CN1070865C - 抑制胃蛋白酶释放的肽 - Google Patents
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Abstract
来自SorbineC端序列并含有至少一个D构型氨基酸的肽,其可抑制胃蛋白酶的释放,因而尤其可用于治疗溃疡和食管炎。本发明还涉及本发明肽的盐和取代衍生物,以及含有它们的药物组合物。
Description
本发明涉及能够抑制胃蛋白酶释放的肽,这种肽的取代衍生物和盐,以及含有这种肽的药物组合物。这些肽可用于治疗与胃蛋白酶释放有关的疾病,特别是用于治疗溃疡或食管炎。
最近,从猪肠中分离到一种新肽,这种肽被称为sorbine,含有153个天然氨基酸(WO89/06241)。sorbine及其C-端肽片段(最多含40个氨基酸)能够促使粘膜吸收过程加快。但通过插入至少一个D构型氨基酸残基修饰这些肽片段,意外地赋予了这些修饰的肽类似物另一生物活性:它们抑制胃蛋白酶的释放,这是未修饰的肽所不具有的生物活性。
在某些情形下这一活性是特别有意义的。实际上,哺乳动物胃分泌的一般机制现在是已知的。胃消化是酶、盐酸和胃蛋白酶的作用结果。胃蛋白酶是一种蛋白质;与胃泌素一样是胃液的主要成分。它的主要生理作用是启动蛋白质的消化。但许多研究已表明胃蛋白酶在溃疡形成中的显著作用。因而在某些情况下希望至少部分抑制胃蛋白酶的释放。
本发明涉及通式I的肽:
A1-A2-A3-X IA1代表L-Thr或D-Thr残基;或下列序列之一且其中至少一个氨基酸残基可以是D构型:Val-Thr,Pro-Val-Thr,Arg-Pro-Val-Thr,Glu-Arg-Pro-Val-Thr,His-Glu-Arg-Pro-Val-Thr,Gln-His-Glu-Arg-Pro-Val-Thr,Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Lys-Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Gly-Lys-Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Pro-Gly-Lys-Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr或Glu-Pro-Gly-Lys-Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr;A2代表序列Lys-Pro-Gln-Ala且其中至少一个氨基酸残基可以是D构型;A3代表一共价键或肽序列-Gly-A4-A5,其中A4和A5每个独立地代表碱性氨基酸残基;及X代表羟基;氨基;烷基氨基,所述式Ⅰ肽的特征在于它含有至少一个D构型氨基酸残基。
本发明还涉及通式Ⅰ肽的取代衍生物,其中一个或多个氨基酸残基被一个或多个通常用于生物用途肽的化学中的保护基所取代;当使用多个保护基时,它们不必相同。优选地,这些保护基选自低级烷基如甲基或叔丁基;苯基;苄基或取代苄基如三甲氧基苄基;2-氯苄氧羰基;9-芴基甲氧羰基;叔丁氧羰基;乙酰基;磺酰基;及磷酰基。
本发明还涉及含有氨基酸序列A1-A2-A3的肽,其中A1、A2和A3如上所定义。
本发明还涉及如上所定义肽的药学上可接受的盐。这些盐可以是与有机酸如乙酸、乳酸、棕榈酸(pamoique)、马来酸、柠檬酸、苹果酸、抗坏血酸、苯甲酸、水杨酸、琥珀酸、甲磺酸、甲苯磺酸,与无机酸如盐酸、硫酸或磷酸,或与聚合物酸如丹宁酸或羧甲基纤维素所成的盐。
当存在于本发明肽中时,A4和A5独立地代表D或L构型的碱性氨基酸残基。优选A4和A5独立地代表Lys、D-Lys、Arg或D-Arg氨基酸残基。
如上文所提及的那样,本发明的肽含有一个或多个D构型的氨基酸残基。本发明更特别涉及含有一个D构型氨基酸残基的肽,所述肽可以被本发明中所定义的保护基所取代。对这些肽可举出下列实例:Thr-Lys-Pro-Gln-D-Ala-NH2,Thr-Lys-Pro-Gln-D-Ala-Gly-Lys-Lys-NH2,Thr-(乙酰)Lys-Pro-Gln-D-Ala-NH2,Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2,Pro-D-Val-Thr-Lys-Pro-Gln-Ala-NH2,Pro-Val-Thr-Lys-Pro-Gln-Ala-Gly-Arg-D-Arg,Pro-Val-Thr-(乙酰)Lys-Pro-Gln-D-Ala-NH2,D-Pro-Val-Thr-Lys-Pro-Gln-Ala-NH2,His-Glu-Arg-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2,Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2和Glu-Pro-Gly-Lys-Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr-Lys-pro-Gin-D-Ala-NH2.
