CN1161156C - (甲基)丙烯酸/顺丁烯二酸共聚物在改善粘膜渗透性中的应用 - Google Patents
(甲基)丙烯酸/顺丁烯二酸共聚物在改善粘膜渗透性中的应用 Download PDFInfo
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- CN1161156C CN1161156C CNB971180563A CN97118056A CN1161156C CN 1161156 C CN1161156 C CN 1161156C CN B971180563 A CNB971180563 A CN B971180563A CN 97118056 A CN97118056 A CN 97118056A CN 1161156 C CN1161156 C CN 1161156C
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- acid
- maleic acid
- acrylic acid
- copolymers
- acrylic
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Abstract
本申请描述了(甲基)丙烯酸/顺丁烯二酸共聚物用于改善粘膜渗透性及包含它们的药物组合物。
Description
本发明涉及(甲基)丙烯酸/顺丁烯二酸共聚物在改善粘膜渗透性中的应用。
上皮组织对于亲水性活性物质,尤其是高分子量的那些跨细胞的转运形成一个重要的渗透屏障。所谓“紧密接点”(相邻上皮细胞间的细胞间连接点,其中原生质膜直接接触)保证了一个器官的内部环境封闭脱离于外界环境。这类上皮细胞的被动跨细胞渗透性是通过细胞间连接点的紧密度测定的。“紧密接点”的扩大导致吸收的改善并因此使活性组分的生物利用度更高。
因此在过去的时期里不少的尝试用来开发打开细胞间连接点的方法。表面活性组分的应用和Ca2+-螯合物质的应用表明它们都是可行的途径。
然而,控制释放杂志(J.Controlled Rel.),29(1994)253中陈述了表面活性物质的应用会产生细胞溶解和与此有关的毒副作用的风险。
大量的公开物,特别是在J.Cotrolled Rel.,36(1995)25;化学药物公报(Chem.Pharm.Bull.)33(1985)4600;细胞生物学杂志(TheJournal of Cell Biology),87(1980)736和国际药物杂志(Int.J.Pharm.),90(1993)229中描述了乙二胺四乙酸(EDTA)和乙二醇二(β-氨基乙醚)四乙酸(EGTA)对于不同细胞体系如Caco-2细胞的渗透性的作用。据此,Ca2+-螯合物质的存在可导致迅速的,但常常是不可逆的紧密接点的打开。另外,就EDTA而言,pH值在中性时需要较高的浓度来得到可观察的作用(跨上皮阻力的减弱)。还有,分子量小于等于20kDa的配位剂会引起它们发生全身性吸收及因此导致不希望的毒副作用的风险。
J.Controlled.Rel.,29(1994)329中可以表明,不可吸收的以交联聚丙烯酸酯为基础的高分子量化合物例如聚亲有机物(polycarbo-phil)(Noveon AA1,B.F.Goodrich)同样地能打开紧密接点。而其应用由于它们的极高分子量(>1.000kDa)和它们甚至在低浓度时的高粘度(≥0.5wt%)而存在技术上的缺陷。
具有生物粘合性质的聚合物还被认为能够提高活性物质的生物利用度。例如,EP-A-587 047描述了(甲基)丙烯酸酯与不同羧酸的共聚物应用于含促孕素的药用组合物。
EP-B-410 422公开了增加低溶解性的活性物质的生物利用度的可能性,这通过它们在配制后因(甲基)丙烯酸/(甲基)丙烯酸酯共聚物的作用而呈无定形且因此更易溶而实现。
本发明的目的是寻找具有螯合性质的聚合物,该聚合物增加上皮细胞渗透性,同时没有上述应用中的技术缺陷或毒性问题。
我们发现此目的可通过应用(甲基)丙烯酸/顺丁烯二酸共聚物,尤其是含有a)10-90mol%(甲基)丙烯酸,b)90-10mol%的顺丁烯二酸及c)0-40mol%其它单体的那些共聚物来改善粘膜渗透性而达到。
原料单体a)为丙烯酸和/或甲基丙烯酸,它们的酸酐,盐或所述两种羧酸,酸酐和盐的混合物。单体b)可为顺丁烯二酸,其盐或顺丁烯二酸酐。
单体a)和b)还可部分以其盐类形式掺混。这可通过例如在聚合前,聚合过程中或聚合后加入碱实现。若单体为它们的盐的形式,则优选碱土金属,碱金属或铵盐或有机胺的盐,更优选碱金属或铵盐。
