CN101194011A - (s)－(+)－s－腺嘌呤核苷－l－甲硫氨酸高含量的干燥和/或微囊化酿酒酵母菌细胞、其制备方法及包含所述细胞的组合物 - Google Patents
(s)－(+)－s－腺嘌呤核苷－l－甲硫氨酸高含量的干燥和/或微囊化酿酒酵母菌细胞、其制备方法及包含所述细胞的组合物 Download PDFInfo
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- CN101194011A CN101194011A CNA2006800202717A CN200680020271A CN101194011A CN 101194011 A CN101194011 A CN 101194011A CN A2006800202717 A CNA2006800202717 A CN A2006800202717A CN 200680020271 A CN200680020271 A CN 200680020271A CN 101194011 A CN101194011 A CN 101194011A
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Classifications
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Abstract
本发明涉及干燥和/或微囊化的酿酒酵母菌细胞，所述细胞包含高含量的游离碱形式的(S)－(+)－S－腺嘌呤核苷－L－甲硫氨酸，其可从选择的高(S)－(+)－SAMe产量的菌株中获得。
Description
技术领域
本发明涉及(S)-(+)-S-腺嘌呤核苷-L-甲硫氨酸高含量的干燥和/或微囊化酿酒酵母菌(Saccharomyces cerevisiae)细胞、其制备方法及包含所述细胞的组合物。
具体地讲，本发明涉及酿酒酵母菌细，其中非对映异构体游离碱(R)-(+)-S-腺嘌呤核苷-L-甲硫氨酸(在下文中称为(R)-(+)-SAMe)的含量小于或等于非对映异构体游离碱(S)-(+)-S-腺嘌呤核苷-L-甲硫氨酸(在下文中称为(S)-(+)-SAMe)含量的10％。
背景技术
众所周知，(S)-(+)-SAMe离子一旦从它的产生细胞中提取出来，将非常不稳定并接着快速降解。事实上，从发现SAMe(Cantoni等人，“磷代谢，Baltimore19522，129；Cantoni等人，生物化学杂志(J.Biol.Chem)，1953，204，403)到将其市场化之间经过了许多年。稳定性问题最初是通过成盐的方法解决的，特别是形成硫酸盐。但是，由于SAMe硫酸盐本身的酸性，所以它们有时会引起副作用，尤其是对胃粘膜。
众所周知，(R，S)SAMe是参与酶催化转甲基反应的甲基基团的生理供体，它在所有的活有机体中都存在，而且对慢性肝疾病、肥胖症、脂血和动脉粥样硬化有治疗作用。
以下事实也是众所周知的(J.W.Cornforth，美国化学会会志(J.A.C.S.)，1977，99，7292-7300；Stolowitz等人，美国化学会会志，1981，103，6015-6019)，即含有(R，S)SAMe的产物包括两种非对映异构体的混合物：(R)-(+)-SAMe和(S)-(+)-SAMe，它们的分子结构如下：
还已征明(De La Haba等人，美国化学会会志，1959，81，3975-3980)，两个非对映异构体中只有一个，即(S)-(+)-SAMe，通过自发的甲基转移和外消旋作用，从而是有酶活性的，并进而导致总计约20％的无活性的非对映异构体(R)-(+)-SAMe生成(Wu等人，生物化学(Biochemistry)，1983，22，2828-2832)。
已观察到，市场上可以获得的含有SAMe的所有产品中，无活性的非对映异构体(R)-(+)-SAMe的量至少有20％；另外观察显示，由于自发外消旋化作用，上述百分比随着时间推移可以增加到40％甚至更高。
细胞中(S)-(+)-SAMe的天然含量近似于100％，但是工业提取和纯化方法得到部分降解的产物，即包含≥20％(R)-(+)-SAMe和≤80％(S)-(+)-SAMe的混合物。