D-构型的氨基酸残基优选位于C-末端或N-末端。在C-末端位置含有D构型氨基酸残基的优选肽是那些其中A2代表Lys-Pro-Gln-D-Ala及A3代表一共价键的肽。在N-末端位置含有D构型氨基酸残基的优选肽是那些其中A1代表D-Thr或如上所定义序列且该序列N-末端位氨基酸为D-构型的肽。
本发明还特别涉及含两个D构型氨基酸残基的肽,所述肽可以被本发明中定义的保护基所取代。对这些肽可举出以下实例:D-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2,D-Pro-Val-Thr-Lys-Pro-Gln-Ala-Gly-D-Lys-Lys-NH2,Pro-D-Val-Thr-Lys-Pro-Gln-D-Ala-NH2和,D-Pro-Val-Thr-(乙酰)Lys-Pro-Gln-D-Ala-NH2.
含两个D构型氨基酸残基的肽优选在C-末端位有一个D-构型氨基酸残基。第二个氨基酸残基可位于肽链上任何地方,但优选位于肽的N-末端。优选的肽是其中A1代表D-Thr或如上定义的序列且该序列N-末端的氨基酸残基为D构型、A2代表Lys-Pro-Gln-D-Ala、A3代表-共价键的肽。这种肽优选被一个或多个保护基取代,特别是被乙酰基这一保护基在Lys残基上取代。
本发明的肽可以按肽合成领域中已知的经典方法制备。例如,可按下述方案在固相中有利地进行合成:肽链形成的开始是将肽链C末端第一个氨基酸借助其羧基固定在一种树脂上;其胺功能团用诸如叔丁氧羰基(Boc)的保护基保护。固定C末端第一个氨基酸以后,用酸洗树脂将胺功能团脱保护。在用Boc基团保护时,可用三氟乙酸洗涤来脱保护。然后其胺功能团被保护的第二氨基酸通过其羧基功能团与肽链C-末端第一个氨基酸的脱保护胺功能团偶联。优选在诸如二环已基碳化二亚胺或二异丙基碳化二亚胺的偶联剂存在下进行偶联。这样形成的肽链含有两个氨基酸,其末端胺功能团被保护。如前法将此末端胺功能团去保护,然后可以安装第三个氨基酸。通过这样一个接一个地安装氨基酸就得到了所希望的肽链。除去所有保护基后将肽从树脂上解离。
下面简要描述本发明一种肽即Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2的合成。通过适当改变以下的肽合成方法可以制备本发明的其他肽,这是本领域技术人员能够做到的。
该合成在室温下固相中进行。所用操作方法包括以下步骤:脱保护、中和和偶联。所用树脂是用1%二乙烯苯交联的聚苯乙烯型(Merrifield树脂)。在甲苯和二甲基甲酰胺(DMF)中在碳酸铯存在下将Boc-D-Ala固定在Merrifield树脂上。所用氨基酸的末端胺功能团被Boc基团保护。该Boc基团用三氟乙酸去除,随后用二氨甲烷和异丙醇洗涤多次。氨基基团用三乙胺中和,然后洗涤多次。苏氨酸和缬氨酸在偶联前在二异丙基碳化二亚胺(DIPCDI)存在下转化为羟基苯并三唑的酯,而谷氨酰胺在反应器中直接制成羟基苯并三唑酯。赖氨酸和两个脯氨酸在偶联前被转化为对称酸酐。这些氨基酸均在二异丙基乙基胺存在下进行偶联。赖氨酸的侧链用Fmoc基团保护,而苏氨酸的侧链不保护。最后一个偶联完成后,在去除脯氨酸N-末端胺功能团的Boc基团前,在二甲基甲酰胺中用哌啶去除Fmoc基团。在甲醇/DMF混合物中用氨处理后从树脂上解离肽。随后纯化这样得到的粗产物。
