CN1200667A - 生物粘着固体剂型 - Google Patents

生物粘着固体剂型 Download PDF

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CN1200667A
CN1200667A CN96197878A CN96197878A CN1200667A CN 1200667 A CN1200667 A CN 1200667A CN 96197878 A CN96197878 A CN 96197878A CN 96197878 A CN96197878 A CN 96197878A CN 1200667 A CN1200667 A CN 1200667A
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P·M·V·吉利斯
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Abstract

本发明涉及生成粘着药物组合物,含有药物有效量活性组分,80%至98.8%(w/w)预胶质化淀粉和1%至10%(w/w)生成亲水基质的聚合物,其特征在于该组合物进一步含有0.2%至5%(w/w)碱金属烷基富马酸盐作为润滑剂;固体剂型例如片剂,适于口内、鼻内、直肠和阴道内给药;还涉及制备这些组合物和固体剂型的方法。

Description

生物粘着固体剂型
本发明涉及生物粘着组合物和由其制成的固体剂型，它们对局部作用组分或者也对全身作用药物具有定期和延长释放模式，并且它们适于口内、鼻内、直肠内和阴道内给药。
例如在GB-2042888(Teijin)中已描述了已知的生物粘着固体剂型。那些剂型包含活性组分，50至95％纤维素醚和50至5％高分子量交联聚丙烯酸(羧乙烯聚合物，Carbomer，Corbopol)。市售生物粘着剂型通常是具有一层粘着层和至少一层非粘着层的两层(多层)制剂(例如Teiji的Aftach，曲安奈德胶接片(Triamcinolone AcetonidePlastering Tablet))。
在EP-0 451 433和欧洲临床药理学杂志(Eur.J.Clin.Pharmacol.)(1992)43：137-140中已公开了含5％聚丙烯酸(Carbopol 934)和预胶质化淀粉(转鼓烘干的蜡状玉米)混合物的改进生物粘着固体剂形。它的主要优点是极好的生物粘着性能和完全不存在组织刺激。但证明使用这些公开的资料工业规模开发颊含片是行不通的，因为不可能获得工业意义量的微粉状(即有很高的比表面)苯甲酸钠润滑剂。制备具有非微粉化润滑剂或无润滑剂的颊含片的一切努力都失败了。润滑剂是从颗粒压片的基础物质。没有它则药片会粘到所用的冲头和模具上。非微粒化润滑剂的缺点是它需要以不能接受的大用量使用，并且由此影响其生物可用性，释放特征，味道和口感等性质。
因此，需要具有可接受性质的不同润滑剂。首先，业已发现若限制所用润滑剂为水溶性润滑剂，便可以解决味道和口感两个问题。难溶于水的润滑剂，如硬脂酸镁，与生物粘着载体结合时，在口中留下类似肥皂的味道。通过使用水溶性碱金属C16-22烷基富马酸盐，特别是硬脂酰富马酸钠作润滑剂，可以满意地解决全部问题。令人惊奇的发现是润滑剂不会引起任何生物粘着性损失，并且不含对药片的释放特性产生不好的影响。当进一步扩大迄今所用的从新的生物粘着组合物制备片剂的湿成粒方法时，还遇到了另一个问题，即颗粒在干燥时(例如流动床干燥器中)会崩解。通过在压片前将一些组分干压，这一问题现已得到解决。
本发明涉及一种生物粘着药物组合物，它含有药物有效量的活性组分，和80％至98.8％(w/w)的预胶质化淀粉混合物，1％至10％(w/w)形成亲水基质的聚合物，其特征在于该组合物还含有0.2％至5％(w/w)碱金属C16-22烷基富马酸盐作润滑剂。
润滑剂的含量低于0.2％不起作用，而其用量超过5％不再改善压片过程，反而赋予制剂不期望的性质。用量大约2％被认为是最合适的。优选所说的润滑剂是硬脂酰富马酸钠，它可以微粉状(Pruv)从市场得到，此外它是水溶性的，并且实际上无味。
本发明的生物粘着组合物中形成亲水基质的聚合物的量，通常在2.5％至7.5％(w/w)范围内，而最优选为约5％(w/w)。形成亲水基质的聚合物的实例是聚丙烯酸(Carbomer)、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、聚乙烯醇，和其混合物聚丙烯酸，特别是Carbomer 974P在确保从生物粘着组合物制备的剂型具有活性组分定时和延长释放模式的方面是有用的。从而本发明生物粘着组合物中它是优选的生成亲水基质的聚合物。