c)组的单体为乙烯基磺酸,和/或丙烯酸或甲基丙烯酸的羟基-C2-C6-烷基酯,和/或饱和直链或支链的C1-C40-醇的丙烯酸酯或甲基丙烯酸酯。具体例子为丙烯酸的甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基,正己基,正辛基,异壬基,正癸基,正十二烷基,正十四烷基,正十六烷基,正十七烷基,正十八烷基,正十九烷基,正二十烷基,正二十二烷基,正二十四烷基,2-乙基己基,异冰片基酯,或丙烯酸环己基酯,或相应的甲基丙烯酸酯。优选丙烯酸或甲基丙烯酸的C1-,C2-和/或C6-C30-烷基酯。最优选丙烯酸或甲基丙烯酸的C8-C22-烷基酯。
单体c)中的羟烷基是衍生自例如(链)烷烃二醇如1,2-乙二醇,1,3-和1,2-丙二醇和其工艺混合物,1,4-,1,3-和2,3-丁二醇和其混合物。可提到的具体例子为丙烯酸羟乙基酯,甲基丙烯酸羟乙基酯,丙烯酸羟丙基酯,甲基丙烯酸羟丙基酯,丙烯酸羟丁基酯,甲基丙烯酸羟丁基酯。优选的羟烷基酯c)为丙烯酸羟乙基酯,丙烯酸羟丙基酯和丙烯酸羟丁基酯。尤其优选的羟烷基酯c)为丙烯酸羟丙基酯,和那些具有特定工业价值的是由丙烯酸与1,2-环氧丙烷反应制备得出的丙烯酸2-羟基-1-丙基酯与丙烯酸1-羟基-2-丙基酯的异构体混合物。
本发明中应用的共聚物中(甲基)丙烯酸∶顺丁烯二酸的摩尔比可在宽范围内改变。例如,它的范围在90∶10-10∶90,优选70∶30-30∶70中。当单体c)存在时,一种有利的单体配比是5-40,优选10-35mol%的c),和95-60mol%的a)和b),在这种情况下a)和b)的比例可如上选择。
共聚物是通过悬浮聚合,沉淀聚合或溶液聚合以常规途径制备的,优选水溶液中的溶液聚合。这种聚合物的实例在EP-A-0 168 547,EP-A-0 075820或EP-A-0 349 810中给出。这些共聚物重均分子量在500-1,000,000之间。适于本发明应用的是分子量在5000-500,000,尤其在10,000-300,000之间的共聚物。
含有或不含有c)的a)和b)的共聚物通常与活性物质共同以药物组合物的形式施予。适宜的药物形式为片剂,挤压剂,颗粒剂,丸剂,粉剂,胶囊,栓剂,软膏剂,溶液剂,混悬剂或乳剂,并且以用途为依据,给药可是口服,舌下,颊部,直肠,通过肺部,鼻或眼粘膜来完成。本发明所应用的共聚物在这类药物剂型中的含量一般超过药物剂型总重量的10wt%,优选超过30wt%,尤其优选超过50wt%。然而,也可以首先用可改善渗透性的共聚物来处理粘膜,如胃,肠,鼻,口腔,咽喉或眼的粘膜,然后再施予药用活性物质。
通常,上述药物组合物通常通过加入填充剂,粘合剂,崩解剂,润滑剂或其他辅助物质而制备。用作片剂的填充剂和干燥粘合剂的特别为乳糖,蔗糖,甘露醇,山梨醇,微晶纤维素,淀粉,磷酸二钙和聚乙二醇。适于制粒的粘合剂为淀粉,藻酸盐,聚乙烯吡咯烷酮,和尤其是羧甲基纤维素。适宜的润滑剂具体例子为淀粉,滑石和二氧化硅。可应用于片剂机械制备的润滑剂为硬脂酸镁和金属皂。可应用的片剂崩解剂包括淀粉,纤维素衍生物,藻酸盐,葡聚糖,和交联聚乙烯吡咯烷酮。
依用途和活性物质,共聚物宜以中和,部分中和或未中和形式应用。若共聚物为未中和形式,有利的是通常存在碱或质子受体,包含另一辅助物质和/或直接包含活性物质。
若活性物质为碱性,则其可与本发明所述的a)和b)的共聚物(含或不含c))全部或部分成盐。
下述的实施例以人肠上皮细胞(caco-2细胞培养物)作为实例来说明本发明所述的(甲基)丙烯酸:顺丁烯二酸共聚物的应用,在体外试验系统中表明其渗透性增加作用。Caco-2细胞具有许多上皮细胞的分化性质例如酶的不对称分布,具有细胞顶端上的微绒毛的形态学相似结构及具有紧密接点的单层的形成。在被称为transwell平皿内的多孔膜上培养这类细胞使准确研究从尖端腔隙(肠腔)向底侧(basolateral)腔隙(淋巴)的转运成为可能。其中,紧密接点打开或关闭的程度可通过跨上皮电阻(TEER)和放射性示踪物(14C-甘露醇)通过细胞单层的渗透来显示。渗透性的可逆性改善可通过测定TEER在用原顶端介质代替顶端实验介质后电阻的重新上升来验证。
实验实施例:
1.跨上皮电阻(TEER)的测定:
在聚碳酸酯滤器(直径6.5mm)上培养的Caco-2细胞进一步在Costartranswell室(Costar Europe Ltd.,Badhoevedorp,NL)内培养以达到104细胞/cm2的细胞密度。用于两份细胞(both half-cells)的培养基是DMEM(Dulbecco’s Modified Eagle’s Medium,Sigma公司),其中加入1%的非必需的氨基酸溶液,10%的胎牛血清,苄基青霉素G(160U/ml)和链霉素硫酸盐(100μg/ml),每天更换培养基。培养皿在37℃于95%空气和5%CO2组成的气氛中保温培养。
被研究的聚合物(见表1)以不同的浓度(1-7.5%)溶于DMEM并用NaOH中和。对照实验在DMEM中完成。各个滤器的跨上皮电阻(TEER)在保温培养后每隔20分钟使用Millipore B.V.(Etten-Leur,NL)公司提供的Millicell电阻系统来测定。为了检测细胞-细胞间相互作用的可逆性,2小时后用纯DMEM代替聚合物溶液并且再测定电阻。