本发明还涉及含有作为活性成分的有效量的至少一种如上定义的式Ⅰ肽、如上定义的这种肽的取代衍生物、或包含如上所定义A1-A2-A3氨基酸序列的肽,以及与其结合的药学上可接受稀释剂或载体的药物组合物。
本发明的肽可经口服、静脉内、胃肠外、皮下、腹膜内或肌内途径给药。
根据所选择的给药方式,所述药物组合物可呈胶囊、片剂、冻干品或液体形式。该药物组合物还可以呈缓释制剂形式。
口服时,本发明肽对人的给药剂量可为5-100μg/kg/日。
静脉内或皮下给药时,本发明化合物对人的给药剂量可为1-12μg/kg,每天1-3次。在动物中,一次大量给药数天后在机体中还能检出大量化合物,尤其是肽Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2的检出量大于10%。毒性
在大鼠和狗体内研究了亚急性毒性。以高达4000μg/kg/天的剂量给药后,4周内没有观察到任何毒性症状和任何突变能力的迹象。在人体中,皮下注射或静脉注射200μg/kg的剂量不会引起任何生物的、临床的或病理的异常。药理
通过以下试验来确定本发明化合物的治疗益处。
通过测定所诱生的胃分泌体积来测量胃反应强度。
在全身麻醉下对猫进行手术:手术使胃分成两部分:所谓的Heidenheim袋和胃瘘。将这两个胃袋朝外引流以在刺激后的基础期同时收集分泌的盐酸、胃蛋白酶和胃液。具有长久胃瘘的猫每周可以接受几次试验,而且以其本身作为对照。在2小时内以2-4μg/kg/h的速度向活动物体内输注五肽胃泌素(PG)和VIP(血管活性肠肽)来刺激胃蛋白酶的分泌。
用五肽胃泌素和VIP刺激后1小时,将本发明肽以100pmol/kg/h剂量加入输注液中。
在输注前30分钟到输注结束期间记录胃液的体积。
用一种蛋白水解分光光度法估测胃液(尽可能均匀)中胃蛋白酶的量。
9-12次试验所得结果列在下表中:胃蛋白酶的分泌以mg/15分钟表示,基础分泌期为2个15分钟时间段的平均值,刺激分泌期为6个15分钟时间段的平均值。
含至少一个D型氨基酸残基的本发明某些肽与其其中所有氨基酸残基均为L构型的类似物进行了比较
表1本发明肽的活性pD1:Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2与其类似物P1Pro-Val-Thr-Lys-Pro-Gln-Ala-NH2.的比较
VIP+PG | VIP+PG+P1 | VIP+PG+pD1 | |
1号猫2号猫3号猫1号猫2号猫3号猫1号猫2号猫3号猫1号猫2号猫3号猫 | 1.7751.3162.0491.8523.3344.0102.5202.4094.2771.7501.5564.442 | 0.9521.3671.6802.9932.4185.3921.7292.4033.989--- | 0.9261.7111.8462.0822.1573.9321.4561.5163.891--- |
均值标准差 | 2.6070.323n=12 | 2.5470.468n=9 | 2.1690.351n=9 |
表2本发明肽的活性pD2:D-Pro-Val-Thr-Lys-Pro-Gln-Ala-NH2,pD3:Pro-Val-Thr-(乙酰)Lys-Pro-Gln-D-Ala-NH2pD4:D-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2.
