | 迅速愈合/未发展 | 无 | 阿昔洛韦 | 症状复发频率减小 |
14 | 2/天 | 3天 | 是 | 迅速愈合/未发展 | 无 | 阿昔洛韦 | 症状复发频率减小 |
15 | 3/天 | 4天 | 是 | 迅速愈合/未发展 | 无 | 阿昔洛韦 | 若冷则预防性应用;开始麻刺感至未发作 |
在用2个男性患者进行的另一试验中试验此软膏的预防作用。至试验末,在通常所说的损伤发生的局部应用此软膏一天一次,持续6个月。治疗结果为症状不再复发,甚至在感冒的情况下。在治疗前两个患者之一的唇疱疹至少一月一次,同时两个患者感冒总是伴随有症状。
本发明为疱疹感染的治疗提供一种新的药物组合物,特别是由HSV-1或HSV-2引起的面或唇疱疹。与其它药物很大的区别在于治疗性或预防性应用此药物的大多数患者以后在相同的局部症状不再复发。
Claims (10)
1.治疗单纯性疱疹病毒感染的药物组合物,在一种药物可接受的基质中含有一种季铵化合物作第一种成分,和/或一种抗病毒剂作第二种成分,和/或一种植物提取物作第三种成分,其中三种成分彼此相容。
2.如权利要求1中所述的药物组合物,其特征在于:第一种成分从由溴棕三甲铵、氯化苯甲烃铵组成的物质组中选择。
3.如权利要求1或2中所述的药物组合物,其特征在于:第二种成分从由阿昔洛韦、bromovinyldesoxuridine(BVDU)、3-氟胸苷(3FT)、idoxuridine、棓酸丙酯、棓酸乙酯、proanthocyanides和葡糖胺组成的物质组中选择。
4.如权利要求1、2或3中所述的药物组合物,其特征在于:第三种成分选自由马栗树;芦荟;Anagallis arvensis L;白花春黄菊;牛蒡;铁线连马兜铃;山金车;欧水苏;金盏花;辣椒(方形);番未瓜树;Carlinaacaulis L;丁香;紫草;狭叶紫锥花;紫色紫锥花;佩兰cannabinum L;汉荭鱼腥草;水杨梅urbanum L;Glechoma hedracea L;北美金缕梅;金丝桃perforatum L;土木香;胡桃;桧oxycedrus L;熏衣草;散沫花;排草nummeralia L;千屈草salicaria L;锦葵;欧夏至草;德甘菊;洋薄荷;妥鲁香树;番樱桃communis L;洋橄榄树;扁桃;榅桲橡树;肥皂草;覆盆子;洋苏草;石硷草;洋菝葜;苦茄;新疆一支黄花;越南安息香;安息香benzoides;安息香;西门肺草;胡芦巴;旱金莲;小荨麻;大荨麻;三色堇的提取物组成的物质组。
5.如权利要求1、2或3中所述的药物组合物,其特征在于:当第一种成分为溴棕三甲铵时,第三种成分从由春黄菊、金盏花、鼠尾草、大芒壳、番泻叶的提取物组成的物质组中选择。
6.如权利要求1、2或3中所述的药物组合物,其特征在于:当第一种成分为氯化苯甲烃铵时,第三种成分从由春黄菊、金盏花、番泻叶的提取物组成的物质组中选择。
7.如权利要求1至6中任一所述的药物组合物,在一种药物可接受的载体中含有:
0.1-5%的一种季铵化合物;
0.01-3%的一种抗病毒剂;以及
1-20%的一种植物提取物。
8.如权利要求7中所述的药物组合物,含有:
PEG400 52%
PEG4000 26%
甘油 9%
溴棕三甲铵 1%
胆碱(任选) 2%
十六烷醇 1%
春黄菊提取物 8%
棓酸丙酯 0.25%
9.一种如权利要求1至8中任一所述的药物组合物用于治疗HSV-1感染的用途。
10.一种如权利要求1至8中任一所述的药物组合物用于治疗HSV-2感染的用途。
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NL9500216A NL9500216A (nl) | 1995-02-06 | 1995-02-06 | Farmaceutische samenstelling voor de behandeling van herpes. |
NL9500216 | 1995-02-06 |
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EP (1) | EP0808168B1 (zh) |
JP (2) | JPH10513193A (zh) |
CN (1) | CN1121232C (zh) |
AT (1) | ATE226081T1 (zh) |
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CA (1) | CA2211802C (zh) |
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US6348503B1 (en) | 1996-02-12 | 2002-02-19 | Meryl J. Squires | Method and topical treatment composition for herpesvirus hominis |
US6355684B1 (en) | 1990-10-11 | 2002-03-12 | Meryl J. Squires | Antimicrobial treatment for herpes simplex virus and other infectious diseases |
US6350784B1 (en) | 1996-02-12 | 2002-02-26 | Meryl J. Squires | Antimicrobial prevention and treatment of human immunedeficiency virus and other infectious diseases |
US8267982B2 (en) * | 1998-08-25 | 2012-09-18 | Advanced Photodynamic Technologies, Inc. | Photodynamic cellular and acellular organism eradication utilizing a photosensitive material and surfactant |