表1:研究的聚合物的结构
聚合物 | 结构 | 平均分子量 |
1 | AA/MA=70/30 | 70000 |
2 | AA/MA=70/30 | 150000 |
3(对照) | AA=100 | 250000 |
4 | AA/MA/HPA=40/40/20 | 20000 |
5 | AA/MA=50/50 | 50000 |
6 | AA/MA/VAS=35/35/30 | 15000 |
简称:AA:丙烯酸
MA:顺丁烯二酸
HPA:丙烯酸羟丙基酯
VAS:乙烯磺酸
图1A/B展示了聚合物1-6(在DMEM中5%浓度的溶液)的实验结果。显然,跨上皮电阻在应用共聚物1,2和4-6时显著降低,而对照聚合物3仅轻微降低。
2.14C甘露醇透过率的测定
跨细胞转运的增加通过在5或7.5%浓度的聚合物溶液中用适宜的亲水性示踪物(14C-甘露醇,4μmol/l,特定活性:0.2μCi/ml)保温培养细胞单层来研究。在每种情况下,30分钟后从接收容器中取200μl的样品并且检测其放射性(Tri-carb 1500闪烁计数器,PackardInstr.B.V.,Groningen,NL)。如图2(DMEM中5和7.5%浓度的聚合物2溶液)和3(DMEM中5%浓度的聚合物1,4-6的溶液,保温培养120分钟)展示,caco-2细胞在所研究的聚合物1,2和4-6存在下保温培养导致上皮细胞间的紧密接点的打开,及与对照相比,放射性示踪物的转运率显著提高。
3.药物剂型实施例
a.阿替洛尔片剂
1000g阿替洛尔,1000gLudipress(BASF),2930g丙烯酸/顺丁烯二酸共聚物(50∶50)钠盐,40gAerosil 200(Degussa),200gKollidonVA64(BASF)和30g硬脂酸镁首先用0.8mm的筛网过筛并且在Turbula混合机中混合5分钟。然后直径为9mm的两面凸片剂在压力为22kN的旋转式片压机中制成。
阿替洛尔 | 50mg |
Ludipress | 50mg |
丙烯酸/顺丁烯二酸共聚物(50∶50)钠盐(分子量50000) | 146.5mg |
Aerosil200 | 2mg |
KollidonVA64 | 1mg |
硬脂酸镁 | 1.5mg |
片剂重量 | 260mg |
b.柳氮磺胺吡啶包膜片剂
柳氮磺胺吡啶 | 250mg |
丙烯酸/顺丁烯二酸共聚物(70∶30)钠盐(分子量70000) | 500mg |
Kollidon30 | 15mg |
Aerosil200 | 2mg |
硬脂酸镁 | 3mg |
片剂重量 | 770mg |
500g柳氮磺胺吡啶和1000g丙烯酸/顺丁烯二酸共聚物(70∶30)钠盐在Stephan混合机中混合2分钟,在搅拌的同时,加入30gKollidon30的230g异丙醇溶液。润湿的组合物用孔径为1.0mm的筛网过筛并且在盘中室温干燥。当干燥物用1.0mm筛网过筛后,加入4.0gAerosil200和6.0g硬脂酸镁并且混合5分钟。粉末混合物在压力为35kN且速度为30rpm的旋转式压机中压缩成面积为19×8.5mm的足球状片剂。
第二步,片剂在水平鼓式包衣机中给予肠溶膜包衣。应用50℃入口空气的喷雾分散体系具有如下组成:
二氧化钛 | 0.5% |
滑石 | 2% |
SicovitRot 30 | 0.5% |
Kollidon30 | 0.5% |
甲基丙烯酸/丙烯酸乙基酯共聚物(1∶1) | 15% |
柠檬酸三乙基酯 | 1.5% |
水 | 80% |
100mg的此分散体系,相应于15mg甲基丙烯酸/丙烯酸乙基酯共聚物,用于每个片剂。
c.呋喃苯胺酸微片
100g呋喃苯胺酸,570g丙烯酸/顺丁烯二酸共聚物(70∶30)钠盐和20gKollidonVA64在Stephan混合机中混合,在搅拌的同时,以105g异丙醇湿润。湿润的组合物以孔径为0.6mm的筛网过筛,并且在室温下在盘中以薄层干燥24小时。干燥颗粒用0.8mm筛网过筛,与硬脂酸镁和同样过筛的Aerosil200混合,并在Turbula混合机中混合5分钟,然后再用0.8mm的筛网过筛。直径2mm厚约2mm的两面凸微片剂在KorschEKO偏心压片机中制成。对每个单剂40mg的剂量,两片明胶胶囊在每种情况下包有40个微片。
呋喃苯胺酸 | 1mg |
丙烯酸/顺丁烯二酸共聚物(70∶30)钠盐 | 5.7mg |
KollidonVA64 | 0.2mg |
Aerosil200 | 0.05mg |
硬脂酸镁 | 0.05mg |
片剂重量 | 7.0mg |
d.甲基多巴片剂
甲基多巴 | 250mg |
丙烯酸/顺丁烯二酸共聚物(50∶50)钠盐(分子量50000) | 347.5mg |
