CN1252285A - 抗爱滋病新药了哥王提取物的制备方法 - Google Patents
抗爱滋病新药了哥王提取物的制备方法 Download PDFInfo
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Abstract
本发明是一种抗爱滋病新药了哥王提取物的制备方法,它以了哥王提取物为原料,制成可以治疗爱滋病的各种制剂。采用溶剂提取法、反相柱层析法等工艺中的一种或者多种工艺,并结合浓缩干燥等常用干燥方法制备成了哥王提取物,将制成的了哥王提取物作为抗爱滋病(AIDS)活性成分,使之与适宜的赋形剂相结合,按照常规方法制成的口服给药的内用剂型及非口服给药的注射剂和外用剂型在爱滋病(AIDS)及其各种并发症治疗中进行应用。
Description
本发明涉及医药技术领域，确切地说它是抗爱滋病(AIDS)新药了哥王提取物的制备方法。
了哥王(Wikstroemia indica)为瑞香科莬花属植物，生于山脚及山坡潮湿的灌丛中，主要分布于广东、广西、福建、台湾、浙江、江西、湖南、四川等地。本植物的茎叶、根和果实均可入药，具有清热解毒、消肿散结、止痛之功效，治痈肿、风湿痛、跌打损伤[江苏新医学院编，中药大辞典(1977年，上海人民出版社)，pp.51-53]。在民间，了哥王常与其他中草药配伍，广泛用于治疗肺癌、宫颈癌、乳腺癌、淋巴癌等多种肿瘤[王冰主编，抗癌中药方选(1992年，人民军医出版社)，pp.16-17]。然而迄今为止，对了哥王的研究较少，多见于化学成分报道，活性研究仅见抑制小鼠体内淋巴癌P-338瘤株作用[Kato et al.，J.Nat.Prod.，1979，42：159-162]以及PKC酶抑制作用[Ko et al.，Biochem.J.，1993，295：321-327；Wang et al.，Euro.J.Pharm.，1995，288：341-348；Chen et al.，Biochem.Pharm.，1996，52：1025-1032]。除此之外，未见任何有关抗爱滋病(AIDS)或者人体免疫缺陷病毒HIV-1和HIV-2的报道。爱滋病是一种传染性很高并且极难治疗的疾病，目前国内外还未发现有治愈率较高的药物的报道。本发明人在寻找中草药抗爱滋病(AIDS)活性成分过程中，发现了哥王提取物具有很好的抗爱滋病(AIDS)活性，并且从中获得多个具有抗爱滋病(AIDS)活性的双香豆素、木脂素、黄酮、黄酮甙以及双黄酮等多种骨架类型的化合物。
本发明的目的在于系统地研究了哥王的抗爱滋病(AIDS)活性成分，寻找得到抗爱滋病(AIDS)有效部位，开发了哥王抗爱滋病(AIDS)新用途，提供了一种抗爱滋病新药了哥王提取物，并且提供了简单实用的工艺路线。
本发明是这样实现的：以了哥王(Wikstroemia indica)的全草、根、茎叶或者果实为原料，采用溶剂提取法、溶剂萃取法、树脂吸附法、聚酰胺吸附柱层析法、正相柱层析法、反相柱层析法等工艺中的一种或者多种工艺，并结合浓缩干燥、冷冻干燥、喷雾干燥等常用干燥方法制备成了哥王提取物。将制成的了哥王提取物作为抗爱滋病(AIDS)活性成分，使之与适宜的赋形剂相结合按照常规方法制成散剂、颗粒剂、片剂、胶囊剂、丸剂、栓剂、肠溶剂、注射剂、糖浆剂、乳剂、混悬剂、酊剂、膏剂、喷雾剂等剂型，用于治疗包括由HIV-1和HIV-2病毒以及其他病毒引起的爱滋病(AIDS)及其各种并发症。
植物原料了哥王(Wikstroemia indica)可以是全草，也可以是根、茎叶或者果实。原料可以是新鲜采集的，也可以是经过炮制的。
作为抗爱滋病(AIDS)活性成分的了哥王提取物包括其中所含的各种类型的香豆素、双香豆素、木脂素、黄酮、黄酮甙、双黄酮以及其他骨架类型的化合物。
所采用的溶剂提取法中，可选用水、甲醇、乙醇或者其他低级脂肪醇中的一种溶媒，也可和其中的任意两种或多种溶剂以任意比例所组成的混合溶媒，在室温下浸润提取或者用超声波振荡仪超声振荡提取，或者在加热状态下浸润提取或回流提取。提取次数可以是一次，也可以是多次。
所采用的溶剂萃取法中，可将经水或者低级脂肪醇中的一种溶媒或者混合溶媒提取并经所获得的提取物混悬于水中，用乙酸乙酯、正丁醇、含水乙酸乙酯或含水正丁醇中的一种或多种直接进行萃取。或者经低极性溶媒(如石油醚)脱脂后，再用乙酸乙酯、正丁醇、含水乙酸乙酯或含水正丁醇中的一种或多种进行萃取。萃取次数可以是一次，也可以是多次。
