CN1216047A - 抗细菌和抗真菌的肽 - Google Patents
抗细菌和抗真菌的肽 Download PDFInfo
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- CN1216047A CN1216047A CN97193823A CN97193823A CN1216047A CN 1216047 A CN1216047 A CN 1216047A CN 97193823 A CN97193823 A CN 97193823A CN 97193823 A CN97193823 A CN 97193823A CN 1216047 A CN1216047 A CN 1216047A
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- peptide
- composition
- active substance
- agent
- hemolymph
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Abstract
本发明公开了一种抗细菌和抗真菌的式(Ⅰ)肽。
Description
本发明涉及一种具有抗细菌和抗真菌特性的新的蛋白质富含的肽(protein-rich peptide)及包含这种肽为活性物质的组合物,其可应用于农业和人类或动物治疗中。发明还涉及应用这种组合物来处理植物的方法,以及制备这种肽的方法。
长时间以来就已知昆虫对细菌有有效的抗性。这种防卫主要来自于几种家族的肽类的快速合成。这种防卫主要是由于具有广谱活性的几种家族的肽类的快速合成。这种合成由腐败性的伤口或低剂量细菌注射诱导。在所诱导的抗细菌肽中,描述最多的是昆虫杀菌肽及防卫素。几种其它抗细菌肽已有部分的描述。
除了昆虫纲外,对其它节肢动物了解极少。就系统发生而言,蝎子比昆虫存在的时间要长得多。
现已从对蝎子Androctonus australis的诱导中分离到了一种肽,这种肽表现出相当突出的特征以及抗细菌和抗真菌的特性。
更具体地说,发明的第一方面涉及具有式Ⅰ的肽:
Arg Ser Val Cys Arg Gln Ile Lys Ile Cys Arg
Arg
Arg
Tyr Pro Arg Asn Thr Cys Lys Tyr Tyr Cys Gly Gly
在下文中,式Ⅰ的分子指的是androctonine。这个相对小的分子包含4个形成两个分子间桥的半胱氨酸残基。
发明的另一方面涉及到获得和分离上述肽的第一种方法,其中依次进行以下各步:
a)获取蝎子Androctonus australis的血淋巴;
b)把上面得到的Androctonus australis血淋巴与酸媒介物接触并搅拌,随后离心,完成提取;
c)在分离柱上用适当的成分洗涤亲水分子并洗脱疏水分子来分离而把上清液分馏开来;
d)纯化提取物;
e)检定肽。
通过切开表皮而得到血淋巴。收集到含有蛋白酶抑制剂的试管中。离心除去血细胞后,血浆保存于-30℃。
第二步(提取)的优选方法是,把Androctonus australis血淋巴与由一种酸的酸性溶液(pH2)组成的酸性媒介相接触。溶液可以是无机或有机酸如三氟乙酸的溶液。所得的提取物4℃30,000×g离心25分钟。
第三步(分馏)优选把提取物置于反相柱以进行固相提取。用稀释的酸溶液洗去水溶性分子,并用适当的洗脱剂洗脱疏水分子。用三氟乙酸洗涤,并用在稀酸溶液中含增加用量的乙腈为洗脱剂可得到良好的结果。
第四步(纯化)优选用与上一步相同或不同的适当的洗脱剂进行。
在位置4,10,16和20上没有检测到信号(Edman降解法)。通过质谱分析法显示出在这些位置上存在有半胱氨酸,因此所得的结构如下:
所测得的上述androctonine的分子量分别是:
3076.65±0.24Da
但是,按照测序数据计算得到的分子量分别是:
3080.65±0.24Da
这种分子量之间的差异对应于两个分子内二硫桥的形成。
