CN1198097A - 贯叶连翘的稳定提取物、其制备方法和药物组合物 - Google Patents
贯叶连翘的稳定提取物、其制备方法和药物组合物 Download PDFInfo
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- CN1198097A CN1198097A CN96197288A CN96197288A CN1198097A CN 1198097 A CN1198097 A CN 1198097A CN 96197288 A CN96197288 A CN 96197288A CN 96197288 A CN96197288 A CN 96197288A CN 1198097 A CN1198097 A CN 1198097A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 15
- 235000017309 Hypericum perforatum Nutrition 0.000 title abstract description 10
- 244000141009 Hypericum perforatum Species 0.000 title abstract description 3
- 238000004519 manufacturing process Methods 0.000 title 1
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 28
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- SSKVDVBQSWQEGJ-UHFFFAOYSA-N pseudohypericin Natural products C12=C(O)C=C(O)C(C(C=3C(O)=CC(O)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 SSKVDVBQSWQEGJ-UHFFFAOYSA-N 0.000 description 12
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明描述了一种至少在12个月期间内稳定的含至少2%贯叶金丝桃素的贯叶连翘的提取物。
Description
药理和临床试验证实贯叶连翘的提取物能够成功地用于普通的严重抑郁症。但不能确切地指明这种温和的抗抑郁总功效是一种或多种组分产生的；参见J.Holzl，S.Sattler和H.Schutt，Johanniskraut：Eine Alternativezu synthetischen Antidepressiva(St.Johns wort：an alternative to syntheticantidepressants)，Pharmazeutische Zeitung，No.46，139.Jahrgang，1994年11月17日，第3959-3977页。然而，近来强烈的暗示贯叶金丝桃素对达到功效起显著的作用(EP-A-0 599 307)。
粗草药是由贯叶连翘的地上部分组成的。贯叶连翘的组分是另外的金丝桃素和贯叶金丝桃素；参见J.Holzl等，见上。
在DE-PS-1 569 849以及S.Niesel和H.Schilcher在Arch.Pharm.，第323卷1990年第755页描述了富含金丝桃素的金丝桃提取物的制备。
从R.Berghofer和J.Holzl，Deutsche Apothekerzeitung，第126卷第47期(1986)第2569-2573页中我们知道一周后从储存的粗草药提取的贯叶金丝桃素已经完全降解而从新鲜植物中提取的提取物更稳定。这些作者推测该新鲜植物包括一种贯叶金丝桃素的稳定剂。
J.Holzl等在Planta Med.，第55卷(1989)第601-602页中报道金丝桃油并推测在金丝桃素的浓度和过氧化值之间有关系。暴露在阳光中的金丝桃油显示出不同的过氧化值。但是按照J.Holzl等，在过氧化值和金丝桃素的浓度之间没有关系。
P.Maisenbacher和K.-A.Kovar在Planta Med.第58卷(1992)第351到354页中报道了金丝桃油的稳定性。该油中也包括了几周内降解的金丝桃素。
从EP-A-0 599 307(对应于DE-OS 4 239 959)已知金丝桃的提取物和它的制备方法，其中的提取物尽可能少地含有金丝桃素和类似的光敏化合物但是经管如此却显示出被正式认为来自金丝桃素的效果。用贯叶金丝桃素的存在可以解释这种效果。
而且，已知通过用一种脂肪油如橄榄油、大豆油、麦芽油或葵花籽油提取捣碎(捣烂的)贯叶连翘的新鲜花来制备金丝桃油(金丝桃油；Oleumhyperici)。金丝桃油包括不同量的贯叶金丝桃素并可用于局部治疗伤口特别是烧伤和擦破；参见P.Maisenbacher和K.-A.Kovar，Planta Med.，Vol158(1992)，第351-354页和J.Holzl，L.Demish和S.Stock，PlantaMed.，第55卷(1989)第601-602页。