VIP+PG | VIP+PG+pD2 | VIP+PG+pD3 | VIP+PG+pD4 | |
1号猫2号猫3号猫4号猫5号猫6号猫7号猫8号猫9号猫10号猫 | 6.7274.7734.3242.4583.7443.2762.7083.9910.3845.184 | 2.6892.0072.5762.0762.6891.1432.4093.1721.0363.164 | 2.3171.8600.8911.7252.6302.2171.8994.3210.7383.811 | 4.4272.9992.8983.7803.7403.1472.4523.9960.2363.362 |
均值标准差 | 3.7570.544n=10 | 2.296**0.235n=10 | 2.241**0.358n=10 | 3.1040.368n=10 |
表3本发明肽的活性pD5:Pro-D-Val-Thr-Lys-Pro-Gln-Ala-NH2,pD6:Pro-D-Val-Thr-Lys-Pro-Gln-D-Ala-NH2pD7:D-Pro-Val-Thr-(乙酰)Lys-Pro-Gln-D-Ala-NH2.
VIP+PG | VIP+PG+pD5 | VIP+PG+pD6 | VIP+PG+pD7 | |
1号猫2号猫3号猫4号猫5号猫6号猫7号猫8号猫9号猫10号猫 | 6.7274.7734.3242.4583.7743.2762.7083.9910.3845.184 | 4.2632.4351.3173.1912.7273.4862.6342.8521.1323.804 | 2.4802.5442.5893.1104.1421.7102.3704.1651.6932.931 | 2.1632.9951.4412.8341.2362.0472.5443.9711.5203.402 |
均值标准差 | 3.7570.544n=10 | 2.7840.315n=10 | 2.7730.270n=10 | 2.4150.284n=10 |
表4本发明肽的活性pD8: His-Glu-Arg-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2.pD9: Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2pD10: Glu-Pro-Gly-Lys-Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2.
VIP+PG | VIP+PG+Pd8 | VIP+PG+pD9 | VIP+PG+pD10 | |
1号猫2号猫3号猫4号猫5号猫6号猫7号猫8号猫9号猫 | 3.8321.8262.1322.8912.0423.2504.0144.2803.273 | 3.1172.7301.6901.7252.0761.3582.4522.6892.920 | 2.4091.4401.9642.2591.2301.5802.4882.4263.790 | 2.6911.7642.5202.4102.8332.8771.7262.0151.953 |
均值标准差 | 3.1710.313n=9 | 2.306*0.206n=9 | 2.176*0.254n=9 | 2.310*0.151n=9 |
表5本发明肽的活性pD8:His-Glu-Arg-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2与其类似物P8 His-Glu-Arg-Pro-Val-Thr-Lys-Pro-Gln-Ala-NH2.的比较
VIP+PG | VIP+PG+P8 | VIP+PG+pD8 | |
1号猫2号猫3号猫4号猫1号猫2号猫3号猫4号猫5号猫 | 4.3854.4603.0793.3333.4102.5102.7642.1914.908 | 3.6934.9153.3502.4423.8962.4321.6261.9255.012 | 2.7174.6302.1981.7462.2702.2452.4522.2472.739 |
均值标准差 | 3.4490.314n=9 | 3.2550.412n=9 | 2.583*0.274n=9 |
表6本发明肽的活性pD11: Thr-Lys-Pro-Gln-D-Ala-NH2pD12: Thr-(乙酰) Lys-Pro-Gln-D-Ala-NH2.