US8173709B2 (en) | 1999-09-22 | 2012-05-08 | Quadex Pharmaceuticals, Llc | Anti-infective methods for treating pathogen-induced disordered tissues |
GB2375113B (en) * | 2000-01-21 | 2004-10-20 | Biovex Ltd | A modified, oncolytic, non-laboratory HSV strain and its use in treating cancer |
GB0317511D0 (en) * | 2003-07-25 | 2003-08-27 | Biovex Ltd | Viral vectors |
ITMI20032287A1 (it) * | 2003-11-24 | 2005-05-25 | Indena Spa | Composizioni per il trattamento delle affezioni del cavo orale e delle prime vie respiratorie |
US7968122B2 (en) * | 2003-12-10 | 2011-06-28 | Adventrx Pharmaceuticals, Inc. | Anti-viral pharmaceutical compositions |
US7250180B2 (en) * | 2004-01-07 | 2007-07-31 | Edwin Cevallos Arellano | Anti-prostate cancer composition and therapeutic uses therefor |
CN100427082C (zh) * | 2005-08-02 | 2008-10-22 | 盛华(广州)医药科技有限公司 | 羟基苯甲酸酯及其类似物在制备预防和治疗病毒性感染药物中的应用 |
US8044098B2 (en) | 2005-08-02 | 2011-10-25 | Shenghua Guangzhou Pharmaceutical Science & Technology Co., Ltd. | Use of hydroxybenzoic acids and their esters and analogues for preventing or treating virus infection |
US7790203B2 (en) * | 2005-12-13 | 2010-09-07 | Lowder Tom R | Composition and regimen for the treatment of herpes simplex virus, herpes zoster, and herpes genitalia epidermal herpetic lesions |
AU2010330812B2 (en) * | 2009-12-18 | 2016-03-10 | Exodos Life Sciences Limited Partnership | Methods and compositions for treating inflammation of skin |
US8247006B2 (en) * | 2010-06-22 | 2012-08-21 | Golio Dominick I | Composition and method of treating lipid encapsulated virus infections |
PT2563374E (pt) | 2010-07-08 | 2014-01-23 | Devirex Ag | Composições de polietileno glicol para o controlo da reincidência de herpes labial, herpes genital, e herpes zóster |
US8846725B2 (en) | 2011-01-24 | 2014-09-30 | Quadex Pharmaceuticals, Llc | Highly penetrating compositions and methods for treating pathogen-induced disordered tissues |
WO2014055659A1 (en) * | 2012-10-03 | 2014-04-10 | Pharma Green Llc | Methods and compositions for production of recombinant pharmaceutical proteins in medicinal plants |
US9463180B2 (en) | 2013-03-14 | 2016-10-11 | Quadex Pharmaceuticals, Llc | Treatment of molluscum contagiosum |
US9125911B2 (en) | 2013-03-14 | 2015-09-08 | Quadex Pharmaceuticals, Llc | Combined systemic and topical treatment of disordered tissues |
US9549930B2 (en) | 2013-03-14 | 2017-01-24 | Quadex Pharmaceuticals, Llc | Combined systemic and topical treatment of disordered and/or prodromal stage tissue |
ITUB20152286A1 (it) * | 2015-07-17 | 2017-01-17 | Harven S A S | Composizione anti herpes |