为了确定二硫桥的连接,用能够在赖氨酸后断裂肽链的一种酶,Lys-C蛋白内切酶切开分子。分离所得的肽,质谱分析表明它是由一个二硫桥连在一起的两段肽。所推导到的序列为Arg Ser Val Cys Arg Gln Ile Lys加上CysThr Asn Arg Asn Pro Tyr以及Lle Cys Arg Arg Arg Gly Gly Cys Tyr Tyr。
这些良好的相关性证实了所提议的序列。
本发明的肽也可毫无困难地依据第二种方法得到,先通过FMOC化学合成(Atherton和Shppard R.C.(1989),Solid Phase Peptide Synthesis(1RL,Oxford UK)),然后在室温下于pH8.5的100毫摩尔/升的乙酸铵溶液搅拌24小时以复性。所得的androctonine具有与天然分子同样的色谱特性,并且二硫桥的连接也与天然分子相同。复性后测得的分子量(3076.61±067)与天然分子非常近似。
合成的分子具有与天然分子一样的对细菌Micrococcus Liteus的抗菌活性。
所有的抗菌和溶血测试都是用合成分子进行的。
1.Androctonine对猪和牛的血红细胞没有溶血效应。
2.这些分子对格兰氏阴性和格兰氏阴性细菌(见表1),致病性细菌及致病性真菌有抗菌特性。
下面的实施例说明了肽的制备和抗菌性,以及本发明的组合物。
实施例1:肽的分离和检定
此方法按照以下步骤进行:
提取和纯化:
通过切开表皮取得血淋巴(3.8毫升)。然后转移到保持冷冻的含有蛋白酶抑制剂(抑蛋白酶肽)的试管中,然后在4℃,30,000×g下离心25分钟。由此所得的上清液立刻进行各纯化步骤。
提取物在Sep-Pak C18柱上的分馏
把提取物沉积到Sep-Pak C18柱上以后,用以0.5%三氟乙酸(TFA)酸化过的5毫升水简单地洗涤就可去除亲水性的分子。
用在酸化水(0.05%TFA,每柱5毫升)的10,40和80%的乙腈洗脱疏水分子。
所收集的馏分被命名为“10%洗脱液”,“40%洗脱液”和“80%洗脱液”并真空浓缩。在HPLC分析之前,馏分用HPLC一级的水重建(reconstituted)。
具抗菌性分子的HPLC纯化
第一步:
在Aquapore OD 300 C18反相柱上,用在酸化水(0.05%TFA)中的2到52%的线性梯度的乙腈以1毫升/分的流速于90分钟(即每分钟增加0.44%的乙腈)的时间分析“40%洗脱液”馏分。
所得活性馏分在“高压惰性”(HPI)Delta Pak C18柱(150*3.9毫米)上纯化。
洗脱以在酸化水(6毫摩尔/升HCl)中的2到11%的时间10分钟和从11到21%的时间50分钟,流速为1毫升/分的线性双相梯度的乙腈进行。活性馏分的纯度控制通过在以Edman降解法和质谱分析确定序列之前的毛细管电泳进行。
实施例2:体外试验:显微分光光度法测定抗菌活性
所用纯化的各菌(E.Coli;M.Luteus),分离柱悬浮于10毫升DIFCO PB培养基(Poor-Brooth,无酵母提取物Luria Bertani培养基)上并在30℃缓慢搅拌过夜培养。
使待测细菌在新鲜培养基上达到光密度600纳米为0.001。把10微升的每种馏分沉积到有100微升菌悬液的微滴定板上。在25℃培养24小时之后,用微滴定板读数器测定600纳米的吸光度以确定生长。
在这些条件下,观察以微摩尔/升表示的如下表所示的浓度的50%抑制:
表1
用同样的方式,但用不同的致病细菌,得到下述结果:
格兰氏+/- | Androctonine最小抑菌浓度(微摩尔/升) | |
细菌 | ||
藤黄微球菌 | + | 0.6-1.5 |
浅绿气球菌 | + | 0.3-0.6 |
枯草芽孢杆菌 | + | 1.5-3.0 |
金黄色葡萄球菌 | + | 15-30 |
密执安棍状杆菌 | + | 6-15 |
大肠杆菌D22 | - | >30 |
大肠杆菌D31 | - | 3-6 |
大肠杆菌1106 | - | 6-15 |
鼠伤寒沙门氏菌 | - | 3-6 |
表2
用同样的方式,但用不同的致病真菌,得到以下结果:
Androctonine最小抑菌浓度(微摩尔/升) | |
细菌 | |
密执安棍状杆菌 | 6-15 |
丁香假单胞菌 | 0.5-1 |
丁香假单胞菌丁香致病变种 | 15-22 |
豌豆绿细菌 | 6-15 |
斑生假单胞菌 | 3-6 |