所采用的树脂吸附法中，树脂可选用D-101型吸附树脂、XAD-2型吸附树脂、CHP-20P吸附树脂以及其他类型的吸附树脂，洗脱溶媒用甲醇、乙醇、丙酮、含水甲醇、含水乙醇或者含水丙酮中的一种或多种。洗脱时可以等浓度洗脱，也可以梯度洗脱。
所采用的聚酰胺吸附柱层析法中洗脱溶媒用甲醇或含水丙酮。洗脱时可以等浓度洗脱，也可以梯度洗脱。
所采用的正相柱层析法中，可选用常压或加压硅胶柱层析，所用柱填料可选柱层析用硅胶，或者薄层层析用硅胶，洗脱剂可选用苯/丙酮、二氯甲烷/丙酮、三氯甲烷/丙酮、二氯甲烷/甲醇、三氯甲烷/甲醇、乙酸乙酯/甲醇、苯/丙酮/水、二氯甲烷/丙酮/水、三氯甲烷/丙酮/水、二氯甲烷/甲醇/水、三氯甲烷/甲醇/水或者乙酸乙酯/甲醇/水等中的一种或者多种。洗脱时可以等浓度洗脱，也可以梯度洗脱。
所采用的反相柱层析法，可选用常压或加压反相柱层析，所用柱填料可选十八烷基键合相(ODS)或八烷基键合相，洗脱剂用含水甲醇或含水乙腈。洗脱时可以等浓度洗脱，也可以梯度洗脱。
所采用的干燥方法包括浓缩干燥、冷冻干燥、喷雾干燥等常用干燥方法。
作为抗爱滋病(AIDS)活性成分，了哥王提取物的用量为成年人每日1～1000mg，优选30～800mg/天，每日服用2～3次。
口服给药可制成片剂、散剂、颗粒剂、胶囊剂等常用剂型，至少需要一种赋型剂，如淀粉、乳糖、蔗糖、甘露糖、羟甲基纤维素等，片剂还可包衣。除这些赋型剂以外，还可使用硬脂酸镁、月桂醇硫酸钠、滑石粉等作为润滑剂，糊精、结晶纤维素、聚乙烯吡咯烷酮、阿拉伯胶、玉米淀粉、明胶等作为粘合剂，马铃薯淀粉、羟甲基纤维素作为崩解剂。此外，还可制成糖浆剂、乳剂、混悬剂等。对于这些剂型，可加入矫味剂、矫臭剂或着色剂等。
外用剂型包括栓剂、软膏剂、外用散剂、喷雾剂、灌肠剂、乳剂等等。这里所使用的固体或液体添加剂是在本技术领域中经常使用的。对于软膏剂，选用由水、脂肪、脂肪油、羊毛脂、凡士林、甘油、蜂蜡、石蜡、液体石蜡、树脂、高级醇、塑料、表面活性剂组成的疏水性基质或亲水性基质(包括乳剂性基质、水溶性基质悬浊性基质)等在内的添加剂。
制成注射剂时，一般用注射用蒸馏水、生理盐水、葡萄糖水溶液、注射用植物油、丙二醇、聚乙二醇等。必要时，还可加入适宜的等张剂、助溶剂、抗氧剂、防腐剂等。
本发明的优点是：为了哥王植物提供了新用途，工艺简单实用，抗爱滋病疗效较好，并且无毒副作用。
下面结合实施例对本发明做进一步详细的描述。
实施例：
1、溶剂提取法/溶剂萃取法合用提取制备了哥王提取物
了哥王1.2kg用90％乙醇(101×3)在90℃下回流，合并提取液，浓缩得乙醇提取物。将乙醇提取物混悬于水中，用乙酸乙酯萃取，经浓缩干燥即可得到了哥王提取物，收率为6.6％。
2、了哥王提取物的体外抑制HIV-1病毒实验
了哥王提取物的体外抑制HIV-1病毒实验采用XTT法。1％的DMSO测试样品溶液与等体积的感染上HIV-1病毒的T4淋巴细胞(CEM cell line)在96孔板上混合并以每孔10倍量依次稀释，在37℃下于含有10％小牛血清(FCS)和50μg/ml gentamicin的PRMI-1640培养基中培养6天。1％的DMSO测试样品溶液与等体积的未感染HIV-1病毒的T4淋巴细胞(CEMcellline)液混合，于相同的培养条件下进行培养作为对照。经6天培养后，每孔加入XTT，通过显微镜观察生存细胞数目以及评价细胞保护活性，并由对照组计算出测试样品的IC50，EC50和TI50(IC50/EC50)。结果表明，了哥王提取物的IC50，EC50和TI50(IC50/EC50)值分别为130μg/ml，0.25μg/ml和520。
3、了哥王提取物50g与微晶纤维素45g及硬脂酸镁5g混合，混合物用单冲压片机打成Ф6mm，重量300mg的片剂。本片剂中每片含了哥王提取物150mg。结合症状。每次1～2次，每日服2～3次。
4、了哥王提取物10g与玉米淀粉40g混合，加水制成软材，过12目筛造粒，干燥，得颗粒剂。本颗粒剂中，每500mg中含了哥王提取物100mg。结合症状，每次0.5～1.0g，每日服用2～3次。
5、了哥王提取物80g与乳糖110g，硬脂酸镁10g混合，以每600mg填充胶囊。本胶囊剂中，每个胶囊含了哥王提取物150mg。结合症状，每次1～2个，每日服用2～3次。