VIP+PG | VIP+PG+pD11 | VIP+PG+pD12 | |
1号猫2号猫3号猫4号猫5号猫6号猫7号猫8号猫9号猫 | 3.2173.7722.1666.5622.2902.0082.0342.548 | 3.4523.1143.3482.1812.2191.6383.2912.0760.850 | 2.6201.9254.0371.8963.5852.1920.6251.3391.385 |
均值标准差 | 3.1310.484n=9 | 2.4630.299n=9 | 2.178*0.364n=9 |
Claims (23)
1.通式Ⅰ的肽:
A1-A2-A3-X I其中A1代表L-Thr或D-Thr残基;或下列序列之一且其中至少一个氨基酸残基可以是D构型:Val-Thr,Pro-Val-Thr,Arg-Pro-Val-Thr,Glu-Arg-Pro-Val-Thr,His-Glu-Arg-Pro-Val-Thr,Gln-His-Glu-Arg-Pro-Val-Thr,Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Lys-Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Gly-Lys-Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr,Pro-Gly-Lys-Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr或Glu-Pro-Gly-Lys-Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr;A2代表序列Lys-Pro-Gln-Ala且其中至少一个氨基酸残基可以是D构型;A3代表一共价键或肽序列-Gly-A4-A5,其中A4和A5每个独立地代表碱性氨基酸残基;及X代表羟基;氨基;烷基氨基,所述式Ⅰ肽的特征在于它含有至少一个D构型氨基酸残基。
2.含有氨基酸序列A1-A2-A3的肽,其中A1、A2和A3如权利要求1中所定义,该肽含有至少一个D构型的氨基酸。
3.权利要求1或2的肽的取代衍生物,其中一个或多个氨基酸残基被一个或多个通常用于生物用途肽的化学中的保护基所取代;当有两上或更多个保护基时,它们不必相同。
4.权利要求3的肽,其至少含有一个被乙酰基保护的赖氨酸残基。
5.以上权利要求任一项的肽,其呈药学上可接受盐的形式。
6.权利要求1-5任一项的肽,其含有一个D构型的氨基酸残基。
7.权利要求6的肽,其D构型氨基酸残基位于C-末端或N-末端。
8.权利要求7的肽,其D构型氨基酸残基位于C-末端。
9.权利要求6-8任一项的肽,其中A2代表Lys-Pro-Gln-D-Ala,A3代表一共价键。
10.权利要求9的肽,它是式Thr-Lys-Pro-Gln-D-Ala-NH2或Thr-(乙酰)Lys-Pro-Gln-D-Ala-NH2的肽。
11.权利要求9的肽,它是式Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2或Pro-Val-Thr-(乙酰)Lys-Pro-Gln-D-Ala-NH2的肽。
12.权利要求9的肽,它是式His-Glu-Arg-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2的肽。
13.权利要求9的肽,它是式Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2的肽。
14.权利要求9的肽,它是式Glu-Pro-Gly-Lys-Ser-Ser-Ile-Leu-Gln-His-Glu-Arg-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2的肽。
15.权利要求7的肽,其D-构型氨基酸残基位于N-末端。
16.权利要求15的肽,其中A1代表D-Thr或如以上定义的一种序列且其中该序列N-末端位的氨基酸残基为D构型。
17.权利要求16的肽,它是式D-Pro-Val-Thr-Lys-Pro-Gln-Ala-NH2的肽。
18.权利要求1-15中任一项的肽,它含有两个D构型的氨基酸残基。
19.权利要求18的肽,其中一个D构型氨基酸残基位于C-末端位。
20.权利要求18或19的肽,其第二个D构型氨基酸残基位于肽的N-末端位。
21.权利要求20的肽,它是式D-Pro-Val-Thr-Lys-Pro-Gln-D-Ala-NH2的肽。
22.权利要求20的肽,它是式D-Pro-Val-Thr-(乙酰)Lys-Pro-Gln-D-Ala-NH2的肽。
23.一种药物组合物,其含有作为活性成分的有效量的权利要求1-22任一项的肽,以及与其配合的药学上所接受的稀释剂或载体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB9405162A GB9405162D0 (en) | 1994-03-16 | 1994-03-16 | Heptapeptides |
GB9405162.0 | 1994-03-16 |
Publications (2)
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CN1143968A CN1143968A (zh) | 1997-02-26 |
CN1070865C true CN1070865C (zh) | 2001-09-12 |
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CN95192125A Expired - Fee Related CN1070865C (zh) | 1994-03-16 | 1995-03-14 | 抑制胃蛋白酶释放的肽 |
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US (1) | US5668109A (zh) |
EP (1) | EP0750635B1 (zh) |
JP (1) | JP3109835B2 (zh) |
KR (1) | KR100359713B1 (zh) |
CN (1) | CN1070865C (zh) |
AP (1) | AP546A (zh) |
AT (1) | ATE174037T1 (zh) |
AU (1) | AU694476B2 (zh) |
BR (1) | BR9507063A (zh) |
CA (1) | CA2144569A1 (zh) |
DE (1) | DE69506390T2 (zh) |
DK (1) | DK0750635T3 (zh) |
DZ (1) | DZ1865A1 (zh) |
ES (1) | ES2127516T3 (zh) |
FI (1) | FI963615A (zh) |
FR (2) | FR2717390B1 (zh) |
GB (2) | GB9405162D0 (zh) |
GR (1) | GR3029513T3 (zh) |
IE (1) | IE950192A1 (zh) |
MA (1) | MA23481A1 (zh) |
NO (1) | NO316802B1 (zh) |
