CN106038601B - 一种高含量、高纯度、低腥味熊胆粉的制备方法 - Google Patents
一种高含量、高纯度、低腥味熊胆粉的制备方法 Download PDFInfo
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Abstract
本发明公开了一种高含量、高纯度、低腥味熊胆粉的制备方法,具体方法是将熊胆粉、活性炭和助滤剂充分混合,然后将混合物用乙醇溶液提取至提取液中胆烷酸为阴性,收集乙醇提取液,浓缩并回收乙醇,收集浓缩液,干燥而得;本发明的方法简单,更具可操作性、可控性好,制得的熊胆粉以牛磺熊去氧胆酸计的含量最高可达45%以上,回收率近100%,以重量计算回收率可达85%以上,该方法适合于工业化大规模生产,成本低,能够用于制备特殊制剂企业所需的高品质高含量、高纯度、低腥味熊胆粉。
Description
技术领域
本发明属于制药领域,具体涉及一种高含量、高纯度、低腥味熊胆粉的制备方法。
背景技术
熊胆粉有较强的止痛镇痉作用,对革兰氏阳性菌有较强的抑制作用。适合于跌打损伤郁火实热的各种痛症、治疗小儿凉风、结膜炎、疔痔恶疮等。还可以促进糖和乳酸合成肝糖原,增强胰岛素的作用和分泌,因而具有降低血糖和尿糖的作用。
现有熊胆粉是从人工饲养的棕熊引流的胆汁,经干燥后的不规则碎片、颗粒或粉末,外观呈深棕褐色,有光泽,易吸潮结块,有粘牙感,味极腥臭,杂质多,吸收缓慢,性质不稳定易腐败,有效成分含量低。WS3-09(B-09)-96(Z)卫生部标准规定,熊胆粉中主要有效成份牛磺熊去氧胆酸不得少于23.0%。对于一些口服含片、咀嚼片企业,为了减少腥臭味、降低苦味、并降低色度以改善片剂色泽,制定了远高于卫生部标准的企业内控标准,但是高纯度的熊胆粉的代价是价格高,如符合WS3-09(B-09)-96(Z)标准的熊胆粉价格在4500元/kg左右,而熊胆粉纯化品价格则在1.2万元以上/kg。目前,市售熊胆粉牛磺熊去氧胆酸含量虽符合WS3-09(B-09)-96(Z)标准,但不能满足色泽应为黄色,腥臭味较弱即A420nm≤0.35的特殊制剂企业内控标准,从而限制了熊胆粉的应用范围。因此,亟待需要开发一种高含量、高纯度、低腥味熊胆粉的制备方法,以满足需方内控质量校准要求。
发明内容
有鉴于此,本发明的目的在于提供一种高含量、高纯度、低腥味熊胆粉的制备方法,该方法简单,可操作性好,条件可控,适合工业化生产,生产效率高,成本低。
为实现上述发明目的,本发明提供如下技术方案:
一种高含量、高纯度、低腥味熊胆粉的制备方法,包括如下步骤:将熊胆粉、活性炭和助滤剂充分混合,得混合物;然后将混合物用乙醇溶液提取至提取液中胆烷酸为阴性,收集乙醇提取液,浓缩并回收乙醇,收集浓缩液,干燥,得高含量、高纯度、低腥味熊胆粉;
所述助滤剂为水和醇不溶的硅酸盐矿物质。
本发明中,所述助滤剂优选为珍珠岩、硅藻土中的至少一种。
优选的,所述熊胆粉、活性炭和助滤剂的质量比为1:0.2~0.3:0.2~0.5。
本发明中,所述提取为超声抽滤提取或隔膜压滤提取。
其中超声抽滤提取优选为将混合物加入乙醇溶液中超声处理15~40min,然后将含有熊胆粉有效成分的提取液转移至抽滤器中进行抽滤提取,滤层用乙醇溶液清洗至清洗液中胆烷酸为阴性;更优选为,将混合物加入相当于熊胆粉重量20-28倍的乙醇溶液中,于温度为20-40℃下超声处理15~40min,然后将提取液分次转入布氏抽滤器中,以双层滤纸在压力不高于-0.08Mpa条件下抽滤,收集滤液;然后用相当于熊胆粉重量10-12倍的乙醇溶液分次清洗超声装置,将分次清洗液再用布氏抽滤器、以双层滤纸在压力不高于-0.08Mpa条件下分次抽滤,收集滤液,滤层用乙醇溶液少量多次清洗至清洗液中胆烷酸为阴性,收集滤液,合并滤液。进一步优选的,如果使用连续化生产可以最后一次滤液作为连续生产的下一批乙醇套用溶剂。
