CN105106307A - 一种治疗前列腺癌的中药组合物及其制备方法和应用 - Google Patents
一种治疗前列腺癌的中药组合物及其制备方法和应用 Download PDFInfo
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- CN105106307A CN105106307A CN201510487031.9A CN201510487031A CN105106307A CN 105106307 A CN105106307 A CN 105106307A CN 201510487031 A CN201510487031 A CN 201510487031A CN 105106307 A CN105106307 A CN 105106307A
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Abstract
本发明涉及一种治疗前列腺癌的中药组合物及其制备方法和应用,由重量比2-3:1-2:1-2:0.5-1.5:0.5-1.5的灵芝、黄芩、冬凌草、三七和甘草为原料制成。通过混合提取或目的物提取制备。本发明简化了组合物的组方,利于质量控制、降低生产成本,同时产品疗效没有受到影响,具有良好的应用前景。
Description
技术领域
本发明属于前列腺癌治疗领域,特别涉及一种治疗前列腺癌的中药组合物及其制备方法和应用。
背景技术
前列腺癌(PCA)是男性常见的恶性肿瘤之一。在欧美国家,前列腺癌已成为男性癌症发病率第一的癌种,死亡率仅次于肺癌。近年来我国随着人口的逐渐老龄化,人们生活水平与生活质量条件的改善,前列腺癌的发病率及死亡率也呈逐年快速上升趋势,对前列腺癌的研究与药物开发已成为世界最热门的课题之一。
前列腺癌可分为性激素依赖性和非性激素依赖性两种类型。通常的用激光从外部照射、放射性物质植入或进行根治手术,复发率较高。对于性激素依赖性前列腺癌给予性激素进行治疗,大部分会转变为激素抵抗型;化疗药物的副作用大且疗效不理想。对于非性激素依赖性前列腺癌,目前尚无有效的治疗手段。当病人被诊断为癌症第三或第四期,或前列腺癌复发转移时,绝大部分患者只能等待死亡。因此,人们很需要副作用小、治疗方便的治疗方法,换言之,临床需要副作用小、疗效高、成本低的新颖药物。
CN103816258公开了一种治疗前列腺癌的中药组合物,由如下重量份数的原料制备得到:珠子参50-70份、水丁香10-20份、土鳖虫40-60份、白花蛇舌草10-20份、白侧耳15-25份、茯苓15-25份、草金杉10-20份、甘草10-20份。而事实上几种组分的作用相似,提高了生产成本。CN1478538公开了一种治疗前列腺癌的中药组合物,但是大青叶与冬凌草都有抑制肿瘤的功效,菊花与黄芩都具有清热解毒功效,类似作用有重叠,同样提高了生产成本。
发明内容
本发明所要解决的技术问题是提供一种治疗前列腺癌的中药组合物及其制备方法和应用,该中药组合物简化了组合物的组方,利于质量控制、降低生产成本,同时产品疗效没有受到影响,具有良好的应用前景。
本发明的一种治疗前列腺癌的中药组合物,由重量比2-3:1-2:1-2:0.5-1.5:0.5-1.5的灵芝、黄芩、冬凌草、三七和甘草为原料制成。