为了防止在压片时颗粒磨损，本发明组合物进一步含有助流剂是有益的。这种助流剂的例子是胶态无水硅石。助流剂的量可在0％至约1％(w/w)范围，优选约0.2％。
本发明的优选组合物含以组合物总重量为基础的如下成分含量：0.001％至10％活性组分；80％至98.8％预胶质化淀粉；1％至10％生成亲水基质的聚合物；0.2％至5％硬脂酰富马酸钠；0％至1％助流剂。
合适的活性组分是发挥局部生理作用的，以及发挥全身作用的，或者随后刺激粘膜或者(在口服情况下)然后随唾液进入肠胃道的成分。从本发明组合物制备的生物粘着剂型对于在延长时间期间发挥其活性的活性成分特别合适。其实例是：镇痛和抗炎药(NSAIDs，乙酰水杨酸、双氯酚酸钠、布洛芬、吲哚美辛、酮洛芬、甲氯灭酸钠、甲芬那酸、萘普生钠、对乙酰氨基酚、吡咯昔康、甲苯酰吡酸钠)；抗心律不齐药(盐酸普鲁卡因、硫酸奎尼丁、盐酸维拉帕米)；抗菌药(阿莫西林、氨苄西林、苄星青霉素、青霉素G、头孢克洛、头孢羟氨苄、头孢氨苄、氯霉素、环丙氯哌酸、克拉维酸、盐酸氯林可霉素、盐酸多西环素、红霉素、氟氯西林钠、硫酸苄那霉素、盐酸林可霉素、盐酸二甲胺四环素、萘夫西林、萘啶酸、新霉素、诺氟沙星、氧氟沙星、苯唑西林、青霉素V)；抗凝血剂(法华林)；抗抑郁药(盐酸阿米替林、阿莫沙平、盐酸丁替林、盐酸氯米帕林、盐酸地昔帕明、盐酸度硫平、盐酸多塞平、氟西丁、吉吡隆、米帕明、碳酸锂、盐酸米安色林、milnacipran、盐酸去甲替林、盐酸帕罗西丁)；抗糖尿病药(格列木脲)；抗真菌药(两性霉素、克霉唑、益康唑、氟康唑、氟胞嘧啶、灰黄霉素、伊曲康唑、酮康唑、硝酸双氯苯咪唑、nystatin)；抗组氨药(阿司咪唑、桂利嗪、盐酸赛庚啶、氟桂利嗪、奥沙米特、异丙嗪、特非拉定)；抗高血压药(卡托普利、依那普利、酮色林、赖诺普利、米诺地尔、盐酸哌唑嗪、雷米普利、利血平)；抗蕈毒碱剂(硫酸阿托品、东莨菪碱)；抗病毒药(阿昔洛韦、AZT、ddC、ddI、更昔洛韦、loviride、tivirapine、3TC、delavirdine、indinavir、nelfinavir、ritonavir、saquinavir)；镇静药(阿普唑仑、盐酸丁螺环酮、chlordiazepoxide HCl、氯丙嗪、氯氮平、地西泮、盐酸三氟噻吨、氟奋乃静、氟西泮、劳拉西泮、mazapertine、olanzapine、奥沙西泮、匹莫齐特、匹泮哌隆、吡拉西坦、丙嗪、利螺环酮、selfotel、seroquel、舒必利、替马西泮、替沃噻吨、三唑仑、三氟哌多、ziprasidone)；抗中风药(lubeluzole、lubeluzoleoxide、riluzole、aptiganel、eliprodil、立马醋胺)；抗偏头痛药(alniditan、舒马坦)；β-肾上腺素能受体阻滞剂(阿替洛尔、卡维地洛、美托洛尔、奈必洛尔、萘心安)；强心剂(洋地黄毒甙、地高辛、米力农)；皮质甾类(二丙酸氯地米松、倍他米松、地塞米松、氢化可的松、甲泼尼龙、泼尼松龙、强的松、曲安西农)；消毒剂(氯己定)；利尿药(乙酰唑胺、呋噻米、氢氮噻嗪、异山梨醇)；抗帕金森病药(甲磺酸溴麦角环肽、左旋多巴、盐酸司来吉兰)；酶；香料油(茴香醚、茴香油、
Figure A9619787800061
蒿、小豆蔻、桂皮油、桉素脑、肉桂油、丁香油、芜荽油、薄荷油、莳萝油、桉叶油、丁香酚、姜油、柠檬油、芥子油、橙花油、肉豆蔻油、橙油、胡椒薄荷、洋苏叶、留兰香、萜品醇、麝香草)；胃肠药(西米替丁、西沙必利、氯波必利、盐酸地芬诺酯、多潘立酮、法莫替丁、兰索拉唑、盐酸洛哌丁胺、氧洛哌丁胺、美沙拉嗪、盐酸甲氧氯普胺、mosapride、奥沙拉嗪、奥美拉唑、雷尼替丁、rabeprazole、ridogrel、柳氮磺胺吡啶)；止血药(氨基己酸)；降血脂药(洛伐他丁、普代他汀、普洛布考、西伐他仃)；局部麻醉药(苯佐卡因、利多卡因)；鸦片镇痛药(盐酸丁丙诺啡、可待因、右吗拉胺、双氢可待因)；抗胆碱药(加兰他敏、新斯的明、physostymine、他克林、donepezil、ENA 713(exelon)、xanomeline)；血管扩张药(氨氯地平、丁咯地尔、亚硝酸异戊酯、地尔硫、双嘧达莫、硝酸甘油、硝酸异山梨酯、利多氟嗪、吗多明、尼卡地平、硝苯地平、己酮可可碱、戊四硝酯)。
本发明的组合物最好以适于口内、鼻内、直肠内或阴道内给药的剂型存在。为此目的将它们制成片剂，优选具有足够表面积以确保有效生物粘着于粘膜。扁平的，碟形片剂特别优选。