Pseudomonas Valerianella | 15-22 |
丁香假单胞菌菜豆致病变种 | 2-4 |
野油菜黄单胞菌野油菜致病变种 | 3-6 |
疱病黄单胞菌687.3 | 1.5-3 |
疱病黄单胞菌B229RI | 1.5-3 |
菜豆黄单胞菌 | 1-2 |
表3
Androctonine最小抑菌浓度(微摩尔/升) | ||
真菌 | 无盐 | 有盐* |
胡萝卜链格孢 | 4.1-8.2 | 16-32 |
匍柄霉属 | 4-8 | 16-32 |
番茄夹孢镰孢(Fusariumoxysporum L) | 2-4 | >32 |
Verticilium toreillis | 2-4 | >32 |
Botrytis petuniae | 4-8 | >32 |
Fusarium oxysporum meloni | 2-4 | - |
*培养基补以1毫摩尔/升的CaCl2和20毫摩尔/升的KCl
在能够利用本发明的化合物进行的抗细菌处理的作物中,可以提到,例如水稻,禾谷类,尤其是小麦和大麦,以及造林的、结果的和结荚的植物。
在能够应用本发明的化合物进行抗真菌处理的作物中,可以提到,例如葫芦科,花卉作物,以及商品园艺作物(胡萝卜,土豆,圆白菜)。
这些结果表明了本发明的肽具有优良的抗菌性,它可适用于人类,动物以及植物上。
本发明的主题还有组合物,它可用作抗菌剂,它含有上述的本发明的一种(或几种)化合物作为活性物质,它与农业上许可的载体以及同样是农业上许可的表面活性剂混在一起。尤其是可以使用普通的惰性载体和普通的表面活性剂。这些组合物不仅包括适于用适当设备,例如喷雾器施用到待处理作物上的组合物,还包括在施用到作物上之前必须稀释的浓缩的商品组合物。
这些组合物还可包括其它任何成分,例如保护性胶体,粘胶剂,加厚剂,触变剂,渗透剂,稳定剂,螯合剂等。更一般地,本发明应用的化合物可与常规配制技术中的任何固体或液体添加剂结合。
一般地,本发明的组合物常包含大约005%到95%(重量比)的本发明的化合物(在下文中指的是活性物质),一种或几种固体或液体载体,以及任选的一种或几种表面活性剂。
本说明书中,“载体”这个术语指的一种天然或合成的,有机或无机的物质,它与化合物结合以便于施用到植物,种子或土壤上。因此这种载体一般是惰性而且应该是农业上可接受的,尤其是对所处理植物而言。这种支持物可以是固体(粘土,天然或合成的硅酸盐,硅石,树脂,蜡,固体肥料,等等)或者液体(水,醇,尤其是丁醇,等等)。
表面活性剂可以是乳化剂,分散剂,或离子型或非离子型的湿润剂或是这些表面活性剂的混合物。可以提到,例如,聚丙烯酸盐,木素磺酸盐,苯酚磺酸或萘磺酸盐,环氧乙烷与脂肪醇或脂肪酸或脂肪胺的缩聚物,取代的酚(尤其是烷基酚或芳基酚),硫代琥珀酸酯的盐,牛磺酸衍生物(尤其是烷基牛磺酸盐),醇或酚的聚氧乙烯化磷酸酯,多羟基化合物的脂肪酸酯,包含上述化合物的硫酸盐、磺酸盐和磷酸盐官能的衍生物。当化合物和/或惰性载体是非水溶性的而所应用的媒介物是水时,至少一种表面活性剂的存在通常是必需的。
因此,本发明用于农业的组合物可包含在从0.05%到95%(重量比)的相当宽的范围的本发明的活性物。其表面活性剂的重量含量在5%到40%之间是有利的。
本发明的这些组合物本身可以是很多种形式的固体或液体。
作为固体组合物形式,可以提到撒粉的粉末(化合物含量可高达100%)和颗粒,尤其是通过挤出,压紧,浸渍颗粒载体或粉末的成粒作用(在后一种情况中,这些颗粒的化合物含量在0.5%到80%之间)而得到的颗粒,以及起泡的片剂或锭剂。
本发明的肽可以以撒粉的粉末应用;也可应用由50克活性物质和950克滑石组成的混合物;还可应用包含20克活性物质,10克研细的硅石,以及970克滑石的组合物;混合并研磨这些组分,组合物以撒粉施用。
作为液体组合物的形式或在施用时要配成液体混合物的形式,可以提到溶液,尤其是水溶性浓缩物,可乳化的浓缩物,乳浊液,浓缩的悬浮液,气溶胶,可湿粉末(或用于喷雾的粉末),浆糊和凝胶。
可乳化或可溶的浓缩物常常包含10到80%的活性物质,而适于施用的乳浊液或溶剂包含0.001到20%的活性物质。
除了溶剂,只要有必要,可乳化的浓缩物可包含2到20%的适当的添加剂,例如上述的稳定剂,表面活性剂,渗透剂,腐蚀抑制剂,染色剂或者粘合剂。