由重量比2-3:1.5-2:1.5-2:1-1.5:1-1.5的灵芝、黄芩、冬凌草、三七和甘草为原料制成。
由重量比3:2:2:1:1的灵芝、黄芩、冬凌草、三七和甘草为原料制成。
由重量比2:1.5:2:1.5:1的灵芝、黄芩、冬凌草、三七和甘草为原料制成。
本发明的一种治疗前列腺癌的中药组合物的制备方法,包括:通过混合提取或目的物提取制备。
所述混合提取方法为:
(1)准备原料:将灵芝、黄芩、冬凌草、三七和甘草以重量比为2-3:1-2:1-2:0.5-1.5:0.5-1.5的比例进行粉碎混合,将所述的中药混合物分成六等份;
(2)提取生物碱:
i)将步骤(1)得到的一份中药混合物用0.1%盐酸乙醇液渗滤或分次浸滤,得到酸性乙醇提取液;
ii)减压浓缩得到浓缩物;
iii)酸性水(pH=4-5)洗涤,过滤,得到残渣,残渣用酸性水洗涤,得到酸性水液;
iv)向步骤iii)中得到的酸性水液中加氨水沉淀,过滤得到总生物碱沉淀;
或者a)向步骤iii)中得到的酸性水液中加稀酸至pH=2,用氯仿萃取,得到氯仿层和水层;蒸发氯仿层中的氯仿,得到弱生物碱;
b)所述的水层加碱至pH=6-7,用氯仿提取,得到水层和氯仿层,蒸发氯仿层中的氯仿,得到强生物碱;
c)上述b)得到的水层用碱调节到pH10,然后用丁醇提取,蒸发丁醇层中的丁醇,得到水溶性的生物碱;
d)合并上述a)、b)和c)得到的生物碱,得到总生物碱;
(3)提取多糖:将步骤(1)得到的一份中药混合物用95-100℃的热水提取,弃去残渣,滤液放置12小时后,向上清液中加入浓度50%以上的乙醇,离心得到多糖沉淀;
(4)提取内酯:将步骤(1)得到的一份中药混合物用乙醚回流,除去色素,回收乙醚,得到总内酯;
(5)提取皂甙:将步骤(1)得到的一份中药混合物用石油醚回流,蒸发石油醚得到脱脂粗粉,用90-95%乙醇提取,减压浓缩得到浓缩液;
a)浓缩液依次用氯仿、乙醇提取,减压回收氯仿、乙醇,得到总甙粗品;
或者b)浓缩液用丁醇提取,减压回收丁醇,得到皂甙粗品;
(6)提取香豆精:将步骤(1)得到的一份中药混合物加水煎煮1-2小时,浓缩水煎液,加浓盐酸,除去杂质不溶物,放置澄清液,得到香豆精的粗结晶;
(7)提取黄酮:将步骤(1)得到的一份中药混合物加70-80%乙醇浸渍,减压回收乙醇液中的乙醇,残留物用水溶解,过滤,得到水液;用乙酸乙酯提取水液,减压浓缩乙酸乙酯液,得到总黄酮;
将步骤(2)~(7)提取得到的生物碱、多糖、内酯、皂甙、香豆精、总黄酮混合,得到中药组合物。
所述目的物提取方法为:
(1)提取黄芩甙:
i)向上述黄芩组分中加入10-15(体积)倍量水煎煮1-2小时,过滤;
ii)用酸将滤液调到pH1-2,在80-90℃下保持30-40分钟,离心沉淀;沉淀物加水搅拌均匀,加碱将pH调节到中性,再加入3-5倍(体积)量的乙醇,过滤;
iii)向滤液中加酸将pH调节到1-2,搅拌,在80-90℃下保持30-40分钟,过滤;
iv)所得的沉淀物用分别用水、50%乙醇洗涤,再用95%乙醇洗涤或重结晶,得到黄芩甙;
(2)提取三七皂甙:
i)用浓度在50%以下的甲醇提取三七根部粗粉中的可溶成分,减压浓缩甲醇提取液,向残留物中加入3-5倍(体积)量水;