隔膜压滤提取优选为向配料搅拌罐中加入乙醇溶液,然后启动隔膜压滤,至乙醇溶液回流入配料搅拌罐时匀速投入所述混合物进行循环提取,然后启动压滤程序,接取压滤液至罐中料液泵尽;然后分次加入乙醇溶液分别进行循环提取和压滤至滤液胆烷酸检查为阴性,最后一次压滤后进行压榨,合并压滤液及压榨液;更优选为,向配料搅拌罐中加入相当于熊胆粉重量20-40倍的乙醇溶液,控制温度为20-30℃,然后启动隔膜压滤,至乙醇溶液配料搅拌罐时匀速投入所述混合物进行循环提取15-25min,然后启动压滤程序,接取压滤液至罐中料液泵尽;然后依次加入相当于熊胆粉重量8倍、6倍、6倍和4倍的乙醇溶液分别进行循环提取和压滤至滤液胆烷酸检查为阴性,最后一次压滤后启动压榨程序,在力为0.4-0.5Mpa条件下压榨至无压榨液流出,合并压滤液及压榨液;进一步优选的,如果使用多批次连续生产,可以将最后一次压滤液及压榨液(压力为0.4-0.5Mpa)作为下一批熊胆粉提取的套用溶剂。
由于熊胆粉价值极高,全国市场供需总量仅在数百千克左右,故宜选最小型的630型设备,如本发明中隔膜压滤采用小型隔膜压滤机1-5组滤板,采用透气量6~36L/m2·s的聚丙烯滤套的隔膜板压滤机隔膜压滤;其板组总数在5组内已充足,实际生产过程中可根据产能需要将滤板调整至1-5组进行生产。
更优选的,所述乙醇溶液为体积分数为93%以上的乙醇溶液,更优选为使用体积分数为95%的乙醇溶液。此步骤中如果乙醇浓度过低水溶性成分引入量多,不利于精制,无水乙醇成本较高一般不采用。
本发明中,浓缩优选采用负压浓缩,如用带冷井的旋转蒸发器浓缩或用真空浓缩器浓缩;干燥负压干燥,如在80℃,-0.08Mpa条件下真空干燥或采用微波真空干燥。
本发明中,胆烷酸可以采用现有的胆烷酸检测方法检测,为了能够快速检测,本发明建 立如下检测方法:
(1)炽灼法
胆烷酸快速检验法的依据:熊胆汁中的次级胆酸包括胆酸及熊去氧胆酸等7个化合物,统称胆烷酸,它们是具有化学结构相似的同分异构体,其结构如下。
当以质量分数为95%的乙醇溶液超声处理含粗品熊胆粉和助滤剂(珍珠岩或硅藻土),其中珍珠岩和硅藻土为水、醇均不溶解的天然硅酸盐矿物质,活性炭为水、醇中不溶的经脱氧炭化的单体碳。在抽滤(或隔膜压滤)洗涤过程中,溶于乙醇中的胆烷酸类醇溶性物质进入滤液中,如果滤液中不再含醇溶性有机物(包括胆烷酸类,即只有溶剂乙醇和少量水分)则滤液挥干后并炽灼至未完全炭化(400~500℃)前,不会出现灰黑色残迹。这一原理是滤洗液炽灼残渣痕量有机物残留快检法的理论基础,检测方法为:取滤液约1ml,于50ml磁蒸发皿中,置电热板或砂浴盘上挥尽乙醇,再加热约1min,观察开始炭化至完全炭化阶段有无黄色→棕色→黑色→无色残渣现象出现,即一直无有色残渣现象,表示有机物已洗净。
(2)硫酸糠醛法
根据文献(李继珩等中国药科大学学报,1992;23(5);310-312),熊胆粉中的牛磺熊去氧胆酸(Taurousodeoxycholic acid简称TUDCA)为天然结合胆汁酸,在酸性条件下,TUDCA与糠醛反应形成紫色物质,称为Gregory-Pascoe反应(TH.J Bord chem1929.83.35),可能是糠醛之羧基与TUDCA分子中羟基缩合成共价化合物之结果(洪盈主编,有机化学,北京:人民卫生出版社,1986,599)。利用此原理,研究试验了本发明的另一种更精准的滤洗液快检方法及最低检出限:接取滤液约1ml,于10ml试管中,加入质量分数为10%的浓硫酸4mL,滴加质量分数为1%的糠醛试液0.5ml,置60~80℃水浴中,与空白管对照如不显紫色,表示滤液中不含胆烷酸而判定已滤洗至净。按照此方法检测牛磺熊去氧胆酸检出限结果如表2所示。
表2、硫酸糠醛法检测牛磺熊去氧胆酸检出限
(3)目视比色法
具体方法如下:取终洗液数毫升于10ml纳氏比色管中,另一支纳氏比色管中盛同体积的洗涤用乙醇,置白色背景下观察洗液的色泽,如供试液管色泽与对照管一致,表示滤饼中的有机物已洗净。
A420nm值检测法
具体方法如下:取终洗液适量,以乙醇为空白,按紫外分光光度法检测420nm波长处的吸收值,不得过0.03Abs。