这些事实清晰地证实这种非对映异构体的混合物随时间推移是不稳定的，已经知道这种现象与产品在溶液中有关(G.L.Creason等人，植物化学(Phytochemistry)，第24卷，第6期，1151-1155，1985；H.C.Uzar，Liebigs Ann.Chem.1989，607-610)。
而且还观察到，(R，S)SAMe及其被批准药用的成盐形式，除了制备和纯化方法的复杂性外，还存在不稳定的问题。
已知的纯化方法涉及使用强酸性树脂(JP 13680/1971)、螯合树脂(JP20998/1978)或昂贵的特殊试剂，如苦味酸或吡啶甲酸(US 3707536和US3954726)；但是，它们导致SAMe的硫部分外消旋化，从而使得到的终产物中无活性的非对映异构体的含量超过20％。
然而，涉及使用弱酸性树脂的纯化方法(JP 14299/1981、FR-A-2531714、EP-A-0141914)仅能使活性非对映异构体部分分离，因此纯度不足以满足药用目的。
虽然上述纯化方法中的一些可以获得更好的纯度，但是都有部分升消旋化的隐患，无论如何，至少存在20％的无活性的非对映异构体；此外，在某些情况下(FR 2531714)，用碳酸氢钾来从细胞中提取产物，进而用高氯酸钾沉淀，这可能引起产物的分离和随后的消除困难。在EP-A-0141914中，在有机溶剂(如乙酸乙酯、丙酮，等)存在时，对含有SAMe的酵母细胞进行溶胞，还使用色谱柱，所述色谱柱需要使用粒度为100-200目的树脂，树脂的再生和清洗需要大量的投资和维护费用。
使用溶剂来提取SAMe必然要使用防火的厂房、溶剂回收和蒸馏系统、以及对衰竭(depleted)的生物质进行分离和必要的干燥以避免它与残留的溶剂一起被去除。所有这些因素很明显与开支和操作费用增加有关。
Morana等人，生物化学与生物物理学学报(Biochimica Biophysica Acta)，1573(2002)，105-108，揭示SAMe在冻干的酵母提取物以及在冻干的酵母细胞中(在较低程度上)可以用海藻糖来稳定。但低压冻干法是有缺点的，它使细胞处于应激条件(在-20℃冷冻，然后再在37℃解冻)下，而且推测无论如何，海藻糖对稳定细胞内SAMe是必不可少的。此外，加入海藻糖将会涉及经济和调控问题。
因此，需要下述SAMe的衍生物或剂型，其中活性(S)-(+)-SAMe非对映异构体的百分率要明显高于无活性(R)-(+)-SAMe异构体的，而且其中所述百分率随时间推移是稳定的。另外还有一个重要目标是制得作为游离碱的(S)-(+)-SAMe的稳定的给药剂型，不再需要将其做成盐和/或加入稳定剂，并且不会使酵母细胞处于应激条件。
发明内容
目前已经发现，即使不添加任何稳定剂，SAMe游离碱在产生它的细胞内是稳定的。酵母细胞完整的细胞壁的保护作用也极大地促进SAMe游离碱在室温下随时间推移有更高的稳定性。
因此，本发明涉及(S)-(+)-S-腺嘌呤核苷-L-甲硫氨酸高含量的干燥和/或微囊化酿酒酵母菌细胞，(S)-(+)-S-腺嘌呤核苷-L-甲硫氨酸以可得自酵母细胞的游离碱形式存在，将所述酵母细胞在20到40℃温度下、任选减压条件下简单干燥，所述酵母细胞特别是具有(S)-(+)-SAMe高产率特征的酿酒酵母菌菌株。
根据本发明的细胞可以以适当的药物剂型给药，尤其是胶囊、片剂、肠溶片剂等。
适当的酿酒酵母菌菌株可如下选择：对得自平板接种在YM琼脂的培养肉汤样品的菌落进行筛选，所述肉汤样品取自前静止期(pre-stationary stage)的工业发酵物，随后检查筛选的菌落产生(S)-(+)-SAMe的能力。
如此挑选的称为GNL24/497的菌株的SAMe产生能力(productivity)在发酵期末期为2.0％-6.0％重量/干重，尤其为3％-4％重量/干重，在富集期末期为7％-20％重量/干重，尤其为10％-16％重量/干重。
酵母酿酒酵母菌GNL24/497是由佩鲁贾大学“工业酵母保藏DBVPG(Industrial Yeast Collection DBVPG)”基于它的形态生理学特征和DNA-DNA重新组合技术分类的。菌株酿酒酵母菌GNL24/497已经按照2005年4月27日签定的布达佩斯条约保藏在DBVPG保藏中心(用于专利目的)，保藏号为DBVPG8P，其构成了本发明的另一主题。