在药物中的常规金丝桃提取物中的贯叶金丝桃素含量，在常规存储几个月内会剧烈地降低直到该物质消失；参见Ph.D.thesis of P.Maisenbacher，Tubingen 1991和the Ph.D.thesis of R.Berghofer，Marburg/L.1987。在早期金丝桃的油性提取物试验中，含有贯叶金丝桃素的组合物的稳定性只有在氩气中存储才能改善的好一点；参见Ph.D.thesisof P.Maisenbacher，见上。在这些提取物中用抗氧化剂如丁基羟基甲苯(BHT)和丁基羟基甲氧基苯(BHA)不能实现稳定。而且，常规的抗氧化剂如Oxynex LM和Oxynex 2004也不能改善稳定性。在金丝桃油时，使用辛基十二烷醇(Eutanol G)作提取剂达到了最好的稳定性(按照P.Maisenbacher的Ph.D.理论)；见P.Maisenbacher’s Ph.D.thesis，第151-154页。
用常规的药用无机或有机溶剂或其混合物能够制备含有贯叶金丝桃素的金丝桃提取物(P.List和P.C.Schmidt，Technologie pflanzlicherArzneizubereitungen，Wissensch.Verlagsgesellschaft mbH，Stuttgart，1984)。
通常金丝桃的含水乙醇提取物和其制备成的药物组合物一般包括少于大约1％的贯叶金丝桃素(以提取物为准)。存储后该值明显下降并根据不同的存储条件趋向于零。人们推测氧化过程对原药材和提取物中的贯叶金丝桃素的降解起作用。
本发明的技术问题是提供含有贯叶金丝桃素的贯叶连翘的稳定提取物，其中贯叶金丝桃素长期保持稳定。本发明的另一个技术问题是提供了一种制备这些稳定提取物的方法以及提供了含有稳定提取物的药物组合物，其中该组合物中的贯叶金丝桃素的量也保持稳定。
按照本发明，这些技术问题用权利要求1到14的提取物、用权利要求15的药物组合物、用权利要求16-26的方法以及权利要求27的该提取物和/或药物组合物的用途已经解决。
本发明首先是以这样一种出人意料的结果为基础的，即含有某些抗氧化剂和/或结合氧的稳定剂或还原剂的贯叶金丝桃素的提取物，这些试剂能够降解氧化剂类如游离基、过氧化物、大气中氧等和/或抑制贯叶金丝桃素的降解，以及任选在惰性气体中如氮气和/或避光和/或用一种高还原氧含量的溶剂进行的提取比未处理的金丝桃提取物稳定很多。这种提取物是与R.Berghofer和J.Holzl从干燥和存储的粗草药得到的观察相反的角度得到的。
通过物理处理如用惰性气体向氮气清洗能够制得高还原氧含量的溶剂。如按照本发明特别是通过加入一种抗氧化剂并优选避光和大气中氧来保护或稳定金丝桃的提取物时，则该提取物中的贯叶金丝桃素长期基本保持稳定。通过相应的药物制剂业能够实现避光和大气中氧的保护。
在本发明制备稳定提取物方法的优选实施方案中，用含水乙醇或甲醇提取新鲜或最好是干燥的贯叶连翘药材，通过物理处理大大降低了试剂的氧含量。由于可能存在氧化剂，将作为稳定剂的抗氧化剂加到提取溶液并使其溶解。提取贯叶连翘优选溶剂的例子还包括低熔点含大约5到8个碳原子的烷烃如戊烷、己烷和庚烷，特别是正庚烷，以及液态和超临界的二氧化碳。术语“含水乙醇或甲醇”是指水含量最好高达大约体积40％体积的甲醇或乙醇。
优选抗氧化稳定剂或抗氧化剂的特殊例子是药学上可接受的物质，其能够抑制贯叶金丝桃素的降解和/或还原提取物或药物组合物中的氧化剂。特殊的例子是有机硫醇化合物，如半胱氨酸和谷胱甘肽，以及抗坏血酸及其衍生物如抗坏血酸的脂肪酸酯，如肉豆蔻酸酯、棕榈酸酯和硬脂酸酯。
向金丝桃提取溶液中加入足以稳定贯叶金丝桃素的量的抗氧化稳定剂。对一般金丝桃提取物讲0.01％到5％浓度的抗氧化稳定剂是足够的。
在另一个实施方案中，如上所述进行，但稳定剂是在干燥提取溶液后即除去溶剂后加入的。
在本发明的另一个优选的实施方案中，在与其它药物添加剂一起制备药物产品阶段加入抗氧化稳定剂。
所有的实施方案最好在避开光和无氧下进行。
所得到的提取物能够与常规药物添加剂一起制备，任选择性地在之后把稳定剂再加入到药物组合物如胶囊、片剂和包衣片中。
药物添加剂是填充剂、粘合剂、崩解剂、润滑剂和用于膜片和包衣片的包衣剂以及用于软胶囊的油类和脂肪类填充剂。
本发明通过下列实施例加以解释，但不限定本发明的范围。如果不另作说明，百分比按重量计。用氮气作惰性气体(保护性气体)。应当清楚其它惰性气体如氩或氪也能使用。实施例1a)和1b)(对照实施例)a)
在碾机中把1kg贯叶连翘的粗草药碾细并加入7kg70(v/v)％的乙醇。在55℃惰性气体下把1kg粗草药的悬浮液和7kg溶剂剧烈搅拌1小时。然后从粗草药中离心分离所得到的提取物。用7kg的溶剂再把药渣提取两次。合并两次提取液测定提取物等分部分的干燥残余物。缓缓地减压浓缩提取物到含大约70％干燥剩余物，再在40℃减压干燥。得到0.42kg干燥提取物。贯叶金丝桃素的含量是2.26％，金丝桃素的中含量是0.27％。b)
按照EP-A-0 599 307所教导的，用聚乙烯吡咯烷酮(PVP)处理进一步加工实施例1a)的干燥提取物来选择性除去金丝桃素。贯叶金丝桃素的含量是2.96％。实施例2
在碾机中把24kg贯叶连翘的粗草药碾细并在用氮气冲洗之前加入156kg80(v/v)％的甲醇。然后在55℃把混合物搅拌1小时。从药物剩余物中离心分离所得到的提取溶液。接着把剩余物提取两次。合并两次提取溶液并加入重量百分比1.0％的抗坏血酸。把该溶液搅拌15分钟。然后缓缓把提取溶液浓缩到干燥残余物含量为70％并在40℃减压干燥。得到贯叶金丝桃素含量3.2％的5.39kg稳定的干燥提取物。提取物中金丝桃素的总含量为0.48％。实施例3
