CN104510809A - 地榆或其提取物抗病毒新用途 - Google Patents
地榆或其提取物抗病毒新用途 Download PDFInfo
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- CN104510809A CN104510809A CN201410524174.8A CN201410524174A CN104510809A CN 104510809 A CN104510809 A CN 104510809A CN 201410524174 A CN201410524174 A CN 201410524174A CN 104510809 A CN104510809 A CN 104510809A
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- radix sanguisorbae
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Abstract
本发明提供了地榆或其提取物在制备抗乳头状瘤病毒药物中的新用途。本发明提供的地榆及其制剂用于预防或治疗病毒性皮肤疾病，例如尖锐湿疣等，能在较短使用时间内获得较好治疗效果，并安全无毒副作用，为临床用药提供了新的选择。
Description
技术领域
本发明涉及地榆或其提取物在制备抗病毒的药物中的用途。
背景技术
病毒性皮肤病是由病毒感染所致。当病毒侵入机体后，对神经组织和皮肤组织有较强的亲合力，亲神经者可引起带状疱疹等，亲皮肤者则形成疣症。疣是病毒引起的良性赘生物。寻常疣、扁平疣、尖锐湿疣为人乳头瘤病毒(HPV)所致。人乳头瘤病毒(HPV)是一种属于乳多空病毒科的乳头瘤空泡病毒A属，是球形DNA病毒，能引起人体皮肤黏膜的鳞状上皮增殖。表现为寻常疣、生殖器疣(尖锐湿疣)等症状。随着性病中尖锐湿疣的发病率急速上升和宫颈癌、肛门癌等的增多，人乳头瘤病毒感染越来越引起人们的关注。
目前病毒性皮肤病主要的治疗手段包括(1)外科治疗，例如激光、微波、冷冻、电灼、手术切除(妇科的LEEP刀等)、光动力疗法等；(2)药物治疗，例如施用0.5％足叶草脂毒素酊，5％咪喹莫特，50％三氯醋酸、氟尿嘧啶软膏，Veregen(PolyphenonE,茶多酚15％软膏)等药物。
外科手术治疗的缺点是使患者很不愉快，还可能导致进一步感染。采用足叶草脂等药物治疗对用药部位易造成腐蚀性，需要保护好周围正常组织，否则易形成周围正常组织的种植，不适合粘膜疣的应用。生殖器疣不好辨认的，不宜患者自行用药，因而其使用不方便，具有一定局限性。采用咪喹莫特霜外用，优点是腐蚀性不大，可方便患者自行用药，缺点是，需要至少4到16周的用药，太费时间，且有一定刺激性，可出现皮肤的浅糜烂面，对于大的疣体不适合单独使用此药物治疗。Veregen(PolyphenonE,茶多酚15％软膏)对外生殖器及肛周尖锐湿疣的临床疗效较好，复发率低且相对安全性好，但是需要每日3次，持续使用16周之久才能起到治疗效果。因此，影响患者的顺应性。
因此，临床上迫切需要一种更加安全有效并能减少患者痛苦，提高患者使用药物的顺应性的治疗方法，例如提供一种患者可自行用于患病部位，能在较短使用时间内获得较好的治疗效果，并安全无毒副作用的药物。
地榆为地榆(学名：Radix Sanguisorbae)为蔷薇科地榆属的植物，具有凉血止血、解毒敛疮之功效。目前已有报道地榆还具有抗炎抗菌、促进伤口愈合、镇吐和升白等多种药理活性。国外还有文献报道称，地榆具有抗癌作用[Bastow kF.Bort LD.Fukushrma Y et al.Inhibition of DNA topoisomerasesby sanguim H-6,a cytotoxic dimeric ella-gitan-ton from sanguisorbaofficinalis.Planta Med,1993；59(3):240-245.]。