6、了哥王提取物30g，加水300ml溶解，加橙皮甙4ml，加单糖浆至100ml得糖浆剂。本糖浆剂1ml中含了哥王提取物30mg。结合症状，每次6～10ml，每日服用2～3次。
7、了哥王提取物50g与微晶纤维素90g及硬脂酸镁10g混合，混合物用单冲压片机打成Ф6mm的片剂，并用CAP薄膜包表，制成重量300mg的肠溶制剂。本处方中每片含了哥王提取物100mg。结合症状，每次2～3片，每日服用2～3次。
8、了哥王提取物40g与乳糖100g、硬脂酸镁10g混合，以每600mg填充肠溶胶囊。本肠溶胶囊剂中，每个胶囊含了哥王提取物160mg。结合症状，每次1～2个，每日服用2～3次。
9、了哥王提取物25g以普通注射剂制造法，用加热至60℃的注射用蒸馏水1000ml溶解，用NaCl调解等张，封入安瓶。本注射剂10ml中含了哥王提取物250mg。结合症状，每次肌肉注射10ml，每日注射2～3次。
Claims (11)
1、一种抗爱滋病(AIDS)新药了哥王提取的制备方法，其特征在于：以了哥王(Wikstroemia indica)为原料，采用溶剂提取法、溶剂萃取法、树脂吸附法、聚酰胺吸附柱层析法、正相柱层析法、反相柱层析法等工艺中的一种或者多种工艺，并结合浓缩干燥、冷冻干燥、喷雾干燥等常用干燥方法制备成了哥王提取物，将制成的了哥王提取物作为抗爱滋病(AIDS)活性成分，使之与适宜的赋形剂相结合，按照常规方法制成的口服给药的内用剂型及非口服给药的注射剂和外用剂型在爱滋病(AIDS)及其各种并发症治疗中进行应用。
2、一种如权利要求1所述的抗爱滋病(AIDS)新药了哥王提取物的制备方法，其特征在于：植物原料了哥王(Wikstroemia indica)可以是全草，也可以是根、茎叶或者果实，原料可以是新鲜采集的，也可以是经过炮制的。
3、一种如权利要求1所述的抗爱滋病(AIDS)新药了哥王提取物的制备方法，其特征在于：作为抗癌活性成分的了哥王提取物包括其中所含的各种类型的香豆素、双香豆素、木脂素、黄酮、黄酮甙、双黄酮以及其他骨架类型的化合物。
4、一种如权利要求1所述的抗爱滋病(AIDS)新药了哥王提取物的制备方法，其特征在于：所采用的溶剂提取法中，可选用水、甲醇、乙醇或者其他低级脂肪醇中的一种溶媒，也可选用其中的任意两种或多种溶剂以任意比例所组成的混合溶媒，在室温下浸润提取或者用超声波振荡仪超声振荡提取，或者在加热状态下浸润提取或回流提取，提取次数可以是一次，也可以是多次。
5、一种如权利要求1所述的抗爱滋病(AIDS)新药了哥王提取物的制备方法，其特征在于：所采用的溶剂萃取法中，可将经水或者低级脂肪醇中的一种溶媒或者混合溶媒提取并经所获得的提取物混悬于水中，用乙酸乙酯、正丁醇、含水乙酸乙酯或含水正丁醇中的一种或多种直接进行萃取。或者经低极性溶媒(如石油醚)脱脂后，再用乙酸乙酯、正丁醇、含水乙酸乙酯或含水正丁醇中的一种或多种进行萃取，萃取次数可以是一次，也可以是多次。
6、一种如权利要求1所述的抗爱滋病(AIDS)新药了哥王提取物的制备方法，其特征在于：所采用的树脂吸附法中，树脂可选用D-101型吸附树脂、XAD-2型吸附树脂、CHP-20P吸附树脂以及其他类型的吸附树脂，洗脱溶媒用甲醇、乙醇、丙酮、含水甲醇、含水乙醇或者含水丙酮中的一种或多种。洗脱时可以等浓度洗脱，也可以梯度洗脱。
7、一种如权利要求1所述的抗爱滋病(AIDS)新药了哥王提取物的制备方法，其特征在于：所采用的聚酰胺吸附柱层析法中洗脱溶媒用甲醇或含水丙酮。洗脱时可以等浓度洗脱，也可以梯度洗脱。
8、一种如权利要求1所述的抗爱滋病(AIDS)新药了哥王提取物的制备方法，其特征在于：所采用的正相柱层析法中，可选用常压或加压硅胶柱层析，所用柱填料可选柱层析用硅胶，或者薄层层析用硅胶，洗脱剂可选用苯/丙酮、二氯甲烷/丙酮、三氯甲烷/丙酮、二氯甲烷/甲醇、三氯甲烷/甲醇、乙酸乙酯/甲醇、苯/丙酮/水、二氯甲烷/丙酮/水、三氯甲烷/丙酮/水、二氯甲烷/甲醇/水、三氯甲烷/甲醇/水或者乙酸乙酯/甲醇/水等中的一种或者多种。洗脱时可以等浓度洗脱，也可以梯度洗脱。
9、一种如权利要求1所述的抗爱滋病(AIDS)新药了哥王提取物的制备方法，其特征在于：所采用的反相柱层析法，可选用常压或加压反相柱层析，所用柱填料可选十八烷基键合相(ODS)或八烷基键合相，洗脱剂用含水甲醇或含水乙腈，洗脱时可以等浓度洗脱，也可以梯度洗脱。