在碾机中把8kg贯叶连翘的粗草药碾细并加入56kg70(v/v)％的乙醇。在用惰性气体冲洗前还原所用溶剂的氧含量。然后在惰性气体55℃下把8kg粗草药的悬浮液和56kg溶剂剧烈搅拌1小时。从药物剩余物中离心分离所得到的提取物同时用氮气作惰性气体冲洗。把药渣用相同方式提取两次。合并两次提取溶液并加入0.05％的L-半胱氨酸。在氮气作惰性气体下把该溶液剧烈搅拌10分钟。然后缓缓减压浓缩到干燥残余物含量为70％并在40℃减压干燥。得到贯叶金丝桃素含量3.9％的2.524kg稳定的干燥提取物。提取物中金丝桃素的总含量为0.28％。实施例4
在压榨机中压榨454g切细的新鲜贯叶连翘。向压榨液(160ml)中加入1.5g抗坏血酸并溶解。然后再把压榨液加入到压榨过的药材中。向湿润的药材中加入1kg正庚烷。在50℃避光一直搅拌下靶混合物提取1小时。用Seitz Supra 1500滤头把混合物吸出并把药渣用相同方式提取两次。在35℃避光下旋转蒸发浓缩合并的提取溶液得到大约70％含量的干燥残余物并冷冻干燥。得到贯叶金丝桃素含量为37.2％的9.11g干燥提取物。实施例5
在压榨机中压榨515g切细的新鲜贯叶连翘。向压榨液(180ml)中加入1.7g抗坏血酸并溶解。然后再把压榨液加入到压榨过的药材中。然后把湿润的药材转到高压提取机上并在350巴40℃用二氧化碳提取。每kg药材用20kg二氧化碳。提取后，减压到60巴来分离提取物。将提取物从提取机中取出并加热到大约60℃，从共同提取的水中分离出来。得到贯叶金丝桃素含量为43.1％的12.3g干燥提取物。实施例6检测贯叶金丝桃素的稳定性
在该实施例中，把按照实施例1制备中没有特别预防方法和加入法得到的提取物的贯叶金丝桃素含量(用HPLC测得)与本发明实施例2到5制得的提取物比较。在室温避光下把本发明制得的提取物储存在氮气中。结果总结在表1中。该结果显示12月后按照本发明制得的提取物的贯叶金丝桃素的含量几乎没有变化。在这期间实施例1到3制得的提取物的金丝桃素总量也没有变化。
表1
实施例7含有贯叶金丝桃素的软明胶胶囊-组合物：
| 干燥提取物 | 贯叶金丝桃素 | 贯叶金丝桃素含量％ | ||
| 实施例 | 最初含量％ | 13周后 | 6月后 | 12月后 |
| 实施例1a) | 2.26 | 0.0 | 0.0 | 0.0 |
| 实施例1b) | 2.96 | 0.0 | 0.0 | 0.0 |
| 实施例2 | 3.2 | 3.2 | 3.17 | 3.15 |
| 实施例3 | 3.90 | 3.90 | 3.88 | 3.85 |
| 实施例4 | 37.2 | 37.2 | 36.5 | 36.1 |
| 实施例5 | 43.1 | 43.1 | 43.0 | 42.4 |
贯叶金丝桃素的干燥提取物 300mg
抗坏血酸 0.25mg
辛基十二烷醇 200mg制备：
分别把实施例3和4的提取物用作干燥提取物。
把干燥提取物和抗坏血酸一起分散到辛基十二烷醇中并在避开大气氧下加工成软明胶胶囊。实施例8含有贯叶金丝桃素提取物的包膜片-组合物：
贯叶金丝桃素的干燥提取物 300mg
纤维素 100mg
改良淀粉 90mg
羧甲基纤维素钠 30mg
高度分散的二氧化硅 5.0mg
抗坏血酸 5.0mg
硬脂酸镁 5.0mg
羟丙基甲基纤维素-包衣 20.0mg制备：
用实施例3的提取物作干燥提取物。
在干燥条件下用混合机把组分混合并直接压成片。把所得到的片用羟丙基甲基纤维素包衣包裹。实施例9商业上可得到的(德国市场，1995年9月)的金丝桃的药物组合物和本发明制成的药物组合物之间的比较
在该实施例中，就制剂中所含提取物为准验次贯叶金丝桃素含量，测定五种制成的金丝桃的药物组合物，它们是1995年9月从德国市场上得到的，并与本发明制得的药物组合物比较。结果显示在表II中。很明显本发明制得的药物组合物具有几乎较高的贯叶金丝桃素的含量，这种含量甚至在12月后几乎保持稳定。
表II
| 组合物 | 金丝桃提取物部分[mg] | 贯叶金丝桃素含量[％] |
| A | 200 | 0.58 |
| B | 250 | 0.20 |
| C | 40 | 0.07 |
| D | 110 | 0.56 |
| E | 250 | 0.71 |
| 按照本发明实施例3制得的组合物 | 300 | 3.9 |
Claims (27)
1.一种基于干燥提取物含有至少2％的贯叶金丝桃素的贯叶连翘的稳定提取物，其特征在于贯叶金丝桃素相对于分解或降解是稳定的或是用一种稳定剂稳定的。
2.一种干燥提取物含有至少2％的贯叶金丝桃素的贯叶连翘的稳定提取物，它是通过加入一种选自于有机硫醇化合物、抗坏血酸或其衍生物和通过用常规药物无机或有机溶剂或其混合物提取新鲜或干燥的贯叶连翘药物，条件是该溶剂是非油性提取溶剂。
3.根据权利要求1或2的贯叶连翘的稳定提取物，其特征在于贯叶金丝桃素的含量至少是3％。
4.根据权利要求1或2的贯叶连翘的稳定提取物，其特征在于贯叶金丝桃素的含量至少是5％。
5.根据权利要求1或2的贯叶连翘的稳定提取物，其特征在于贯叶金丝桃素的含量至少是20％。
6.根据权利要求1到5的任何稳定的提取物，其特征在于该稳定剂是基于提取物的0.01％到5％，优选0.2％到1％存在的。
7.根据权利要求1到6的任何稳定的提取物，其特征在于该稳定剂是半胱氨酸。
8.根据权利要求1到6的任何稳定的提取物，其特征在于该稳定剂是谷胱甘肽。