然而，至今为止尚未见将地榆药材或其提取物应用于由乳头状瘤病毒引起的各种病毒性皮肤病的相关报道。
发明内容
本发明的目的在于提供地榆或其提取物的新用途。
本发明提供了地榆或其提取物在制备抗乳头状瘤病毒的药物中的用途。
进一步地，所述乳头状瘤病毒是人乳头状瘤病毒。
更进一步地，所述药物是预防和/或治疗乳头状瘤病毒所致皮肤疾病的药物。
其中，所述皮肤疾病为疣症。
优选地，所述疣症为足底疣、寻常疣、扁平疣、疣症表皮发育不良或尖锐湿疣。
其中，所述地榆药材为蔷薇科植物地榆Sanguisorba officinalis L.和/或长叶地榆Sanguisorba officinalis L.var.longifolia(Bert.)Yu et Li的根。
其中，所述提取物为水或与水混溶溶剂的提取物。
进一步地，所述与水混溶溶剂是指能与水以任意比例混合的溶剂，例如甲醇、乙醇、丙三醇、甲酸、乙酸、丙酮或四氢呋喃，优选为乙醇或丙酮。
其中，所述地榆提取物为地榆皂苷、地榆鞣质中的一种或两种的组合。
在一具体实例中，所述地榆提取物是由下述方法制备而成：
(1)提取：取地榆药材粉碎成粗粉，例如过20目，用水、乙醇、含水乙醇、丙酮或含水丙酮提取后，滤过，浓缩，得浓缩液；
(2)纯化：取浓缩液，再经常规分离方法处理后，即得。
其中，所述常规分离方法包括色谱法、蛋白质沉淀法、溶剂法或上述方法的结合。
进一步地，所述色谱法为吸附色谱，优选使用凝胶和/或大孔吸附树脂。
进一步地，所述蛋白质沉淀法，优选采用明胶进行沉淀。
进一步地，所述溶剂法例如是将含浓缩液的水溶液脱脂处理后，再用乙酸乙酯萃取；或者可以是将浓缩液溶于乙醇和乙酸乙酯中，加乙醚或石油醚析出沉淀，收集所得沉淀即得地榆提取物。
更进一步地，该提取物是由下述方法之一制备而成：
方法一：取地榆药材，以水为溶剂提取，即得地榆提取物；
方法二：取地榆药材，以无水乙醇为溶剂提取，即得地榆提取物；
方法三：(1)提取：取地榆药材粉碎成粗粉，例如过20目，用水、乙醇、10％-90％的含水乙醇、丙酮或50-90％的含水丙酮提取后，滤过，浓缩，得浓缩液；
(2)纯化：取浓缩液，采用大孔吸附树脂进行吸附除杂，先用水洗脱至无色，再用10％乙醇洗脱，最后用60％乙醇洗脱，收集60％乙醇洗脱液，干燥，即得地榆提取物；或
取浓缩液，脱脂后，用乙酸乙酯萃取，即得地榆提取物。
优选地，所述的含水乙醇的浓度为70wt％；含水丙酮的浓度为70wt％。
其中，所述大孔吸附树脂为非极性树脂或低极性树脂，优选DA-201、D-101、LSA-20、HP-10或AB-8型大孔吸附树脂。
以上所述的提取，可以采用现代技术中大生产上和药物上可接受的各种提取方法进行提取，如浸渍提取、渗漉提取、回流提取、微波辅助提取、超声提取、超临界提取等；提取液浓缩，可以采用常压浓缩、也可以采用减压浓缩等；浓缩液干燥，可以采用热风干燥、真空减压干燥、微波(真空)干燥、喷雾干燥等大生产上和药物上可接受的各种干燥方式。
本发明的又一目的在于提供一种用于预防和/或治疗病毒性皮肤疾病的制剂，其含有所述地榆药材或其提取物。地榆药材或地榆药材细粉或其各种提取物，直接制成散剂、颗粒剂、胶囊剂、片剂、软膏剂或栓剂等临床上可接受的制剂；或加入药学上可接受的适宜的载体或辅助性成分(辅料)，制成丸剂、颗粒剂、口服液、胶囊剂、片剂、糖浆剂、注射剂、软膏剂、栓剂或凝胶剂等临床上可接受的制剂。所述制剂优选为局部外用制剂，例如软膏剂或栓剂，更优选施用于生殖器或阴道感染部位的软膏剂或栓剂。这样可以方便患者自行施用于患病部位。