酵母按照已知的技术和条件在工业水平下生长，并被用作制备面包制造的生物质(biomass)，其中将DL甲硫氨酸加入到基于糖蜜的普通培养基(F.Schlenk和R.E.De Palma，生物化学杂志(J.Biol.Chem.)1957 229，1051；F.Schlenk，J.L.Dainko和S.M.Stanford，生物化学和生物物理学档案(Archives of Biochemistryand Biophysics)1959，83，28-34)中，DL甲硫氨酸的量为0.5％-4.0％w/v，更特别是1.0％-3.0％w/v。
通过离心收集生物质，将其洗涤、重悬并在一种培养基(在下文中称为“活化培养基”)中进行活化过程，该培养基含有磷酸钾；硫酸铵；柠檬酸钠；镁、锰、锌和钙盐；葡萄糖和L-甲硫氨酸或DL-甲硫氨酸(F.Schlenk和R.E.De Palma，生物化学杂志，1957，229，1051-F.Schlenk等人，Enzymologia 29，283，1965)。
活化过程可以重复2-5次，更特别为2-3次，该过程可以在下列条件下进行：在无菌或非无菌的条件下；在大气压或微压下；在控制pH或自由pH下；通气速度为0.1-0.5v/v/m，或更特别为0.2-1.0v/v/m；温度在25℃-35℃，或更特别为28℃-32℃；活化6-24h，或更特别为8-18h。
活化培养基中的生物质浓度可以在2.5％到18％干重/体积的范围内变化，更特别为5％-15％干重/体积。富集之后，用离心或微孔过滤的方法收集生物质，用无菌水或pH5.2(±0.2)的磷酸缓冲液洗涤几次，然后根据常期技术干燥或微颗粒化。
根据一个优选的方面，微颗粒化的方法可以包括：
a)从培养肉汤中离心或微孔过滤酵母细胞；
b)用水洗涤酵母细胞然后重混悬在无菌水中；
c)如果可能，在b)获得的悬浮液中加入皂粘土、白陶土、硅土、微晶纤维素(microcellulose)、lecithinated钠和/或天然或氢化的植物或动物油；
d)在20℃到40℃温度下低压干燥c)中得到的混合物，至含水量为0.5到5％；
e)加入赋形剂到干燥过的物质中，将混合物直接压片；
f)将e)中得到的片制粒；
g)用融化的蜡对f)中得到的颗粒包衣。
这一方法公布在由申请人于2005年2月18日提交的申请号为05425084.0的欧洲专利申请中。
用干燥过的微颗粒化酵母的生物质制备片剂，片剂的重量在1.0到2.5g之间，更特别为1.3-1.8g，活性组分(S)-(+)-SAMe的含量在100到400mg之间，更特别为150到300mg。片剂可以按照公知的技术，用高(S)-(+)-SAMe含量的干燥酵母或加入赋形剂进行制备，所述赋形剂为如微晶纤维素、硅土、山嵛酸甘油酯(glycerol behenate)、硬脂酸镁(等等)。由此得到的片剂还可以用赋形剂包衣，所述赋形剂如BIOGAPRESSVEGETAL、LabrafacCC、EUDRAGITL30D-55、二氧化钛、滑石粉、二氧化硅胶体、柠檬酸三乙酯、FD&C黄色5号(FD&C yellow 5)等，以符合肠溶(gastric resistance)标准。
具体实施方式
用下面的例子更加详细地举例说明本发明。
实施例1
酵母酿酒酵母菌GNL-24/497(DBVPG 8 P)在一种基于糖蜜(制作面包的酵母所用的)的工业培养基中生长，该培养基中已加入30g/l的DL-甲硫氨酸，在28℃生长24h。用离心的方法，收集生物质，用自来水洗涤两次：得到20％±2g/干重/体积的膏状物和3％(±0.5％)重量/干重的总SAMe。在10升发酵罐中制备培养基，该培养基包含：
葡萄糖82g/l、DL-甲硫氨酸12g/l、Na2NO3 10g/l、KH2PO4 3.5g/l、KOH 0.385g/l、(NH4)2SO4 7.0g/l、MgSO4 0.5g/l、止泡剂0.03g/l。加热培养基到28℃，加入膏状物，直到浓度达到100g/l干重。活化条件：200rpm振荡，气流速度0.25v/v/min。葡萄糖消耗完的时候，即大约12h后，通过离心收集细胞，回收100-102g/l干重生物质，其包含量为11.5％的总SAMe，其中(R)-(+)-SAMe异构体为4.5％，(S)-(+)-SAMe异构体为95.5％。
将生物质在28℃干燥到含水量≤0.5％w/w。
分析证实(R)-(+)-SAMe异构体含量小于5％，且(S)-(+)-SAMe异构体含量大于95％。
实施例2
操作同实施例1，但是将生物质活化两次。得到14.2％重量/干重的总SAMe，其中(R)-(+)-SAMe异构体为4.3％w/w，(S)-(+)-SAMe异构体为95.7％。
实施例3