9.根据权利要求1到6的任何稳定的提取物，其特征在于该稳定剂是抗坏血酸。
10.根据权利要求1到6的任何稳定的提取物，其特征在于该稳定剂是抗坏血酸的脂肪酸酯。
11.根据权利要求1到10的任何稳定的提取物，其特征在于该溶剂是含水乙醇。
12.根据权利要求1到10的任何稳定的提取物，其特征在于该溶剂是含水甲醇。
13.根据权利要求1到10的任何稳定的提取物，其特征在于该溶剂是正庚烷。
14.根据权利要求1到10的任何稳定的提取物，其特征在于该溶剂是液态或超临界二氧化碳。
15.一种药物组合物，它含有权利要求1到14中任何一种提取物和常规的药物添加剂。
16.一种制备稳定提取物的方法，其中用常规的药物无机或有机溶剂或其混合物提取筛选过的新鲜或干燥贯叶连翘药材，条件是该溶剂是非油性提取溶剂，和在制备期间或制备后加入选自于有机硫醇化合物类、抗坏血酸及其衍生物中的稳定剂，以及其中从这样获得的液态提取物中得到干燥提取物。
17.根据权利要求16的方法，其特征在于把半胱氨酸用作稳定剂。
18.根据权利要求16的方法，其特征在于把谷胱甘肽用作稳定剂。
19.根据权利要求16的方法，其特征在于把抗坏血酸用作稳定剂。
20.根据权利要求16的方法，其特征在于把抗坏血酸的脂肪酸酯用作稳定剂。
21.根据权利要求16到20中任何一种方法，其特征在于以基于提取物的0.01％到5％，优选0.2％到1％的浓度加入稳定剂。
22.根据权利要求16到21中任何一种方法，其特征在于提取溶剂的氧含量较低或显著还原。
23.根据权利要求16到22中任何一种方法，其特征在于用含水乙醇或含水甲醇或大约5到8个碳原子的烷烃或液态或超临界二氧化碳作溶剂。
24.根据权利要求16到23中任何一种方法，其特征在于干燥提取溶液后加入稳定剂。
25.根据权利要求16到23中任何一种方法，其特征在于在与常规药物添加剂一起制备药物组合物的阶段加入稳定剂。
26.根据权利要求16到25中任何一种方法，其特征在于避开光和/或氧。
27.权利要求15的药物组合物治疗抑郁和植物性神经疾病的用途。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1304019C (zh) * | 2003-05-29 | 2007-03-14 | 斯拉甫·艾白 | 复方一枝蒿胶囊 |
| CN1315480C (zh) * | 2003-05-17 | 2007-05-16 | 广西化工生物技术研究所 | 治疗疱疹病毒的药物组合物及其生产方法 |
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| CN106668088A (zh) * | 2017-02-08 | 2017-05-17 | 内蒙古昶辉生物科技股份有限公司 | 一种贯叶连翘提取物的制备方法 |
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Families Citing this family (40)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19714450A1 (de) * | 1997-04-08 | 1998-10-15 | Schwabe Willmar Gmbh & Co | Stabiler Extrakt aus Hypericum perforatum L., Verfahren zu seiner Herstellung und pharmazeutische Zubereitung |
| US6113907A (en) * | 1997-04-15 | 2000-09-05 | University Of Southern California | Pharmaceutical grade St. John's Wort |
| US6607754B1 (en) * | 1997-07-11 | 2003-08-19 | Upsher-Smith Laboratories, Inc. | Delivery of Hypericum perforatum (St. John's Wort) in tablet form |
| WO1999027919A2 (en) * | 1997-07-17 | 1999-06-10 | Nicogen Inc. | Cyp2a enzymes and their use in therapeutic and diagnostic methods |
| ATE204759T1 (de) | 1998-02-13 | 2001-09-15 | Schwabe Willmar Gmbh & Co | Verwendung von hyperforin und hyperforinhaltigen extrakten zur behandlung und prophylaxe von demenzerkrankungen |
| CA2320091A1 (en) * | 1998-02-13 | 1999-08-19 | Dr. Willmar Schwabe Gmbh & Co. | Stable hyperforin salts, methods of manufacturing them, and their use for the treatment of alzheimer's disease |