可以釆用常规制剂技术制备含有本发明所述地榆提取物和药学上可接受的赋形剂的各种剂型。对于剂型及其所采用的相应制剂手段和药学上可接受的赋形剂本发明不作限制。
在一些具体实例中，所述药学上可接受的赋形剂可以是任何制备口服或局部外用制剂常用的或者常规药学上可接受的载体，例如：蔗糖、糊精、淀粉、乳糖、甘露醇、木糖醇、甲壳胺、壳聚糖、双岐糖、滑石粉、羧甲基纤维素钠(CMS-Na)、微晶纤维素(MCC)、微粉硅胶、α-环糊精(α-CD)、β-环糊精(β-CD)、聚乙烯吡咯烷酮(聚维酮)、羟丙基纤维素、聚乙二醇(PEG)、肉豆蔻酸异丙脂、丙二醇棕榈酸硬脂酸酯、油醇、黄原胶、单甘酯、蔗糖酯、凡士林、白蜡、可可脂、明胶或阿拉伯胶。还可添加染料，例如氧化铁黄和/或氧化铁红，和/或二氧化钛，其目的是进行配色。上述药学上可接受的赋形剂可以单独使用，也可以联合使用。本领域的普通技术人员可以理解，只要能够实现本发明的目的，任何药学上可接受的辅料或赋形剂均可用于制备本发明制剂。
本发明所述局部外用制剂优选软膏剂、油膏、乳霜、栓剂或凝胶剂。更优选软膏剂和栓剂，优选局部用于发生病变或患病的皮肤或粘膜区域。
制备各种油包水型和/或水包油型软膏剂的乳化剂可釆用阴离子、阳离子或中性表面活性剂，例如，碱金属型皂、金属型皂类、胺型皂类、磺基化化合物、转化型皂、高级脂肪醇、羊毛蜡、羊毛脂中的一或多种。
制备油膏、乳霜或乳剂可釆用凡士林、天然或合成蜡、脂肪酸、脂肪醇、脂肪酸酯，例如单甘油酯、二甘油酯、三甘油酯、石蜡油或植物油、氢化蓖麻油或椰子油、猪油，合成脂肪例如以辛酸、羊脂酸、月桂酸或硬脂酸为基础的合成脂肪中的一或多种。
为提高稳定性，可釆用，例如具有渗透活性的酸或碱溶液，例如，盐酸、柠檬酸、氢氧化钠溶液、氢氧化钾溶液、碳酸氢钠以及缓冲溶液，例如柠檬酸盐、磷酸盐、tris缓冲液或三乙醇胺以供调整pH值。还可加入防腐剂，例如苯甲酸甲酯，或苯甲酸丙酯或山梨酸。
适用栓剂基质可采用，例如可可脂、甘油、明胶或聚乙二醇。
适合用于凝胶剂的辅料的例子包括但不限于：褐藻酸钠、胍尔豆胶、黄原胶、氢氧化铝、聚乙烯基吡咯烷酮、微晶纤维素或羧甲基纤维素、磷脂、凡士林、蜡、油基醇或棕榈硬脂酸丙二醇酯。
本发明可获得的有益效果至少包括：
1.本发明提供了地榆药材的一种新的临床应用价值，并且原生药粉即可实现临床疗效；
2.本发明提供的地榆及其制剂用于预防或治疗病毒性皮肤疾病，例如尖锐湿疣等，能在较短使用时间内获得较好治疗效果，并安全无毒副作用；
3.本发明所提供的局部外用制剂，例如软膏剂、栓剂可供患者自行施用于感染部位，使用方便、疗效确切，患者顺应性提高。
具体实施方式
为使本发明更加容易理解，下面将结合实施例来详细说明本发明，这些实施例仅起说明性作用，并不局限于本发明的应用范围，下列实施例中未提及的具体实验方法，通常按照常规实验方法进行。
未特别说明之处，“％”表示重量百分比。本发明表述药材粉碎程度所用的单位是“目”，未特别说明之处，所述“目”采用中国药典标准筛规格，例如200目就是该物料能通过1英寸*1英寸内有200个网孔的筛网，200目筛孔尺寸为0.0750mm。
实施例1地榆原生药粉及含有地榆原生药粉的丸剂的制备
取地榆药材1000g，净制，按常规方法粉碎成细粉，过100目筛，混匀，即得地榆原生药粉。取地榆原生药粉，每100g粉末用炼蜜大约40g，合坨、制丸，包装，制成丸剂，规格为每丸含原生药粉0.7g，即得地榆丸。
【用法用量】口服。每天2～3次，每次1～2丸。
实施例2地榆提取物及含有该地榆提取物的软膏剂的制备
取地榆药材粉碎成粗粉，例如过40目，取地榆药材粗粉1000g，水煎煮2次，每次1.5h，加水第一次10倍量，即10L水，第二次8倍量，即8L水，合并滤液，减压浓缩，干燥即得地榆提取物375g。
按表1所示的原辅料配比，采用常规制剂方法制备成软膏剂。