使用这些浓缩剂,以水稀释可得到任何所想要的浓度的乳浊液,这些乳浊液尤其适于作物施用。
一些可乳化的浓缩剂的组合物以例子的形式在下文中给出:
EC(可乳化浓缩剂)实施例1:
-活性物质 400克/升
-碱性十二烷基苯磺酸盐 24克/升
-由10个分子环氧乙烷
氧乙烯化的壬基酚 16克/升
-环己酮 200克/升
-芳香溶剂 足1升
根据另一种可乳化的浓缩物的配方,下面是所用的:
EC(可乳化浓缩物)实施例2:
-活性物质 250克
-环氧化植物油 25克
-烷基芳基磺酸盐与聚乙二醇脂肪醇醚的混合物 100克
-diAndhylformamide 50克
-二甲苯 575克
为了得到不会沉积的稳定的流体产品,制备浓缩的悬浮液,它也可应用于喷雾,它们常包含10到75%的活性物质,0.5到15%的表面活性剂,0.1到10%的触变剂,以及0到100%的适当的添加剂,如防沫剂,腐蚀抑制剂,稳定剂,渗透剂及粘合剂,以及作载体的水或有机液体,在其中活性物质仅仅是微溶或不溶的:特定的固体有机物或无机盐可溶于载体以帮助防止沉淀,或作为水的防冻剂。
作为实例,这是一个浓缩的悬浮液的组合物:
CS(浓缩的悬浮液)实施例1:
-活性物质 500克
-聚乙氧基化的三苯乙烯酚磷酸盐 50克
-聚乙氧基化的烷基酚 50克
-聚羧酸钠 20克
-1,2-亚乙基二醇 50克
-有机多分子硅醚油(防沫剂) 1克
-多糖 1.5克
-水 316.5克
可湿粉末(或用于喷雾的粉末)制备时一般包含20到95%的活性物质,除了固体载体外,它们一般还包含0到30%的湿润剂,3到20%的分散剂,必要时,还有0.1到10%的一种或更多的稳定剂和/或其它添加剂,例如渗透剂,粘合剂,防结块剂,染色剂,等等。
为了得到用于喷雾的粉末或可湿粉末,把活性物质与添加物在适当的混合器中密切混合,并在磨中或其它适当的研磨器中研磨。用于喷雾的粉末因而具有便利的可湿性及悬浮形式;它们可以任何想要的浓度悬浮于水中,这些悬浮液可以非常便利地施用,尤其是应用于植物叶片上。
可用浆糊代替可湿粉末。制备和应用这些浆糊的条件和方法与那些可湿粉末或用于喷雾的粉末相似。
作为实例,这里是可湿粉末的不同组合物(或用于喷雾的粉末):
WP(可湿粉末)实施例1:
-活性物质 50%
-乙氧基化的脂肪醇(湿润剂) 2.5%
-乙氧基化的苯乙基酚(分散剂) 5%
-白垩(惰性载体) 42.5%
WP(可湿粉末)实施例2:
-活性物质 10%
-支链型的合成C13氧代醇,
被8到10[lacuna]个环氧乙烷乙氧基化(湿润剂) 0.75%
-中性的木素磺酸钙(分散剂) 12%
-羧酸钙(惰性填充剂) 足 100%
可湿粉末实施例3:
这处可湿粉末包含与上述实施例相同的成分,比例如下:
-活性物质 75%
-湿润剂 1.50%
-分散剂 8%
-羧酸钙(惰性填充剂) 足 100%
可湿粉末实施例4:
-活性物质 90%
-乙氧基化的脂肪醇(湿润剂) 4%
-乙氧基化的苯乙基酚(分散剂) 6%
可湿粉末实施例5:
-活性物质 50%
-阴离子型和非离子型表面活性剂的混合物 2.5%
-木素磺酸钠(分散剂) 5%
-高岭粘土(惰性载体) 42.5%
水的乳浊液或悬浮液,例如通过把本发明的可湿粉末或可乳化的浓缩物用水稀释所得的组合物,都包括在本发明的一般范围之内。乳浊液可以是油包水或水包油型的,并且它们可以有“蛋黄酱(mayonnaise)”式的厚稠度。
本发明的化合物可以配制成水可分散性颗粒的形式,它也包括在本发明的范围之内。
这些可分散性的颗粒其表观密度一般在0.3到0.6之间,颗粒大小一般在150到2000微米之间,优选300到1500微米。
这些颗粒的活性物质的含量一般在1%至90%之间,优选25%到90%。
颗粒的其它部分基本上由固体填充剂和任选的给予颗粒水分散性的表面活性剂配料组成。这些颗粒根据所选的填充剂是否溶于水而分成明显的两种类型。当填充剂是溶于水的时候,它可以是无机的或者优选有机的。用尿素可得到非常好的结果。在非水溶性的填充剂的情况下,优选无机的,例如高岭土或膨润土。然后它可以便利地和表面活性剂(以颗粒重量的2到20%的比例)用在一起,其中超过一半以上包含例如至少一种分散剂,它一般是阴离子型的,例如碱金属或碱土金属聚萘磺酸盐或碱金属或碱土金属木素磺酸盐,其余由非离子型或阴离子型的湿润剂,例如碱金属或碱土金属烷基萘磺酸盐组成。