本发明的有益效果在于:本发明提供了一种高含量、高纯度、低腥味熊胆粉的制备方法,通过采用活性炭和助滤剂在进行超声辅助提取或隔膜压滤提取,然后干燥制得熊胆粉精品,制得的熊胆粉精品以牛磺熊去氧胆酸计的含量最高可达45%以上,以熊去氧胆酸计的回收率近100%,以重量计算回收率可达85%以上,并且该方法操作简单,可操作性好,条件可控,适合工业化生产,生产效率高,成本低。此外,本发明还提供一种生产线抽滤洗涤至净的快速检测方法及其检测限的精密度,使生产控制有章可循,准确可靠,对工业化生产具有重要意义。
具体实施方式
下面将对本发明的优选实施例进行详细的描述。实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。
实施例1
一种高含量、高纯度、低腥味熊胆粉的制备方法,包括如下步骤:
(1)称取符合WS3-09(B-09)-96(Z)标准的熊胆粉500g,粉碎,然后与150g活性炭和220g硅藻土(粗土)于方盘中用不锈钢铲充分混匀,得混合物,备用;
(2)将步骤(1)所得混合物置于盛有温度为30℃、14L体积分数为95%的乙醇溶液的超声清洗器的清洗槽中,然后超声提取30min;
(3)将经过步骤(2)的超声提取液分次转入布氏抽滤器中,以双层滤纸在压力不高于-0.08Mpa条件下抽滤,收集滤液,记为滤液A;为了避免熊胆粉有效成分的损失,将清洗槽用3L体积分数为95%的乙醇溶液分次清洗,然后再分次用布氏抽滤器、以双层滤纸在压力不高于-0.08Mpa条件下抽滤,收集滤液,记为滤液B;再将滤层以5-6L体积分数为95%的乙醇溶液每次以20-30ml淋洗滤层至终滤液1ml用硫酸糠醛法或炽灼法或A420nm检测法检测胆烷酸为阴性,收集滤液,记为滤液C;
(4)将步骤(3)中的滤液A、滤液B和滤液C合并,然后用旋转蒸发器浓缩并回收乙醇,浓缩液转入盘中,水浴蒸干,再置80℃,-0.08Mpa真空干燥箱中烘干;为了能够将蒸馏瓶中熊胆粉有效成分完全转移,用乙醇分次洗涤蒸馏甁,并与浓缩液合并后水浴蒸干、真空干燥,得高含量、高纯度、低腥味熊胆粉。
经本实施例纯化后得到熊胆粉精品452g,牛磺熊去氧胆酸含量为42.13%,A420nm值为0.2481。以牛磺熊去氧胆酸含量计算的回收率为98.17%,以重量计算的回收率达90.4%。
上述实施例中,如果使用连续化生产可以将步骤(3)中的滤液C作为连续生产的下一批乙醇套用溶剂。
实施例2
一种高含量、高纯度、低腥味熊胆粉的制备方法,包括如下步骤:
(1)称取符合WS3-09(B-09)-96(Z)标准的熊胆粉5kg,粉碎,与1.5kg活性炭,1kg过60目的珍珠岩粉混合均匀,得混合物,备用;
(2)向200升K形配料搅拌罐中加入140L体积分数为93%的乙醇溶液,控制温度为30℃,然后使用630型隔膜压滤机两组滤板,采用透气量36L/m2·s聚丙烯滤套的隔膜板压滤机隔膜压滤,隔膜压滤时当体积分数为93%的乙醇回流入已开启搅拌的K形罐中时匀速投入步骤(1)所得混合物循环提取20min,然后启动压滤程序,接取压滤液至罐中料液泵尽,收集压滤液,记为压滤液A;
(3)在搅拌下分次加入体积分数为95%乙醇40L,30L,30L,20L按上述程序分次循环提取和压滤(压力0.2Mpa以下)至终滤液胆烷酸检查为阴性,收集压滤液,记为压滤液B;
(4)将步骤(2)所得压滤液A与步骤(3)所得压滤液B合并,然后于250L真空浓缩器中浓缩并回收乙醇,浓缩至相对密度1.25-1.35/40-50℃的稠膏,然后将稠膏转入20L微波真空干燥机的两只10L聚丙烯干燥盒中,启动B或C运行程序干燥,收集干燥物料,得高含量、高纯度、低腥味熊胆粉。
本实施例中,得到熊胆粉精品4.53kg,牛磺熊去氧胆酸含量38.5%,A420nm值为0.2416,以牛磺熊去氧胆酸含量计算的回收率100.7%(>100%为试验误差),以重量计算的回收率为90.6%。
本实施例中,如果使用多批次连续生产,可以将最后一次压滤液及压榨液(压力为0.5-0.6Mpa)作为下一批熊胆粉提取的套用溶剂。
实施例3