Aerosil200 | 3.5mg |
KollidonVA64 | 26mg |
硬脂酸镁 | 3mg |
片剂重量 | 630mg |
2500g甲基多巴,3475g丙烯酸/顺丁烯二酸共聚物(50∶50)钠盐,35gAerosil 200,260gKollidon VA64和30g硬脂酸镁首先用0.8mm筛网过筛并且在Turbula混合机中混和5分钟。此粉末混合物在压力30kN和转速30转/分钟的旋转式片压机中压缩成双翼斜倾的直径为12mm的片剂。
e.S-腺苷甲硫氨酸锭剂
S-腺苷甲硫氨酸 | 100mg |
丙烯酸/顺丁烯二酸共聚物(50∶50)钠盐 | 700mg |
甘露醇 | 200mg |
阿司帕坦 | 3mg |
橘味调味剂 | 5mg |
KollidonVA64 | 82mg |
Aerosil200 | 5mg |
硬脂酸镁 | 5mg |
锭剂重量 | 1100mg |
500gS-腺苷甲硫氨酸,3500g丙烯酸/顺丁烯二酸共聚物(50∶50)钠盐,1000g甘露醇,15g阿司帕坦,25g橘味调味剂和410gKollidonVA64首先用0.8mm筛网过筛并且在Turbula混合机中混合5分钟。然后,将25g硬脂酸镁和事先用0.5mm筛网过筛的25g Aerosil200加入并且混合2.5分钟。在压力30kN和转速30转/分钟的旋转式片压机中制成重量为1100mg的双翼斜倾的片剂。
f.头孢呋辛颗粒剂
头孢呋辛新酯(等价于250mg头孢呋辛) | 300.7mg |
丙烯酸/顺丁烯二酸共聚物(50∶50)钠盐(分子量为50 000) | 1000mg |
甲基丙烯酸/甲基丙烯酸甲基酯共聚物(1∶1) | 150mg |
蔗糖 | 502.3 |
橘味调味剂 | 5mg |
阿司帕坦 | 2mg |
KollidonVA64 | 40mg |
颗粒重量 | 2000mg |
300.7g头孢呋辛新酯(等价于250mg头孢呋辛),1000g丙烯酸/顺丁烯二酸共聚物(50∶50)钠盐,150g甲基丙烯酸/甲基丙烯酸甲基酯共聚物(1∶1),502.3g蔗糖,5g橘味调味剂和2g阿司帕坦在Stephan混合机中混合,在搅拌的同时,用40gKollidonVA64的310g异丙醇溶液润湿。润湿组合物以孔径1.2mm的筛网过筛并且在室温下在盘中缓慢干燥24小时。干燥颗粒以2000mg剂量包于封闭的药包中。
g.戈那瑞林鼻用喷雾剂
戈那瑞林 | 1.0mg |
苯甲醇 | 20mg |
丙烯酸/顺丁烯二酸共聚物(50∶50)钠盐(分子量50000) | 75mg |
1N HCl调至pH=7.0 | |
水 | 加至1000mg |
700g纯化的无菌水与20g苯甲醇混合。然后将50g丙烯酸/顺丁烯二酸共聚物溶于其中,并且用1N HCl在搅拌下调节pH至7.0。加入戈那瑞林后混合物搅拌半小时,加入其余的水至重量为1000g,溶液由0.22μm的过滤器过滤灭菌并且装入鼻用喷雾瓶中。
h.雷尼替丁溶液
盐酸雷尼替丁 | 20mg |
丙烯酸/顺丁烯二酸共聚物(50∶50)钠盐(分子量50000) | 100mg |
蔗糖 | 50mg |
氯苄烷铵 | 1mg |
1N HCl | 54mg |
纯化水 | 775mg |
溶液重量 | 1000mg |
20g盐酸雷尼替丁,50g蔗糖和1g氯苄烷铵溶于775g的纯化水中并搅拌。加入100g丙烯酸/顺丁烯二酸共聚物(50∶50)钠盐和54g1N盐酸后,搅拌至所有的物质都溶解,并且将溶液用5μm的过滤器过滤,并装于50g瓶中。
Claims (5)
1.丙烯酸/顺丁烯二酸共聚物或甲基丙烯酸/顺丁烯二酸共聚物在改善粘膜渗透性中的用途,该共聚物的平均分子量为10,000至300,000,其包括:
a)30-70mol%丙烯酸或甲基丙烯酸;
b)30-70mol%顺丁烯二酸,和
c)0-40mol%的丙烯酸羟烷基酯,甲基丙烯酸羟烷基酯,丙烯酸烷基酯,甲基丙烯酸烷基酯和/或乙烯基磺酸。
2.一种改善粘膜渗透性的药物组合物,包括如权利要求1所述的丙烯酸/顺丁烯二酸共聚物或甲基丙烯酸/顺丁烯二酸共聚物。
3.根据权利要求2的药物组合物,剂型为片剂,挤压剂,颗粒剂,丸剂,粉剂,胶囊剂,栓剂,软膏剂,混悬剂,溶液剂或乳剂。
4.根据权利要求2或3的药物组合物,其中共聚物以中和,部分中和或未中和形式存在,且在共聚物为未中和形式的情况下,组合物另外包括碱或质子受体。
5.根据权利要求2或3的药物组合物,其中活性成分全部或部分以与丙烯酸/顺丁烯二酸共聚物或甲基丙烯酸/顺丁烯二酸共聚物的盐的形式存在。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE19631085.7 | 1996-08-01 | ||