另外,虽然并非必需,但也可加入其它添加剂,例如防沫剂。
本发明的颗粒可以按此方法制备,先把必要成份混在一起,然后再用已知的几种技术进行颗粒化(混合器,流化床,雾化器,挤压,等等)。
颗粒优选通过挤压得到,方法如以下实施例说明。
DG1实施例:可分散颗粒
在混合器中混合占重量90%的活性物质及10%的尿素颗粒。然后在旋转磨上研磨混合物。所得的粉末用占重量8%的水湿润。用带孔滚筒的挤压器挤压湿粉。然后粉碎筛选所得的颗粒,以仅仅保留颗粒大小在150到2000微米之间的颗粒。
DG2实施例:可分散颗粒
把以下成分在混合器中混在一起:
-活性物质 75%
-湿润剂(烷基萘磺酸钠) 2%
-分散剂(聚萘磺酸钠) 8%
-水不溶性惰性填充剂(高岭土) 15%
在有水存在的情况下在流化床中粒化混合物,然后干燥,粉碎筛选,以得到颗粒大小在0.15到0.80毫米之间的颗粒。
这些颗粒可单独使用,或溶于水或悬浮于水以得到所要的剂量。它们也可与其它活性物质优选抗菌剂一起制备混合物,后一种为可湿粉剂或水悬浮液或颗粒。
作为适于保存和运输的组合物,它们含有0.5到95%的活性物质是更加便利的。
本发明还涉及通过给予有效剂量的本发明的肽对人或动物所进行的治疗性的抗菌处理的方法,以自由的形式,或当适当时以与酸的加成盐,Andallic盐的形式,或药学允许的碱的加成盐形式,可以是纯的,或者是它与其它药学允许的产品组合成的混合物,这种产品可以是惰性的或是有生理活性的。本发明的药剂给药可以是经口的,肠胃外的,直肠的或局部的。
片剂,药丸,粉末(尤其在明胶胶囊中或扁囊剂)或颗粒都可用作经口服用的固体组合物。在这些组合物中,本发明的活性产品与一种惰性稀释剂混合,例如淀粉,纤维素,蔗糖,乳糖或硅石。这些组合物也可含有其它物质,例如一种或更多的润滑剂,例如硬脂酸镁或滑石,染料,包衣(糖衣片)或釉。
药物学允许的溶液,悬浮液,乳浊液,糖浆和含有惰性稀释剂如水,乙醇,甘油,植物油或液体石蜡的酏剂都可用作经口给药的组合物。这些组合物也可包括其它物质,例如湿润品,增甜剂,增稠剂,矫味剂或稳定剂。
肠胃外给药的无菌组合物优选乳浊液,悬浊液或水或非水溶液。水,丙二醇,聚乙二醇,植物油,尤其是橄榄油,以及适当的有机酯都可用作溶剂或载体。这些组合物可含辅助剂,尤其是湿润剂,张度剂,乳化剂,分散剂和稳定剂。其灭菌可通过不同方法,例如无菌过滤,在组合物中加入灭菌剂,照射或加热而进行。它们可以制备成无菌固体组合物,在给药时可溶解于可注射的无菌介质中。
通过直肠给药的组合物是栓剂或直肠胶囊,除活性肽外,它还包含赋形剂,例如可可脂,半合成的甘油酯或聚乙二醇。
通过局部给药的无菌组合物可以是,例如乳膏,软膏,洗剂,滴眼剂,口腔洗剂,点鼻剂或气雾剂。
人类治疗中,本发明的肽在抗菌处理中尤其有用。其剂量依赖于所需的效果和处理所持续的时间;成人经口途径给药时一般是每天50和1000毫克,以一剂或多剂药摄入。
一般而言,医生会确定他/她所认为的最恰当的剂量,这决定于待治疗者的年龄和体重以及所有其它个人因素。
下面所给出的实施例没有任何暗含的限制,它说明了本发明的组合物。
实施例A:
按常规技术制备具有下述成分的含有50毫克剂量的活性肽的片剂:
-androctonine肽M1 50毫克
-淀粉 60毫克
-乳糖 50毫克
-硬脂酸镁 2毫克
实施例B:
制备具有下述成份的含有20毫克活性肽的可注射的溶液:
-androctonine肽M2 22.4毫克
-无菌水 足量 2立方厘米(毫升)
Claims (10)
2.一种抗菌组合物,它含有如权利要求1中的肽作为活性物质。
3.如权利要求2的组合物,可用于防治植物病原性细菌。
4.如权利要求2的组合物,它可用于人类或动物体的治疗处理。
5.一种抗真菌组合物,它含有如权利要求1中的肽作为活性物质。
6.如权利要求5的组合物,它可用于防治植物病原细菌。
7.如权利要求5的组合物,它可用于人类或动物体的治疗处理。
8.一种用于植物细菌疾病防治的方法,其中如权利要求1的肽用作活性物质。
9.一种用于植物真菌疾病防治的方法,其中如权利要求1的肽用作活性物质。