| US6238671B1 (en) | 1998-04-22 | 2001-05-29 | Bionorica Arzneimittel Gmbh | Process for the gentle recovery of extract fractions from hypericum, pharmaceutical preparations containing the same and their use |
| EP0965348B1 (de) * | 1998-04-22 | 2000-07-19 | Bionorica Arzneimittel GmbH | Verfahren zur schonenden Gewinnung von Extraktfraktionen aus Hypericum perforatum L., diese enthaltende pharmazeutische Zubereitungen und Verwendung derselben |
| US6063401A (en) * | 1998-05-06 | 2000-05-16 | M.E. Cody Products, Inc. | Plantago major and hypericum perforatum compound for use in treating a tobacco or nicotine habit |
| IT1301679B1 (it) * | 1998-06-10 | 2000-07-07 | Indena Spa | Derivati dell'iperforina, loro uso e formulazioni che licontengono. |
| IT1301678B1 (it) * | 1998-06-10 | 2000-07-07 | Indena Spa | Estratti di hypericum perforatum e formulazioni che li contengono. |
| US6045825A (en) | 1998-06-17 | 2000-04-04 | M. E. Cody Products, Inc. | Plantago major and Piper methysticum compound for use in treating a tobacco or nicotine habit |
| EP1126882B1 (de) * | 1998-11-04 | 2009-12-30 | Dr. Willmar Schwabe GmbH & Co. KG | Stabile zubereitungen mit hyperforin |
| DE19913333C2 (de) * | 1999-03-24 | 2001-10-11 | Univ Ludwigs Albert | Hyperforin als Zytostatikum |
| EP1034782A1 (en) * | 1999-03-04 | 2000-09-13 | Andrea Singer | Treatment of depression by using compounds which elevate the intracellular sodium concentration |
| AU3744100A (en) * | 1999-03-15 | 2000-10-04 | Shaman Pharmaceuticals, Inc. | Bicyclo(3.3.1)nonenes useful for the treatment of diabetes |
| US7195783B2 (en) | 1999-07-09 | 2007-03-27 | Fx Life Sciences International Gmbh | Hypericin and hypericum extract: specific T-type calcium channel blocker, and their use as T-type calcium channel targeted therapeutics |
| ES2159270B1 (es) * | 2000-03-06 | 2002-04-01 | Asac Compania De Biotecnologia | Oleorresina de hypericum perforatum l., procedimiento de obtencion y usos. |
| KR100407399B1 (ko) * | 2000-08-22 | 2003-11-28 | 주식회사 뉴로넥스 | 세로토닌 ｎ-아세틸트란스퍼라제의 활성 억제제 |
| DE10131641A1 (de) * | 2000-12-22 | 2002-06-27 | Schwabe Willmar Gmbh & Co | Verbesserter und stabiler Extrakt aus Hypericum perforatum L., Verfahren zu seiner Herstellung und Verwendung als topisches Arzneimittel |