NZ (1) | NZ270704A (zh) |
OA (1) | OA10136A (zh) |
PL (1) | PL180672B1 (zh) |
RO (1) | RO112729B1 (zh) |
RU (1) | RU2144038C1 (zh) |
TN (1) | TNSN95019A1 (zh) |
TW (1) | TW380141B (zh) |
UA (1) | UA55369C2 (zh) |
WO (1) | WO1995025123A1 (zh) |
ZA (1) | ZA951923B (zh) |
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GB9405162D0 (en) * | 1994-03-16 | 1994-04-27 | Scras | Heptapeptides |
TW201318665A (zh) * | 2011-11-03 | 2013-05-16 | San Huei United Co Ltd | 摺疊式之立體口罩 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1989006241A1 (fr) * | 1988-01-08 | 1989-07-13 | Institut National De La Sante Et De La Recherche M | Sorbine et peptides derives, elevant l'absorption par les muqueuses |
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US3971736A (en) * | 1975-01-21 | 1976-07-27 | Merck & Co., Inc. | Cathepsin in D inhibitors |
FR2601020B1 (fr) * | 1986-07-03 | 1989-05-12 | Inst Nat Sante Rech Med | Sorbine purifiee, nouveaux peptides ayant des sequences peptidiques en commun avec la sorbine et compositions pharmaceutiques les contenant |
PT93320B (pt) * | 1990-03-02 | 1996-07-31 | Univ Tulane | Processo para a preparacao de peptideos terapeuticos |
GB9405162D0 (en) * | 1994-03-16 | 1994-04-27 | Scras | Heptapeptides |
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1994
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1995
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- 1995-03-09 GB GB9504733A patent/GB2287942B/en not_active Expired - Fee Related
- 1995-03-09 AP APAP/P/1995/000724A patent/AP546A/en active
- 1995-03-13 TW TW084102349A patent/TW380141B/zh not_active IP Right Cessation
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- 1995-03-14 TN TNTNSN95019A patent/TNSN95019A1/fr unknown
- 1995-03-14 UA UA96103911A patent/UA55369C2/uk unknown
- 1995-03-14 DK DK95912309T patent/DK0750635T3/da active
- 1995-03-14 FR FR9502900A patent/FR2717390B1/fr not_active Expired - Fee Related
- 1995-03-14 CN CN95192125A patent/CN1070865C/zh not_active Expired - Fee Related
- 1995-03-14 WO PCT/FR1995/000296 patent/WO1995025123A1/fr active IP Right Grant
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- 1995-03-14 RU RU96118282A patent/RU2144038C1/ru not_active IP Right Cessation
- 1995-03-14 EP EP95912309A patent/EP0750635B1/fr not_active Expired - Lifetime
- 1995-03-14 AT AT95912309T patent/ATE174037T1/de not_active IP Right Cessation
- 1995-03-14 KR KR1019960705102A patent/KR100359713B1/ko not_active IP Right Cessation
- 1995-03-14 AU AU14870/95A patent/AU694476B2/en not_active Ceased
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- 1995-03-15 DZ DZ950030A patent/DZ1865A1/fr active
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1996
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989006241A1 (fr) * | 1988-01-08 | 1989-07-13 | Institut National De La Sante Et De La Recherche M | Sorbine et peptides derives, elevant l'absorption par les muqueuses |
Non-Patent Citations (1)
Title |
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GOSTROENTEROLOGY 1992.1.1 CHARPIN GNISLAINE EFFECF OF SORIN ON DUODENAL ABSORPTION OF WATER AND ELECTRDJTES IN THE RAT * |
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