为了研究活性炭用量对熊胆粉精品A420nm值及收率的影响,按表3中熊胆粉与活性炭用量,按实施例1的方法制备高含量、高纯度、低腥味熊胆粉,然后检测熊胆粉精品重量,提取液A420nm值及收率,结果如表3所示。
表3、活性炭用量对熊胆粉品质影响
结果显示,活性炭用量与A420nm值(即色泽深浅)、精品干重(收率)呈负相关,与精品纯度呈正相关。结果表明,1g粗品熊胆粉活性炭用量在0.2~0.3g范围内效果更佳。
实施例4
将本发明制备高含量、高纯度、低腥味熊胆粉的方法与公开号为CN1311002A的中国专利公开的乙醇搅拌提取法(专利法一)、乙醇搅拌活性炭脱色法(专利法二)和醋酸乙酯分离法(专利法三)及活性炭乙醇回流法、活性炭乙醇索氏提取法、活性炭乙醇柱层析法进行比较,其中活性炭乙醇回流法、活性炭乙醇索氏提取法和活性炭乙醇柱层析法分别是将熊胆粉与活性炭按实施例1的方法超声提取后分别进行回流法、索氏法和柱层析法提取,结果如表1所示。
表1、不同方法制备熊胆粉的区别
上述结果可以看出,使用本发明的方法能够避免操作过程中结块难溶出的问题,即完全消除了“口香糖”状胶状物中包裹的目标物质难于溶出的弊病,故转移率高,脱色效果显著。远优于现有已公开的方法及未使用助滤剂的方法,并且适用于工业化大生产。
最后说明的是,以上优选实施例仅用以说明本发明的技术方案而非限制,尽管通过上述优选实施例已经对本发明进行了详细的描述,但本领域技术人员应当理解,可以在形式上和细节上对其作出各种各样的改变,而不偏离本发明权利要求书所限定的范围。
Claims (4)
1.一种高含量、高纯度、低腥味熊胆粉的制备方法,其特征在于,包括如下步骤:将熊胆粉、活性炭和助滤剂充分混合,得混合物;然后将混合物用乙醇溶液提取至提取液中胆烷酸为阴性,收集乙醇提取液,浓缩并回收乙醇,收集浓缩液,干燥,得高含量、高纯度、低腥味熊胆粉;所述助滤剂为水和醇不溶的硅酸盐矿物质;所述熊胆粉、活性炭和助滤剂的质量比为1:0.2~0.3:0.2~0.5;所述提取为超声抽滤提取或隔膜压滤提取;
所述超声抽滤提取为将混合物加入相当于熊胆粉重量20-28倍的乙醇溶液中,于温度为20-35℃下超声处理15~40min,然后将提取液分次转入布氏抽滤器中,以双层滤纸在压力不高于-0.08Mpa条件下抽滤,收集滤液;然后用相当于熊胆粉重量10-12倍的乙醇溶液分次清洗超声装置,将分次清洗液再用布氏抽滤器、以双层滤纸在压力不高于-0.08Mpa条件下分次抽滤,收集滤液,滤层用乙醇溶液分次清洗至清洗液中胆烷酸为阴性,收集滤液,合并滤液;
所述隔膜压滤提取为向配料搅拌罐中加入相当于熊胆粉重量20-40倍的乙醇溶液,控制温度为20-30℃,然后启动隔膜压滤,至乙醇溶液配料搅拌罐时匀速投入所述混合物进行循环提取15-25min,然后启动压滤程序,接取压滤液至罐中料液泵尽;然后依次加入相当于熊胆粉重量8倍、6倍、6倍、4倍的乙醇溶液分别进行循环提取和压滤至滤液胆烷酸检查为阴性,最后一次压滤后启动压榨程序,在力为0.4-0.5Mpa条件下压榨至无压榨液流出,合并压滤液及压榨液。
2.根据权利要求1所述一种高含量、高纯度、低腥味熊胆粉的制备方法,其特征在于:所述助滤剂为珍珠岩、硅藻土中的至少一种。
3.根据权利要求1所述一种高含量、高纯度、低腥味熊胆粉的制备方法,其特征在于:所述隔膜压滤采用透气量6~36L/m2·s 的聚丙烯滤套的隔膜板压滤机隔膜压滤。
4.根据权利要求1~3任一项所述一种高含量、高纯度、低腥味熊胆粉的制备方法,其特征在于:所述乙醇溶液为体积分数为93%以上的乙醇溶液。
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CN102526107B (zh) * | 2010-12-27 | 2013-11-27 | 福建归真堂药业股份有限公司 | 一种熊胆提取物、制备方法及其在制备治疗烫伤药物中的应用 |
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