| CN100534420C (zh) * | 2001-09-25 | 2009-09-02 | 北京北大维信生物科技有限公司 | 一种治疗抑郁症的口服药 |
| US7037524B2 (en) * | 2001-10-03 | 2006-05-02 | Herbalscience, Llc | Oral delivery of a botanical |
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| US7291352B2 (en) | 2001-10-03 | 2007-11-06 | Herbalscience Llc | Methods and compositions for oral delivery of Areca and mate' or theobromine |
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| US7029707B2 (en) * | 2001-10-03 | 2006-04-18 | Herbalscience, Llc | Method of producing a processed kava product having an altered kavalactone distribution and processed kava products produced using the same |
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| AU2003286725B2 (en) * | 2002-10-29 | 2007-07-12 | Transform Pharmaceuticals, Inc. | Propofol with cysteine |
| US7294353B2 (en) * | 2003-10-24 | 2007-11-13 | Herbalscience, Llc | Methods and compositions comprising ilex |
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| US20050176650A1 (en) * | 2004-02-09 | 2005-08-11 | Xanodyne Pharmacal, Inc. | Stable parenteral formulation of levomepromazine and a method for stabilizing said formulation |
| US20060115556A1 (en) * | 2004-12-01 | 2006-06-01 | Foulger Sidney W | Nutritional supplement drink containing xanthone extracts |
| US20060115555A1 (en) * | 2004-12-01 | 2006-06-01 | Foulger Sidney W | Nutritional supplements containing xanthone extracts |
| FR2908996A1 (fr) * | 2005-11-25 | 2008-05-30 | R & D Pharma | Nouveau procede d'extraction de principes actifs et l'utilisation de ceux-ci en therapeutique |
| FR2908997B1 (fr) * | 2005-11-25 | 2014-03-14 | R Et D Pharma | Nouvelles compositions therapeutiques et le procede de production des principes actifs |
| FR2894829A1 (fr) * | 2005-12-19 | 2007-06-22 | R & D Pharma | Nouveau procede d'extraction de principes actifs et l'utilisation de ceux-ci en therapeutique |
| RU2623084C2 (ru) * | 2015-06-23 | 2017-06-21 | Федеральное государственное бюджетное учреждение науки Институт биологии Коми научного центра Уральского отделения Российской академии наук | Способ одновременного получения гиперицина и псевдогиперицина |
| CN106588827B (zh) * | 2016-12-29 | 2019-03-08 | 广州领鲜生物科技有限公司 | 用于治疗溃疡性结肠炎的金丝海棠提取物的提取方法及应用 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE876309C (de) | 1951-09-29 | 1953-05-11 | Chemiewerk Homburg Ag | Verfahren zur Herstellung farbstabiler waessriger Azulenloesungen |