ii)水溶液用乙醚提取,水层再用正丁醇萃取,减压蒸干,经硅胶柱层析,用CHCl3、MeOH和H2O以65∶35∶10洗脱得到三七皂甙;
(3)提取冬凌草甲素用乙醚提取冬凌草叶干粉,弃去残渣,回收乙醚液中的乙醚,得到绿褐色残留物;用甲醇溶解残留物,脱色得到澄明甲醇液,减压浓缩后室温放置过夜,过滤,甲醇母液蒸干,研细;用乙醚洗脱,结晶;优选地,再用中性Al2O3吸附,用乙醚洗脱,结晶;
(4)提取甘草素、异甘草素甘草用3-4倍(体积)量的90-95%乙醇提取,乙醇液经石油醚萃取,水层拌入硅胶,用MeOH和H2O以7∶3洗脱,浓缩洗脱液,得到残留物;向残留物中加水至完全溶解,向水溶液中加乙酸乙酯萃取,乙酸乙酯层用5%Na2CO3水液萃取,用稀酸将碳酸钠水液调节到pH5-6,再用乙酸乙酯萃取,干燥乙酸乙酯液,经聚酰胺柱分离,用10-90%乙醇水溶液梯度洗脱得到甘草素和异甘草素;
(5)使包含灵芝糖肽和灵芝β-D葡聚糖的灵芝多糖(有市售,上海农科所出品)与上述步骤(1)-(4)提取得到的活性成分混合得到中药组合物。
还包括步骤(6):
a)将所述步骤(1)-(5)得到的活性成分粉碎至≤200微米细粉;
b)粉碎,干燥无漏籽/海枣籽或酸石榴籽/矮石榴籽,用8倍体积量的无水乙醇提取,减压浓缩,用乙炔化钾处理,得到粉末;
c)将a)、b)所得的物质以100-200∶1的重量比混合。
还包括步骤d):将c)中得到的混合物装入胶囊。
本发明的一种治疗前列腺癌的中药组合物在制备治疗前列腺癌的药物中的应用。
本发明注重人体的整体调节,标本兼治,对激素依赖型和非依赖型前列腺癌都有一定的治疗作用,毒副作用小;联合化疗药物治疗前列腺癌可增强疗效,降低不良反应;对手术后与放、化疗的癌症患者,可明显促进机体正常功能的恢复;对术后复发者有较强的抑制癌细胞生长作用。本发明可填补市场上前列腺癌中药制剂的空白,同时填补激素非依赖性前列腺癌国产药物的空白,并可弥补全球激素非依赖型前列腺癌治疗药物的不足。
有益效果
本发明简化了组合物的组方,利于质量控制、降低生产成本,同时产品疗效没有受到影响,具有良好的应用前景。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
(1)准备原料:将灵芝、黄芩、冬凌草、三七和甘草以重量比为3千克、2千克、2千克、1千克、1千克的比例进行粉碎混合,将所述的中药混合物分成六等份;
(2)提取生物碱:
i)将步骤(1)得到的一份中药混合物用0.1%盐酸乙醇液渗滤或分次浸滤,得到酸性乙醇提取液;
ii)减压浓缩得到浓缩物;
iii)酸性水(pH=4-5)洗涤,过滤,得到残渣,残渣用酸性水洗涤,得到酸性水液;
iv)向步骤iii)中得到的酸性水液中加氨水沉淀,过滤得到总生物碱沉淀;
或者a)向步骤iii)中得到的酸性水液中加稀酸至pH=2,用氯仿萃取,得到氯仿层和水层;蒸发氯仿层中的氯仿,得到弱生物碱;
b)所述的水层加碱至pH=6-7,用氯仿提取,得到水层和氯仿层,蒸发氯仿层中的氯仿,得到强生物碱;
c)上述b)得到的水层用碱调节到pH10,然后用丁醇提取,蒸发丁醇层中的丁醇,得到水溶性的生物碱;
d)合并上述a)、b)和c)得到的生物碱,得到总生物碱;回收上述的氯仿、丁醇,供提取步骤循环使用;使所述的生物碱残渣低温干燥,结晶;