表1含有地榆提取物的软膏剂的原辅料配比
| 材料成分 | 重量百分比(％) |
| 实施例2制得的地榆提取物 | 15 |
| 凡士林 | 3 |
| 肉豆蔻酸异丙基酯 | 6 |
| 羊毛脂 | 5 |
| 卵磷脂 | 13 |
| 硫酸镁 | 1 |
| 铁氧红 | 0.5 |
| 山梨酸 | 0.5 |
| 纯水 | 56 |
将软膏剂常规制剂手段，按表1所示原辅料配比制备而成。
【用法用量】外服。涂抹于患病部位，每天2～3次。
实施例3地榆提取物及含有该地榆提取物的栓剂的制备
取地榆药材粉碎成粗粉，例如过40目，取1000g地榆药材粗粉，70％乙醇回流提取3次，每次2h，溶媒量第一次10倍量，第二次8倍量，第三次6倍量，合并滤液，减压浓缩，除去沉淀，上清液进行大孔树脂分离，先用水洗脱至无色，再用2倍柱体积的10％乙醇洗脱，最后用2倍柱体积的60％乙醇洗脱，收集60％乙醇洗脱液，经膜浓缩至适量，然后喷雾干燥，即得地榆提取物284g。
按表2所示的原辅料配比，采用常规制剂方法制备成栓剂。
表2含有地榆提取物的栓剂的原辅料配比
| 材料成分 | 重量百分比(％) |
| 实施例3所制得的地榆提取物 | 15 |
| 凡士林 | 4.5 |
| 聚乙二醇 | 35 |
| 硬脂酸钠 | 20 |
| 甘油 | 6 |
| 山梨酸 | 4.5 |
| 纯水 | 15 |
【用法用量】外服。每天2～3次，每次1粒。
实施例4地榆提取物及含有该地榆提取物的软膏剂的制备
取地榆药材粉碎成粗粉，例如过40目，取地榆药材粗粉1000g，无水乙醇煎煮2次，每次1.5h，加无水乙醇第一次10倍量，即10L，第二次8倍量，即8L，合并滤液，减压浓缩，干燥，即得地榆提取物332g。
按表3所示的原辅料配比，采用常规制剂方法制备成软膏剂。
表3含有地榆提取物的软膏剂的原辅料配比
| 材料成分 | 重量百分比(％) |
| 实施例4所制得的地榆提取物 | 10 |
| 凡士林 | 3 |
| 肉豆蔻酸异丙基酯 | 6 |
| 羊毛脂 | 5 |
| 卵磷脂 | 13 |
| 柠檬酸钠 | 0.5 |
| 硫酸镁 | 1 |
| 铁氧红 | 0.5 |
| 山梨酸 | 0.5 |
| 纯水 | 60.5 |
【用法用量】外服。涂抹于患病部位，每天2～3次。
实施例5地榆治疗尖锐湿疣的临床观察
尖锐湿疣(CA)是临床较为常见的一种性传播疾病，多因感染人类乳头状瘤病毒(Hpv)而引起，目前尖锐湿疣在我国的发病率呈现逐年升高的趋势。临床传统治疗尖锐湿疣多采取电烧或激光治疗，但治疗对机体的损害大，治疗后复发率较高。本发明人采用含有地榆原生药粉或其提取物的制剂分别治疗了50例尖锐湿疣患者，临床疗效满意。具体实验方法及结果如下：
1、实验对象
所选病例均来自成都中医药大学附属医院患者。根据皮损和醋酸白试验阳性而确诊。排除梅毒、淋病及非淋菌性尿(阴)道炎。伴有其他性病者不作为观察对象。选取了250例患者用于本研究。
2、实验方法
250例患者随机分为5组，每组50例。其中有四个治疗组和一个对照组，四个对照组分别施用实施例1～4所得的制剂；对照组采用激光治疗。各治疗组按上述实施例1～4中所述用法用量施用。
对照组年龄l8～55岁，平均30.7岁；病程l4天～27个月，平均11.6个月；治疗组年龄19～53岁，平均28.4岁；病程16天～25个月，平均10.8个月。诊断标准符合卫生部2000年公布《性病诊断标准和处理原则》。
临床观察时间为3周。治疗期间禁止性生活，配偶同时需要接受检查和治疗，以防再次交叉感染。治疗结束后3个月内性生活必须带安全套。
3、疗效标准
疗效评定标准依据《临床疾病诊断依据治愈好转标准》。痊愈：症状全部消失，观察2个月内无复发；显效：症状基本消失或全部消失，观察2个月内无复发；有效：症状减轻；无效：症状无明显改善甚或加重，有新疣体产生。