| US4178372A (en) | 1978-03-06 | 1979-12-11 | Coats Billy C | Hypoallergenic stabilized aloe vera gel |
| EP0051789B1 (de) | 1980-10-31 | 1986-09-03 | Rainer Bähr | Mittel zur Haarwuchsaktivierung |
| RO79428B1 (ro) * | 1980-12-25 | 1983-02-28 | Titus Puiu Trestioreanu | Compozitie medicamentoasa destinata tratamentului dermatozelor |
| CS228038B1 (en) * | 1981-07-10 | 1984-05-14 | Bedrich Mudr Dolezel | Production of tissue preparation |
| US4446131A (en) | 1982-06-09 | 1984-05-01 | Aloe Vera Of America, Inc. | Controlled temperature process for manufacturing of improved stabilized aloe vera |
| DE3641220A1 (de) | 1986-12-03 | 1988-06-16 | Christian Calarasu | Arzneimittel zur behandlung von psoriasis oder neurodermatitis |
| DE4131313A1 (de) | 1991-09-20 | 1993-03-25 | Karl Konrad | Arzneimittel aus kamillenblueten |
| DE4201179A1 (de) * | 1992-01-17 | 1993-07-22 | Alfatec Pharma Gmbh | Wirkstoff(e) enthaltendes granulat oder pellet mit einem geruest aus hydrophilen makromolekuelen und verfahren zu seiner herstellung |
| DE4239959A1 (de) * | 1992-11-27 | 1994-06-01 | Schwabe Willmar Gmbh & Co | Johanniskraut-Trockenextrakt, Verfahren zu seiner Herstellung und seine Verwendung |
-
1996
- 1996-05-14 DE DE19646977A patent/DE19646977A1/de not_active Ceased
- 1996-09-27 ES ES96945476T patent/ES2118686T5/es not_active Expired - Lifetime
- 1996-09-27 AU AU15891/97A patent/AU709877B2/en not_active Ceased
- 1996-09-27 BR BRPI9611096A patent/BRPI9611096B8/pt not_active IP Right Cessation
- 1996-09-27 EA EA199800304A patent/EA000948B1/ru not_active IP Right Cessation
- 1996-09-27 PL PL96328136A patent/PL186727B1/pl unknown
- 1996-09-27 CN CN96197288A patent/CN1087943C/zh not_active Expired - Fee Related
- 1996-09-27 AT AT96945476T patent/ATE174511T1/de active
- 1996-09-27 DE DE59601019T patent/DE59601019D1/de not_active Expired - Lifetime
- 1996-09-27 WO PCT/DE1996/001876 patent/WO1997013489A2/de active IP Right Grant
- 1996-09-27 JP JP51377897A patent/JP3245654B2/ja not_active Expired - Fee Related
- 1996-09-27 EP EP96945476A patent/EP0854726B2/de not_active Expired - Lifetime
- 1996-09-27 US US09/043,939 patent/US6280736B1/en not_active Expired - Lifetime