(3)提取多糖:将步骤(1)得到的一份中药混合物用95℃的热水提取上述得到的中药粗粉达2小时,弃去残渣,滤液放置12小时后,向上清液中加入浓度60%的乙醇,离心得到多糖沉淀;所述的多糖沉淀用乙醚精制;
(4)提取内酯:将步骤(1)得到的一份中药混合物用乙醚回流,除去色素,回收乙醚,得到总内酯;
(5)提取皂甙:将步骤(1)得到的一份中药混合物用石油醚回流,蒸发石油醚得到脱脂粗粉,用95%乙醇提取,减压浓缩得到浓缩液;
a)浓缩液依次用氯仿、乙醇提取,减压回收氯仿、乙醇,得到总甙粗品;
或者b)浓缩液用丁醇提取,减压回收丁醇,得到皂甙粗品;
(6)提取香豆精:将步骤(1)得到的一份中药混合物加水煎煮1小时,浓缩水煎液,加浓盐酸(30%),除去杂质不溶物,放置澄清液,得到香豆精的粗结晶;干燥后用丙酮洗涤该结晶,干燥,加水重结晶,加热,过滤,脱色,得到水溶液,冷却后得到淡黄色膏状产物的香豆精;
(7)提取黄酮:将步骤(1)得到的一份中药混合物加70%乙醇浸渍,减压回收乙醇液中的乙醇,残留物用水溶解,过滤,得到水液;用乙酸乙酯提取水液,减压浓缩乙酸乙酯液,得到总黄酮;
将步骤(2)~(7)提取得到的生物碱、多糖、内酯、皂甙、香豆精、总黄酮混合,得到中药组合物。
实施例2
1)提取黄芩甙:
i)向1.5千克黄芩中加入10倍(体积)量水煎煮1小时,过滤;
ii)用酸将滤液pH调到2,在80℃下保持30分钟,离心沉淀;沉淀物加水搅拌均匀,加碱将pH调节到中性,再加入5倍(体积)量的乙醇,过滤;
iii)向滤液中加盐酸,将pH调节到2,搅拌,在80℃下保持30分钟,过滤;
iv)所得的沉淀物分别用水、50%乙醇洗涤,再用95%乙醇洗涤或重结晶,得到黄芩甙。
2)提取三七皂甙:
i)用40%的甲醇提取1.5千克三七根部粗粉中的可溶成分,减压浓缩甲醇提取液,向残留物中加入5倍(体积)量水;
ii)水溶液用乙醚提取,水层再用正丁醇萃取,减压蒸干,经硅胶柱层析,用CHCl3-MeOH-H2O体积比65∶35∶10洗脱得到三七皂甙。
3)提取冬凌草甲素
用乙醚提取2千克冬凌草叶干粉,弃去残渣,回收乙醚液中的乙醚,得到绿褐色残留物;甲醇溶解残留物,脱色得到澄明甲醇液,减压浓缩后室温放置过夜,过滤,甲醇母液蒸干,研细;再用中性Al2O3吸附,用乙醚洗脱,结晶。
4)提取甘草素、异甘草素
1千克甘草用3倍(体积)量的95%乙醇提取,乙醇液经石油醚萃取,水层经硅胶柱洗脱,用MeOH-H2O体积比7∶3洗脱,浓缩洗脱液,得到残留物;向残留物中加水至完全溶解,向水液中加乙酸乙酯萃取,乙酸乙酯层用5%Na2CO3水液萃取,用稀盐酸将碳酸钠水液调节到pH5-6,再用乙酸乙酯萃取,干燥乙酸乙酯液,经60目聚酰胺柱分离,10-90%的乙醇水溶液梯度洗脱得到甘草素和异甘草素。
5)使包含灵芝糖肽和灵芝β-D葡聚糖的灵芝多糖(用量相当于灵芝原料量4千克,上海农科所)与上述步骤(1)-(4)提取得到的活性成分混合得到中药组合物。
将中药组合物(1)粉碎至≤200微米细粉(2);粉碎,干燥无漏籽/海枣籽(PHOENIXDACTYLIFERAL),用8倍体积量的无水乙醇提取,优选的是提取三次,合并滤液,减压浓缩,用乙炔化钾处理,得到粉末(3);将细粉(2)和粉末(3)以100-200∶1的重量比混合,然后装入胶囊,得到本发明的中药组合物的胶囊。