DE19631085A DE19631085A1 (de) | 1996-08-01 | 1996-08-01 | Verwendung von (Meth)acrylsäure-Maleinsäure-Copolymeren zur Verbesserung der Permeabilität der Schleimhaut |
Publications (2)
Publication Number | Publication Date |
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CN1176138A CN1176138A (zh) | 1998-03-18 |
CN1161156C true CN1161156C (zh) | 2004-08-11 |
Family
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CNB971180563A Expired - Fee Related CN1161156C (zh) | 1996-08-01 | 1997-07-31 | (甲基)丙烯酸/顺丁烯二酸共聚物在改善粘膜渗透性中的应用 |
Country Status (6)
Country | Link |
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US (1) | US6004575A (zh) |
EP (1) | EP0821965B1 (zh) |
JP (1) | JPH1067686A (zh) |
CN (1) | CN1161156C (zh) |
DE (2) | DE19631085A1 (zh) |
ES (1) | ES2229301T3 (zh) |
Families Citing this family (13)
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DE19631084A1 (de) * | 1996-08-01 | 1998-02-05 | Basf Ag | Verwendung von (Meth)acrylsäure-Copolymeren zur Erhöhung der Permeabilität der Schleimhaut |
CA2209868C (en) * | 1997-08-15 | 2001-08-14 | Bernard Charles Sherman | Pharmaceutical compositions comprising cefuroxime axetil |
US7070799B1 (en) * | 1998-02-10 | 2006-07-04 | Generex Pharmaceuticals, Inc. | Method for administering insulin to the buccal region |
AT413647B (de) * | 1998-11-26 | 2006-04-15 | Sandoz Ag | Verwendung eines copolymerisats aus 1-vinyl-2-pyrrolidon und vinylacetat zur herstellung von cefuroximaxetil-hältigen tabletten |
ITPI20010015A1 (it) * | 2001-03-05 | 2002-09-05 | Ivo Pera | Metodo per la somministrazione di s-adenosil-metionina,sottoforma di micropolvere secca,tramite inalazione |
ITMI20012462A1 (it) * | 2001-11-22 | 2003-05-22 | Gnosis Srl | Processo per la preparazione di compresse comprendenti s-adenosilmetionina |
CA2472449C (en) * | 2002-01-16 | 2010-03-09 | Yamanouchi Pharmaceutical Co., Ltd. | Pharmaceutical composition for oral use with improved absorption |
US20090088404A1 (en) * | 2007-01-31 | 2009-04-02 | Methylation Sciences International Srl | Extended Release Pharmaceutical Formulations of S-Adenosylmethionine |