US10744175B2 (en) * | 2016-02-23 | 2020-08-18 | Apurve Mehra | Herbal composition for the treatment of Herpes |
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US4053628A (en) * | 1971-05-12 | 1977-10-11 | Fisons Limited | Composition |
AU553789B2 (en) * | 1982-06-30 | 1986-07-24 | Biorex Laboratories Ltd. | Glycyrrhetinic acid derivatives in cream compositions |
US4478818A (en) * | 1982-12-27 | 1984-10-23 | Alza Corporation | Ocular preparation housing steroid in two different therapeutic forms |
US4902720A (en) * | 1983-01-10 | 1990-02-20 | Baldone Joseph A | Treatment of virus infections with quaternary ammonium compounds |
JPH0655676B2 (ja) * | 1984-07-26 | 1994-07-27 | ザ リポソ−ム カンパニ−、インコ−ポレ−テツド | 脂質小胞体中に含有された抗菌物質の混合物による抗菌活性の増高 |
US4895727A (en) * | 1985-05-03 | 1990-01-23 | Chemex Pharmaceuticals, Inc. | Pharmaceutical vehicles for exhancing penetration and retention in the skin |
MY102648A (en) * | 1986-12-03 | 1992-08-17 | Rudov David | Pharmacological / cosmetic preparation |
CA1273576A (en) * | 1987-09-16 | 1990-09-04 | Patrick A. Beauchamp | Topical treatment for diseased skin disorders |
ATE78396T1 (de) * | 1987-09-23 | 1992-08-15 | Atlantic Pharma Prod | Zusammensetzung zur hemmung oder vernichtung mindestens eines einzelligen lebewesens, enthaltend ein quaternaeres ammoniumfluorid, und verfahren zur herstellung dieses salzes. |
JP2862951B2 (ja) * | 1990-04-23 | 1999-03-03 | 花王株式会社 | 殺菌消毒剤組成物 |
FR2687314A1 (fr) * | 1992-02-18 | 1993-08-20 | Oreal | Dispersion de vesicules lipidiques, composition cosmetique et/ou pharmaceutique la contenant et procede de preparation de ladite dispersion. |
US5229423A (en) * | 1992-03-06 | 1993-07-20 | Albert Einstein College Of Medicine Of Yeshiva University | Use of butylurea as a contraceptive agent |
US5455033A (en) * | 1993-05-21 | 1995-10-03 | Degree/Silverman M.D. Inc. | Medicinal composition for treatment of inflammation |
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EP0808168B1 (en) | 2002-10-16 |
NL9500216A (nl) | 1996-09-02 |
DK0808168T3 (da) | 2003-02-17 |
CA2211802A1 (en) | 1996-08-15 |
WO1996024367A1 (en) | 1996-08-15 |
AU4678896A (en) | 1996-08-27 |
CN1121232C (zh) | 2003-09-17 |
DE69624340D1 (de) | 2002-11-21 |
EP0808168A1 (en) | 1997-11-26 |
US6284289B1 (en) | 2001-09-04 |
JP2008074872A (ja) | 2008-04-03 |
ES2185760T3 (es) | 2003-05-01 |
AU712744B2 (en) | 1999-11-18 |
ATE226081T1 (de) | 2002-11-15 |
CA2211802C (en) | 2009-06-02 |
DE69624340T2 (de) | 2003-06-18 |
JPH10513193A (ja) | 1998-12-15 |
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