为表明本发明中药组合物对前列腺癌的治疗作用,现选取8位病人服用本发明中药组合物,其效果见表1:
表18位病人服用本发明中药组合物后的效果
注PSA是前列腺癌的一个重要的特异性抗原指标,PSA的变化可说明前列腺癌的变化。
从上述结果中可见,全部患有前列腺癌的病人在服用本发明中药组合物后,其PSA指标下降,即本发明的中药组合物对前列腺癌有治疗作用。全体病人的生活品质获得改善,食欲增加,精力旺盛。
在另一起临床试验中,33例性激素依赖性的前列腺癌服用本发明的中药组合物后全部有效。33例非性激素依赖性的前列腺癌服用本发明的中药组合物后有效率达72-75%。
Claims (10)
1.一种治疗前列腺癌的中药组合物,其特征在于:由重量比2-3:1-2:1-2:0.5-1.5:0.5-1.5的灵芝、黄芩、冬凌草、三七和甘草为原料制成。
2.根据权利要求1所述的一种治疗前列腺癌的中药组合物,其特征在于:由重量比2-3:1.5-2:1.5-2:1-1.5:1-1.5的灵芝、黄芩、冬凌草、三七和甘草为原料制成。
3.根据权利要求2所述的一种治疗前列腺癌的中药组合物,其特征在于:由重量比3:2:2:1:1的灵芝、黄芩、冬凌草、三七和甘草为原料制成。
4.根据权利要求2所述的一种治疗前列腺癌的中药组合物,其特征在于:由重量比2:1.5:2:1.5:1的灵芝、黄芩、冬凌草、三七和甘草为原料制成。
5.一种如权利要求1所述的治疗前列腺癌的中药组合物的制备方法,包括:通过混合提取或目的物提取制备。
6.根据权利要求5所述的一种治疗前列腺癌的中药组合物的制备方法,其特征在于:所述混合提取方法为:
(1)准备原料:将灵芝、黄芩、冬凌草、三七和甘草以重量比为2-3:1-2:1-2:0.5-1.5:0.5-1.5的比例进行粉碎混合,将所述的中药混合物分成六等份;
(2)提取生物碱:
i)将步骤(1)得到的一份中药混合物用0.1%盐酸乙醇液渗滤或分次浸滤,得到酸性乙醇提取液;
ii)减压浓缩得到浓缩物;
iii)酸性水洗涤,过滤,得到残渣,残渣用酸性水洗涤,得到酸性水液;
iv)向步骤iii)中得到的酸性水液中加氨水沉淀,过滤得到总生物碱沉淀;
或者a)向步骤iii)中得到的酸性水液中加稀酸至pH=2,用氯仿萃取,得到氯仿层和水层;蒸发氯仿层中的氯仿,得到弱生物碱;
b)所述的水层加碱至pH=6-7,用氯仿提取,得到水层和氯仿层,蒸发氯仿层中的氯仿,得到强生物碱;
c)上述b)得到的水层用碱调节到pH10,然后用丁醇提取,蒸发丁醇层中的丁醇,得到水溶性的生物碱;
d)合并上述a)、b)和c)得到的生物碱,得到总生物碱;
(3)提取多糖:将步骤(1)得到的一份中药混合物用95-100℃的热水提取,弃去残渣,滤液放置12小时后,向上清液中加入浓度50%以上的乙醇,离心得到多糖沉淀;
(4)提取内酯:将步骤(1)得到的一份中药混合物用乙醚回流,除去色素,回收乙醚,得到总内酯;
(5)提取皂甙:将步骤(1)得到的一份中药混合物用石油醚回流,蒸发石油醚得到脱脂粗粉,用90-95%乙醇提取,减压浓缩得到浓缩液;
a)浓缩液依次用氯仿、乙醇提取,减压回收氯仿、乙醇,得到总甙粗品;
或者b)浓缩液用丁醇提取,减压回收丁醇,得到皂甙粗品;