AU2008334580A1 (en) * | 2007-12-12 | 2009-06-18 | Basf Se | Salts of active ingredients with polymeric counter-ions |
US20110027342A1 (en) * | 2009-07-28 | 2011-02-03 | Msi Methylation Sciences, Inc. | S-adenosylmethionine formulations with enhanced bioavailability |
US8329208B2 (en) | 2009-07-28 | 2012-12-11 | Methylation Sciences International Srl | Pharmacokinetics of S-adenosylmethionine formulations |
EP2753336B1 (en) | 2012-10-17 | 2015-05-06 | Methylation Sciences International SRL | Compositions comprising s-adenosylmethionine and a gallic acid ester |
CN107519139A (zh) * | 2016-06-21 | 2017-12-29 | 北京科信必成医药科技发展有限公司 | 一种呋塞米微片及其制备方法 |
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DE1617393C2 (de) * | 1966-01-06 | 1982-11-11 | Československá akademie věd, Praha | Verfahren zur Herstellung von biologisch aktive Stoffe enthaltenden hydrophilen vernetzten Copolymeren |
WO1993023011A1 (en) * | 1992-05-18 | 1993-11-25 | Minnesota Mining And Manufacturing Company | Transmucosal drug delivery device |
JPH09308863A (ja) * | 1996-05-20 | 1997-12-02 | Dainippon Printing Co Ltd | 帳票処理装置 |
-
1996
- 1996-08-01 DE DE19631085A patent/DE19631085A1/de not_active Withdrawn
-
1997
- 1997-07-24 EP EP97112660A patent/EP0821965B1/de not_active Expired - Lifetime
- 1997-07-24 DE DE59712023T patent/DE59712023D1/de not_active Expired - Lifetime
- 1997-07-24 ES ES97112660T patent/ES2229301T3/es not_active Expired - Lifetime
- 1997-07-30 JP JP9204421A patent/JPH1067686A/ja not_active Withdrawn
- 1997-07-30 US US08/902,938 patent/US6004575A/en not_active Expired - Lifetime
- 1997-07-31 CN CNB971180563A patent/CN1161156C/zh not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
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EP0821965A2 (de) | 1998-02-04 |
EP0821965B1 (de) | 2004-10-20 |
US6004575A (en) | 1999-12-21 |
JPH1067686A (ja) | 1998-03-10 |
DE19631085A1 (de) | 1998-02-05 |
EP0821965A3 (de) | 2001-03-14 |
DE59712023D1 (de) | 2004-11-25 |
CN1176138A (zh) | 1998-03-18 |
ES2229301T3 (es) | 2005-04-16 |
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