操作同实施例1和实施例2，但是生物质进行三次富集，得到15.1％重量/干重的总SAMe，其中(R)-(+)-SAMe异构体为4.4％，(S)-(+)-SAMe异构体为95.6％重量/干重。
实施例4
操作同实施例1-3，其中将干燥过的生物质通过加入皂粘土并在5mbars压力和32℃(±2℃)条件下干燥进行微囊化，研成细粉，再加入到用于微囊化的颗粒中，如下所示：
g％
·酿酒酵母菌粉末 10
·甘露醇 50
·微晶纤维素 10
·二氧化硅胶体 2
·硬脂酸镁 3
·山嵛酸甘油酯888 5
·氢化的植物脂肪(Biogapress Vegetal 8M297，GATTEFOSSE) 20
将所述粉未与除氢化的植物脂肪之外的其它组分适当混合。该混合物用于制成直径20-25mm的片，然后在一台摇摆式颗粒机中将上述片制粒，得到300-1500微米的颗粒。用一种再循环式螺杆捏合机将颗粒用融化的植物脂肪包衣，并冷却到环境温度，得到包含3.0(±5％)×109CFU/g的500-1600微米的微囊。
实施例5
如实施例1所述制备和干燥酵母酿酒酵母菌GNL-24/497(DBVPG 8P)。
干燥的生物质在环境温度(T＝25±2℃，RH＝60±5％)进行稳定性实验。
为进行分析，将细胞在+4℃机械溶胞。
下表给出得到的结果：
| 样品天数 | KF％ | (S)-(+)-SAMe％含量 | (R)-(+)SAMe％含量 |
| 0 | 0.40(±0.05) | 94.50(±0.1) | 5.50(±0.1) |
| 15 | 0.40(±0.05) | 94.10(±0.1) | 5.90(±0.1) |
| 45 | 0.40(±0.05) | 94.10(±0.1) | 5.90(±0.1) |
| 75 | 0.40(±0.05) | 94.00(±0.1) | 6.00(±0.1) |
| 100 | 0.40(±0.05) | 94.10(±0.1) | 5.90(±0.1) |
| 120 | 0.42(±0.05) | 93.80(±0.1) | 6.20(±0.1) |
| 150 | 0.42(±0.05) | 94.00(±0.1) | 6.00(±0.1) |
| 180 | 0.46(±0.05) | 93.90(±0.1) | 6.10(±0.1) |
实施例6
根据公知技术，用干燥的生物质(如同实施例1、2、3、4所示的)制备含有如下细分的片剂。
| 组分 | 作用 | 量 |
| 干燥细胞 | 活性组分≥200mg | 1350mg |
| 微晶纤维素二氧化硅胶体山嵛酸甘油酯硬脂酸镁 | 赋形剂：核粘合剂吸附剂润滑剂抗粘剂 | 86.00mg7.00mg20.00mg7.00mg |
| 总重 | 1470mg |
实施例7
根据公知技术，用干燥的生物质(如同实施例1、2、3、4所示的)制备含有如下组分的片剂。
每片组分
| 组分 | 作用 | 量 |
| 干燥细胞 | 活性组分≥200mg | 1350mg |
| 微晶纤维素二氧化硅胶体山嵛酸甘油酯硬脂酸镁 | 赋形剂：核粘合剂吸附剂润滑剂抗粘剂 | 86.00mg7.00mg20.00mg7.00mg |
| Biogapressvegetal(Glyceryl glycerolpalmitost.)LabrafacCC*Eudragit L30D-55**二氧化钛滑石粉二氧化硅胶体(Aerosol 200)柠檬酸三乙酯酒石黄 | 赋形剂(spinning)保护剂保护剂膜剂遮光剂抗粘剂干燥剂增塑剂着色剂 | 11.20mg11.20mg43.20mg7.20mg14.25mg1.00mg11.55mg0.08mg |
| 总重 | 1569.68mg | |
·*LABRAFAC(长链甘油三酯类)
·**EUDRAGIT(异丁烯酸共聚物)
·***FD(酒石黄)
实施例8
采用PHARMATEST PTL-5粉碎机装置，将实施例7中提到的片剂按照欧洲药典进行肠溶实验。1小时后片剂全部保持完整。
Claims (11)
1.(S)-(+)-S-腺嘌呤核苷-L-甲硫氨酸高含量的干燥和/或微囊化的酿酒酵母菌细胞，(S)-(+)-S-腺嘌呤核苷-L-甲硫氨酸以可得自酵母细胞的游离碱形式存在，所述酵母细胞在20到40℃温度、任选减压、无稳定剂条件下干燥。
2.干燥形式的如权利要求1中所要求保护的细胞。