10.一种制备如权利要求1的肽的方法,其中依次进行以下各步:
a)从蝎子Androctonus australis中取得血淋巴;
b)把上述Androctonus australis的血淋巴或含血淋巴的研磨物与酸性或中性介质接触并搅拌,然后离心进行提取;
c)以在分离柱上用适当的成分洗涤亲水分子和洗脱疏水分子的分离来分馏上清液;
d)纯化提取物;
e)进行测序。
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CN101063103B (zh) * | 2007-04-26 | 2010-05-19 | 武汉大学 | 一种海南斑等蝎抗菌肽及制备方法和应用 |
AR074941A1 (es) | 2009-01-07 | 2011-02-23 | Bayer Cropscience Sa | Plantas transplastomicas exentas de marcador de seleccion |
EP2531601B1 (en) | 2010-02-02 | 2016-11-16 | Bayer Intellectual Property GmbH | Soybean transformation using HPPD inhibitors as selection agents |
CU24055B1 (es) * | 2010-09-27 | 2014-12-26 | Grupo Empresarial De Producciones Biofarmacéuticas Y Químicas Labiofam | Composiciones farmacéuticas de veneno de escorpión rhopalurus junceus |
CN105254722B (zh) * | 2015-11-03 | 2019-01-25 | 南京农业大学 | 一种抗菌肽fk及其制备方法和应用 |
US11174288B2 (en) | 2016-12-06 | 2021-11-16 | Northeastern University | Heparin-binding cationic peptide self-assembling peptide amphiphiles useful against drug-resistant bacteria |
FR3071505B1 (fr) | 2017-09-22 | 2022-04-08 | Capsum | Capsules bactericides ou bacteriostatiques ou antifongiques comprenant des cellules vivantes et leurs utilisations |
WO2022215495A1 (ja) * | 2021-04-08 | 2022-10-13 | 株式会社カネカ | 環状リポペプチド化合物のバイオバーデンの低減方法 |
WO2024141638A1 (en) * | 2022-12-30 | 2024-07-04 | Biotalys NV | Self-emulsifiable concentrate |
-
1996
- 1996-02-16 FR FR9602168A patent/FR2745004B1/fr not_active Expired - Fee Related
-
1997
- 1997-02-17 EA EA199800731A patent/EA000843B1/ru not_active IP Right Cessation
- 1997-02-17 KR KR1019980706334A patent/KR19990082596A/ko active IP Right Grant
- 1997-02-17 CA CA002245518A patent/CA2245518A1/fr not_active Abandoned
- 1997-02-17 EP EP97905217A patent/EP0882063A2/fr not_active Withdrawn