10、一种如权利要求1所述的抗爱滋病(AIDS)新药了哥王提取物的制备方法，其特征在于：蒸馏浓缩的同时回收有机溶媒。
11、一种如权利要求1所述的抗爱滋病(AIDS)新药了哥王提取物的制备方法，其特征在于：所制成的制剂包括以下剂型：散剂、颗粒剂、片剂、胶囊剂、丸剂、栓剂、肠溶剂、注射剂、糖浆剂、乳剂、混悬剂、酊剂、膏剂、喷雾剂。
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006012779A1 (fr) * | 2004-08-06 | 2006-02-09 | Nihon University | Extraits de wikstroemia indeca, production de ceux-ci et utilisation de ceux-ci dans la production de produits pharmaceutiques anti-inflammatoires |
| CN100463906C (zh) * | 2007-03-07 | 2009-02-25 | 哈尔滨医科大学附属第二医院 | 西瑞香素的提取方法 |
| CN102000215A (zh) * | 2010-12-03 | 2011-04-06 | 沈阳药科大学 | 一种了哥王总木脂素的制备方法 |
| CN101601666B (zh) * | 2009-07-10 | 2011-05-25 | 暨南大学 | 了哥王提取物及其制备方法和用途 |
| CN109512901A (zh) * | 2018-12-31 | 2019-03-26 | 广东罗浮山国药股份有限公司 | 了哥王提取物及其在制备镇痛抗炎药物中的应用 |
| CN110538243A (zh) * | 2018-05-29 | 2019-12-06 | 复旦大学 | 瑞香科植物中活性总二萜的制备方法及其在制药中的用途 |
-
1998
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006012779A1 (fr) * | 2004-08-06 | 2006-02-09 | Nihon University | Extraits de wikstroemia indeca, production de ceux-ci et utilisation de ceux-ci dans la production de produits pharmaceutiques anti-inflammatoires |
| CN101014560B (zh) * | 2004-08-06 | 2010-04-28 | 学校法人日本大学 | 了哥王提取物、其制备方法及其在制备抗炎药物中的应用 |
| CN100463906C (zh) * | 2007-03-07 | 2009-02-25 | 哈尔滨医科大学附属第二医院 | 西瑞香素的提取方法 |
| CN101601666B (zh) * | 2009-07-10 | 2011-05-25 | 暨南大学 | 了哥王提取物及其制备方法和用途 |
| CN102000215A (zh) * | 2010-12-03 | 2011-04-06 | 沈阳药科大学 | 一种了哥王总木脂素的制备方法 |
| CN102000215B (zh) * | 2010-12-03 | 2012-08-29 | 沈阳药科大学 | 一种了哥王总木脂素的制备方法 |
| CN110538243A (zh) * | 2018-05-29 | 2019-12-06 | 复旦大学 | 瑞香科植物中活性总二萜的制备方法及其在制药中的用途 |
| CN109512901A (zh) * | 2018-12-31 | 2019-03-26 | 广东罗浮山国药股份有限公司 | 了哥王提取物及其在制备镇痛抗炎药物中的应用 |
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| CN1181832C (zh) | 2004-12-29 |
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