3.微囊形式的如权利要求1或2中所要求保护的细胞。
4.如上述权利要求的任何一项中所要求保护的细胞，所述细胞可如下获得：对得自平板接种在YM琼脂的培养肉汤样品的菌落进行筛选，所述样品取自前静止期的工业发酵物，随后检查筛选的菌落产生(S)-(+)-SAMe的能力。
5.如上述权利要求的任何一项中所要求保护的酿酒酵母菌细胞，所述酿酒酵母菌细胞在DBVPG保藏中心的保藏号为DBVPG 8P。
6.如上述权利要求的任何一项中所要求保护的细胞，该细胞的SAMe产生能力在发酵结束时为2.0％-6.0％重量/干重，在富集阶段结束时为7％-20％重量/干重。
7.药物组合物，该药物组合物包含权利要求1-6中所要求保护的细胞，所述细胞作为活性组分并与适当赋形剂混合。
8.如权利要求7中所要求保护的组合物，该组合物以片剂、肠溶片剂和胶囊的形式存在。
9.如权利要求7或8中所要求保护的组合物，该组合物中活性组分(S)-(+)-SAMe的含量为100至400mg。
10.制备权利要求1-6中所要求保护的细胞的方法，所述方法包括：
-将DL甲硫氨酸以0.5％-4.0％w/v的量加入到基于制造面包的糖蜜的培养基中；
-离心生物质，将其洗涤、重悬，并在培养基中进行活化过程，所述培养基含有磷酸钾；硫酸铵；柠檬酸钠；镁、锰、锌和钙盐；葡萄糖和L-甲硫氨酸或DL-甲硫氨酸；
-活化过程可能重复2-5次，以0.1-1.5v/v/w通气和25℃-35℃条件下进行6-24小时；
-在活化培养基中生物质浓度为2.5％至18％干重/体积；
-将生物质离心或微孔过滤，将生物质用无菌水或pH5.2(±0.2)的磷酸盐缓冲液洗数遍，然后根据常规技术干燥或微颗粒化。
11.酿酒酵母菌菌株，该菌株在DBVPG保藏中心的保藏号为DBVPG8P。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05425413.1 | 2005-06-09 | ||
| EP05425413A EP1731596B1 (en) | 2005-06-09 | 2005-06-09 | Dried, freeze-dried and/or microencapsulated Saccharomyces cerevisiae cells with a high content of (S)-(+)-S-adenosyl-L-methionine |
| PCT/EP2006/005521 WO2006131382A1 (en) | 2005-06-09 | 2006-06-09 | Dried and/or microencapsulated saccharomyces cerevisiae cells with a high content of (s)-(+)-s-adenosyl-l-methionine, process for their preparation, and compositions containing said cells |
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| CN101194011A true CN101194011A (zh) | 2008-06-04 |
| CN101194011B CN101194011B (zh) | 2012-10-31 |
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| Country | Link |
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| US (1) | US9365817B2 (zh) |
| EP (1) | EP1731596B1 (zh) |
| JP (1) | JP5037501B2 (zh) |
| KR (1) | KR101418597B1 (zh) |
| CN (1) | CN101194011B (zh) |
| AU (1) | AU2006256926B2 (zh) |
| CA (1) | CA2610877A1 (zh) |
| DK (1) | DK1731596T5 (zh) |
| ES (1) | ES2406412T3 (zh) |
| IL (1) | IL187971A (zh) |
| NZ (1) | NZ564097A (zh) |