- 1997-02-17 TR TR1998/01582T patent/TR199801582T2/xx unknown
- 1997-02-17 AU AU18843/97A patent/AU722891B2/en not_active Ceased
- 1997-02-17 JP JP9529059A patent/JP2000505440A/ja active Pending
- 1997-02-17 BR BR9707292A patent/BR9707292A/pt not_active IP Right Cessation
- 1997-02-17 IL IL12577897A patent/IL125778A/en not_active IP Right Cessation
- 1997-02-17 PL PL97328579A patent/PL328579A1/xx unknown
- 1997-02-17 HU HU9900935A patent/HUP9900935A3/hu unknown
- 1997-02-17 CN CN97193823A patent/CN1216047A/zh active Pending
- 1997-02-17 US US09/125,234 patent/US6127336A/en not_active Expired - Fee Related
- 1997-02-17 WO PCT/FR1997/000295 patent/WO1997030082A2/fr not_active Application Discontinuation
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2000
- 2000-03-13 US US09/524,675 patent/US6331522B1/en not_active Expired - Fee Related
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103421100A (zh) * | 2012-05-22 | 2013-12-04 | 中国科学院动物研究所 | 一种抗菌肽及其制备方法和应用 |
CN103421100B (zh) * | 2012-05-22 | 2015-11-18 | 中国科学院动物研究所 | 一种抗菌肽及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
WO1997030082A2 (fr) | 1997-08-21 |
AU1884397A (en) | 1997-09-02 |
TR199801582T2 (xx) | 1998-11-23 |
FR2745004B1 (fr) | 1998-03-27 |
BR9707292A (pt) | 1999-07-20 |
US6127336A (en) | 2000-10-03 |
CA2245518A1 (fr) | 1997-08-21 |
US6331522B1 (en) | 2001-12-18 |
PL328579A1 (en) | 1999-02-01 |
WO1997030082A3 (fr) | 1997-09-25 |
EA199800731A1 (ru) | 1999-02-25 |
AU722891B2 (en) | 2000-08-10 |
KR19990082596A (ko) | 1999-11-25 |
HUP9900935A3 (en) | 2001-08-28 |
FR2745004A1 (fr) | 1997-08-22 |
JP2000505440A (ja) | 2000-05-09 |
EP0882063A2 (fr) | 1998-12-09 |
IL125778A (en) | 2001-05-20 |
HUP9900935A2 (hu) | 1999-07-28 |
EA000843B1 (ru) | 2000-04-24 |
IL125778A0 (en) | 1999-04-11 |
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