(6)提取香豆精:将步骤(1)得到的一份中药混合物加水煎煮1-2小时,浓缩水煎液,加浓盐酸,除去杂质不溶物,放置澄清液,得到香豆精的粗结晶;
(7)提取黄酮:将步骤(1)得到的一份中药混合物加70-80%乙醇浸渍,减压回收乙醇液中的乙醇,残留物用水溶解,过滤,得到水液;用乙酸乙酯提取水液,减压浓缩乙酸乙酯液,得到总黄酮;
将步骤(2)~(7)提取得到的生物碱、多糖、内酯、皂甙、香豆精、总黄酮混合,得到中药组合物。
7.根据权利要求5所述的一种治疗前列腺癌的中药组合物的制备方法,其特征在于:所述目的物提取方法为:
(1)提取黄芩甙:
i)向上述黄芩组分中加入10-15倍量水煎煮1-2小时,过滤;
ii)用酸将滤液调到pH1-2,在80-90℃下保持30-40分钟,离心沉淀;沉淀物加水搅拌均匀,加碱将pH调节到中性,再加入3-5倍量的乙醇,过滤;
iii)向滤液中加酸将pH调节到1-2,搅拌,在80-90℃下保持30-40分钟,过滤;
iv)所得的沉淀物用分别用水、50%乙醇洗涤,再用95%乙醇洗涤或重结晶,得到黄芩甙;
(2)提取三七皂甙:
i)用浓度在50%以下的甲醇提取三七根部粗粉中的可溶成分,减压浓缩甲醇提取液,向残留物中加入3-5倍量水;
ii)水溶液用乙醚提取,水层再用正丁醇萃取,减压蒸干,经硅胶柱层析,用CHCl3、MeOH和H2O以65∶35∶10洗脱得到三七皂甙;
(3)提取冬凌草甲素:
用乙醚提取冬凌草叶干粉,弃去残渣,回收乙醚液中的乙醚,得到绿褐色残留物;用甲醇溶解残留物,脱色得到澄明甲醇液,减压浓缩后室温放置过夜,过滤,甲醇母液蒸干,研细;用乙醚洗脱,结晶;
(4)提取甘草素、异甘草素:
甘草用3-4倍量的90-95%乙醇提取,乙醇液经石油醚萃取,水层拌入硅胶,用MeOH和H2O以7∶3洗脱,浓缩洗脱液,得到残留物;向残留物中加水至完全溶解,向水溶液中加乙酸乙酯萃取,乙酸乙酯层用5%Na2CO3水液萃取,用稀酸将碳酸钠水液调节到pH5-6,再用乙酸乙酯萃取,干燥乙酸乙酯液,经聚酰胺柱分离,用10-90%乙醇水溶液梯度洗脱得到甘草素和异甘草素;
(5)使包含灵芝糖肽和灵芝β-D葡聚糖的灵芝多糖与上述步骤(1)-(4)提取得到的活性成分混合得到中药组合物。
8.根据权利要求7所述的一种治疗前列腺癌的中药组合物的制备方法,其特征在于:还包括步骤(6):
a)将所述步骤(1)-(5)得到的活性成分粉碎至≤200微米细粉;
b)粉碎,干燥无漏籽/海枣籽或酸石榴籽/矮石榴籽,用8倍体积量的无水乙醇提取,减压浓缩,用乙炔化钾处理,得到粉末;
c)将a)、b)所得的物质以100-200∶1的重量比混合。
9.根据权利要求8所述的一种治疗前列腺癌的中药组合物的制备方法,其特征在于:还包括步骤d):将c)中得到的混合物装入胶囊。
10.一种如权利要求1所述的治疗前列腺癌的中药组合物在制备治疗前列腺癌的药物中的应用。
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CN108169387A (zh) * | 2016-12-07 | 2018-06-15 | 中国科学院大连化学物理研究所 | 一种中药制剂中吡咯里西啶生物碱的液/质分析样品前处理法 |
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