| PL (1) | PL1731596T3 (zh) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103841985A (zh) * | 2011-10-06 | 2014-06-04 | 狮王株式会社 | 睡眠质量改善剂 |
| CN105054068A (zh) * | 2014-01-25 | 2015-11-18 | 北京凯因科技股份有限公司 | 一种酵母谷胱甘肽营养配制品 |
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| JPWO2009081833A1 (ja) * | 2007-12-20 | 2011-05-06 | 株式会社カネカ | 安定化された（ｓｓ）−ｓ−アデノシル−ｌ−メチオニンを含有する微生物乾燥菌体又は微生物エキス、及びその製造方法 |
| EP2095828A1 (en) * | 2008-02-29 | 2009-09-02 | Gnosis S.p.A. | Use of S-adenosylmethionine (SAM) and superoxide dismutase (SOD) for the preparation of medicaments for the treatment of Alzeimer's disease |
| US8329208B2 (en) | 2009-07-28 | 2012-12-11 | Methylation Sciences International Srl | Pharmacokinetics of S-adenosylmethionine formulations |
| CN102858950A (zh) * | 2010-04-07 | 2013-01-02 | 三菱瓦斯化学株式会社 | 保存稳定性优异的含有s-腺苷-l-蛋氨酸的干酵母组合物及其制造方法 |
| CN103704723A (zh) * | 2013-12-11 | 2014-04-09 | 北京凯因科技股份有限公司 | 一种富含活性氨基酸的营养配制品 |
| ES2704201B2 (es) | 2017-09-14 | 2019-11-18 | Tomsa Destil S L | Cepa de Saccharomyces cerevisiae y su uso para la elaboración de productos alcohólicos |
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| US3962034A (en) | 1973-02-01 | 1976-06-08 | Ajinomoto Co., Inc. | Method for producing s-adenosylmethionine or methylthioadenosine by yeast |
| GB2116172B (en) | 1982-02-25 | 1986-07-09 | Nippon Zeon Co | Microbial cells containing s-adenosyl methionine in high concentrations and process for production of s adenosyl methionine |
| JPH01174386A (ja) | 1987-12-28 | 1989-07-10 | Kanegafuchi Chem Ind Co Ltd | Ｓ−アデノシル−ｌ−メチオニンの蓄積を高める遺伝子およびその用途 |
| CN1058989A (zh) * | 1991-08-28 | 1992-02-26 | 中国生物工程开发中心宜昌食用酵母基地 | 耐高温酒精活性干酵母生产工艺 |
| FR2806417B1 (fr) * | 2000-03-16 | 2003-12-26 | Lallemand Sa | Particules enrobees contenant des microorganismes vivants, procede de production et application desdites particules dans les compositions pharmaceutiques, dietetiques ou alimentaires |