- 1996-09-27 TR TR1998/00569T patent/TR199800569T1/xx unknown
- 1996-09-27 HU HU9900657A patent/HU227069B1/hu not_active IP Right Cessation
- 1996-09-27 CA CA002233277A patent/CA2233277C/en not_active Expired - Fee Related
-
1998
- 1998-03-25 NO NO981352A patent/NO981352D0/no unknown
-
1999
- 1999-02-16 GR GR990400494T patent/GR3029412T3/el unknown
-
2001
- 2001-08-23 US US09/938,245 patent/US20020031560A1/en not_active Abandoned
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315480C (zh) * | 2003-05-17 | 2007-05-16 | 广西化工生物技术研究所 | 治疗疱疹病毒的药物组合物及其生产方法 |
| CN1304019C (zh) * | 2003-05-29 | 2007-03-14 | 斯拉甫·艾白 | 复方一枝蒿胶囊 |
| CN101744890A (zh) * | 2008-12-08 | 2010-06-23 | 上海四埃美微科技有限公司 | 一种贯叶连翘提取物中金丝桃素的精制的方法 |
| CN101984980A (zh) * | 2010-11-05 | 2011-03-16 | 北京世纪博康医药科技有限公司 | 一种贯叶连翘提取物的提取方法、提取物和制药用途 |
| CN101984980B (zh) * | 2010-11-05 | 2012-12-19 | 北京世纪博康医药科技有限公司 | 一种贯叶连翘提取物的提取方法、提取物和制药用途 |
| CN106668088A (zh) * | 2017-02-08 | 2017-05-17 | 内蒙古昶辉生物科技股份有限公司 | 一种贯叶连翘提取物的制备方法 |
| CN108936612A (zh) * | 2018-06-28 | 2018-12-07 | 燕生（福建）生物工程有限公司 | 一种制备具有强抗氧化作用的燕窝提取液的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2118686T3 (es) | 1999-04-16 |
| EP0854726B1 (de) | 1998-12-16 |
| US6280736B1 (en) | 2001-08-28 |
| BRPI9611096B8 (pt) | 2015-12-08 |
| BR9611096A (pt) | 1999-10-05 |
| EP0854726A2 (de) | 1998-07-29 |
| EA000948B1 (ru) | 2000-06-26 |
| WO1997013489A2 (de) | 1997-04-17 |
| EP0854726B2 (de) | 2009-07-29 |
| NO981352L (no) | 1998-03-25 |
| AU1589197A (en) | 1997-04-30 |
| EA199800304A1 (ru) | 1998-10-29 |
| ES2118686T5 (es) | 2009-12-11 |
| PL186727B1 (pl) | 2004-02-27 |
| GR3029412T3 (en) | 1999-05-28 |
| HUP9900657A2 (hu) | 1999-09-28 |
| WO1997013489A3 (de) | 1997-08-14 |
| CA2233277C (en) | 2002-04-02 |
| BR9611096B1 (pt) | 2010-09-21 |
| US20020031560A1 (en) | 2002-03-14 |
| ATE174511T1 (de) | 1999-01-15 |
| HU227069B1 (hu) | 2010-06-28 |
| HUP9900657A3 (en) | 2000-02-28 |
| DE19646977A1 (de) | 1998-01-15 |
| CA2233277A1 (en) | 1997-04-17 |
| ES2118686T1 (es) | 1998-10-01 |
| PL328136A1 (en) | 1999-01-18 |
| TR199800569T1 (xx) | 1998-06-22 |
| NO981352D0 (no) | 1998-03-25 |
| JP3245654B2 (ja) | 2002-01-15 |
| DE59601019D1 (de) | 1999-01-28 |
| JPH11500743A (ja) | 1999-01-19 |
| AU709877B2 (en) | 1999-09-09 |
| CN1087943C (zh) | 2002-07-24 |
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