4、统计方法
实验数据采用SPSS 13.0软件进行处理，采用t检验以及X2检验，P<0.05有显著性差异。
5、结果
5.1疗效比较
表4患者临床疗效比较(人)
※表示与对照组比较P<0.05
治疗结束后，各治疗组有效率明显高于对照组。
5.2复发率比较
表5两组患者治疗后连续3个月复发率比较(％)
注：上标为a的数据表示复发人数，括号内的数据表示复发率。※表示与对照组比较P<0.05
对照组和各治疗组随访3个月后复发率比较结果表明，治疗组复发率明显低于对照组，有显著性差异。
5.3不良反应
各治疗组未出现不良反应，对照组有5例不良反应，皮肤瘙痒，溃烂，后经药物治疗痊愈。
6、讨论
尖锐湿疣系人乳头瘤病毒(HPV)感染所致生殖器肛周增生性损害。目前治疗主要采用激光、冷冻、手术切除、外用药物和免疫调节等，但反复用激光、电灼及冷冻治疗易造成局部疤痕和萎缩。尖锐湿疣的治疗原则是尽可能去除可见的疣体并减少复发。激光治疗对人体有一定损害，而且易复发，但是采用地榆药材、提取物或其制剂治疗以后，其对皮肤组织刺激作用和毒副作用比较轻，患者病情得到明显改善，疗程短，疗效确切，减轻患者的痛苦，且治愈后不易复发。
由此可见，地榆药材或其提取物以及它们的制剂可用于预防或治疗由乳头瘤病毒(HPV)感染所致的尖锐湿疣。然而，本发明没有穷举地榆及其制剂在其它由乳头瘤病毒(HPV)感染所致的病毒性皮肤疾病中的应用。本领域技术人员可以由此得知地榆药材或其提取物可用于预防或治疗其它病毒性皮肤疾病，特别是由乳头瘤病毒(HPV)引起的病毒性皮肤疾病，例如足底疣、寻常疣、扁平疣、疣症表皮发育不良等其它疣症。
以上所述仅是本发明的优选实施例而已，并非对本发明做任何形式上的限制，虽然本发明已以优选实施例揭露如上，然而并非用以限定本发明，任何熟悉本专业的技术人员，在不脱离本发明技术方案的范围内，当可利用上述揭示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。
Claims (10)
1.地榆或其提取物在制备抗乳头状瘤病毒的药物中的用途。
2.根据权利要求1所述的用途，其特征在于：所述乳头状瘤病毒是人乳头状瘤病毒。
3.根据权利要求1或2所述的用途，其特征在于：所述药物是预防和/或治疗乳头状瘤病毒所致皮肤疾病的药物。
4.根据权利要求3所述的用途，其特征在于：所述皮肤疾病为疣症。
5.根据权利要求4所述的用途，其特征在于：所述疣症为足底疣、寻常疣、扁平疣、疣症表皮发育不良或尖锐湿疣。
6.根据权利要求1所述的用途，其特征在于：所述提取物为水或与水混溶溶剂的提取物；所述与水混溶溶剂是指能与水以任意比例混合的溶剂。
7.根据权利要求6所述的用途，其特征在于：所述与水混溶溶剂选自甲醇、乙醇、丙三醇、甲酸、乙酸、丙酮或四氢呋喃。
8.根据权利要求1所述的用途，其特征在于：所述提取物由如下方法之一制备：
方法一：取地榆药材，以水为溶剂提取，即得地榆提取物；
方法二：取地榆药材，以无水乙醇为溶剂提取，即得地榆提取物；
方法三：(1)提取：取地榆药材粉碎成粗粉，用10％-90％的含水乙醇提取后，滤过，浓缩，得浓缩液；
(2)纯化：取浓缩液，采用大孔吸附树脂进行吸附除杂，先用水洗脱至无色，再用10％乙醇洗脱，最后用60％乙醇洗脱，收集60％乙醇洗脱液，干燥，即得地榆提取物。
9.根据权利要求8所述的用途，其特征在于：所述的含水乙醇的浓度为70wt％。
10.根据权利要求8所述的用途，其特征在于：所述大孔吸附树脂为非极性树脂或低极性树脂，优选DA-201、D-101、LSA-20、HP-10或AB-8型大孔吸附树脂。
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