| JP3455158B2 (ja) * | 2000-03-29 | 2003-10-14 | 日本甜菜製糖株式会社 | 焼酎の製造方法 |
| IT1318535B1 (it) * | 2000-05-25 | 2003-08-27 | Chementecno Srl | Processo per la preparazione di sali farmaceuticamente accettabili di(ss,rs)-s-adenosil-l-metionina. |
| US20020025926A1 (en) * | 2000-08-30 | 2002-02-28 | Hebert Rolland F. | Enantiomers of S-adenosyl-l-methionine |
| US20040005335A1 (en) * | 2002-06-28 | 2004-01-08 | Cheung Ling Yuk | Oral compositions for HIV-infected subjects |
| DE10230224A1 (de) | 2002-07-04 | 2004-04-01 | Axaron Bioscience Ag | Verfahren zur Produktion von S-Adenosyl-L-Methionin durch Fermentation von genetisch modifizierten Mikroorganismen |
| JP2005229812A (ja) * | 2004-02-17 | 2005-09-02 | Kohjin Co Ltd | 安定化されたｓａｍを含有する乾燥微生物又は微生物抽出物、及びその製造方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103841985A (zh) * | 2011-10-06 | 2014-06-04 | 狮王株式会社 | 睡眠质量改善剂 |
| CN105054068A (zh) * | 2014-01-25 | 2015-11-18 | 北京凯因科技股份有限公司 | 一种酵母谷胱甘肽营养配制品 |
Also Published As
| Publication number | Publication date |
|---|---|
| IL187971A (en) | 2012-05-31 |
| ES2406412T3 (es) | 2013-06-06 |
| KR101418597B1 (ko) | 2014-07-25 |
| CA2610877A1 (en) | 2006-12-14 |
| KR20080032028A (ko) | 2008-04-14 |
| US9365817B2 (en) | 2016-06-14 |
| PL1731596T3 (pl) | 2013-08-30 |
| EP1731596B1 (en) | 2013-03-27 |
| CN101194011B (zh) | 2012-10-31 |
| NZ564097A (en) | 2011-02-25 |
| US20100028315A1 (en) | 2010-02-04 |
| PT1731596E (pt) | 2013-05-10 |
| JP2008541773A (ja) | 2008-11-27 |
| JP5037501B2 (ja) | 2012-09-26 |
| AU2006256926A1 (en) | 2006-12-14 |
| WO2006131382A1 (en) | 2006-12-14 |
| AU2006256926B2 (en) | 2011-07-07 |
| DK1731596T3 (da) | 2013-06-10 |
| DK1731596T5 (da) | 2013-09-23 |
| EP1731596A1 (en) | 2006-12-13 |
| IL187971A0 (en) | 2008-03-20 |
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