为口内施用，开发了一些颊含片。模仿在欧洲临床药理学杂志(1992)43：137-140中所述的咪康唑片剂，用硬脂酰富马酸钠盐制成了类似咪康唑的片剂，但如下所述现已在工业规模制备。所说片剂含有以该片剂总重量为基础的如下成分含量：10％硝酸双氯苯咪唑微粉；82.8％转鼓烘干的蜡状玉米淀粉；2％硬脂酰富马酸钠；5％Carbomer 974P；和0.2％胶态无水硅石。
此外，也制备了分别含1％和5％活性组分硝酸双氯苯咪唑，91.8％和87.8％转鼓烘干的蜡状玉米淀粉的两种片剂。
也制备了含曲安西龙的颊含片(模仿Teijin’s Aftach)这种颊含片含有以该片总重量为基础的下述成分含量：1％曲安西龙微粉；91.8％转鼓烘干的蜡状玉米淀粉；2％硬脂酰富马酸钠；5％Carbomer 974P；和0.2％胶态无水硅石。
本发明组合物能在小规模用湿成粒法制备，包括下述步骤：-将活性组分，预胶质化淀粉，和任意地与生成亲水基质的聚合物紧密混合，直至在合适的混合器中形成均一混合物；-将这样得到的混合物用药学可接受的非水溶剂润湿；-将湿混合物压过筛孔为1至1.8mm的筛；干燥所得颗粒；并且
-将干燥的颗粒与硬脂酰富马酸钠盐混合并任意地与助流剂一起混合。为制得片剂，所述方法接着再进行下述步骤：-将颗粒与润滑剂和任选的助流剂一起压成片。
然而，此方法在大规模生产中不成功，因为在干燥(例如流动床干燥器中)过程中颗粒会崩解。
然而通过包括下述步骤的干法加工可制得该片剂：-将活性组分，预胶质化淀粉和形成亲水基质的聚合物在干燥状态下紧密混合；-将这样得到的混合物压实成薄片；-将该薄片破碎成颗粒；-将该颗粒过筛；-将该颗粒与润滑剂和任意地加有助流剂一起混合；并且-将该混合物压成片。
在此方法中，混合步骤可在现有技术已知的行星式混合器中方便地完成。同样地，干压过程在现有技术已知的压制机中，以4至15kN，优选6至8kN压力下方便地完成。最后的加压步骤可以在1500至3000kg·cm-2，特别在1600至2000kg·cm-2压力范围内完成。
本发明之意义可以加以延伸，并且包括用前述方法所得的产品。
本发明也涉及使用0.2％至5％(w/w)硬脂酰苯甲酸钠作润滑剂和80％至98.8％(w/w)预胶质化淀粉，1至10％生成亲水基质的聚合物，来生产生物粘着剂型。
本发明的颊含片可如下施用。将含片置于龈上，优选在上犬牙部位，通过在面颊上轻轻加压1分钟来固定。然后优选将该药片用舌润湿以防止药片粘到面颊上。
由于有长的粘着时间(约9小时)和缓慢的从口腔中的清除速度，牙龈被认为是最好的位置或施用点。
试验部分实施例1：硝酸双氯苯咪唑10mg缓释颊含片。现有技术配方(欧洲临床药理学杂志(1992)43：137-140)硝酸双氯苯咪唑                 10mg转鼓烘干的蜡状玉米             82.8mgCarbopol 934                5mg二氧化硅                    0.2mg苯甲酸钠                    2mg将粉末在Turbula混合器中混合10分钟，并直接压成总重量为100mg的片。改进的配方硝酸双氯苯咪唑(微粉)        10mg转鼓烘干的蜡状玉米          82.8mgCarbopol 974P               5mg胶态无水硅石                0.2mg硬脂酰富马酸钠              2mg乙醇*                      适量
*乙醇仅在湿成粒制片法中使用，并且不存在于最终产品中(每克干燥的最终制剂中使用大约0.1克乙醇)。湿成粒法(小规模)
将硝酸双氯苯咪唑和转鼓干燥的蜡状玉米和Carbopol 974P，在行星式混合器中进行混合直至均匀，然后用乙醇润湿。将类似生面团的膏加压过筛(筛孔1.8mm)，并于环境温度和常压下干燥。当干燥时，将颗粒与胶态无水硅石和润滑剂一起混合至均匀。然后在装有6.5mm扁平冲头的Korsch压制机上将上述颗粒压成总重量为100mg的片。干压(工业规模)
在行星式混合器中，将1公斤硝酸双氯苯咪唑(微粉)，8.28公斤转鼓烘干的蜡状玉米和0.5公斤玻璃纤维增强剂聚碳酸酯(Carbopol974P)混合至均匀。将混合物移至滚筒压力机并压紧成薄片。将所得薄片破碎并在振动筛(筛孔1mm)上过筛标定。然后收集这样得到的颗粒并和20克胶态无水硅石(Aerosil 200)和200克硬脂酰富马酸钠混合至均匀。在装有6.5mm扁平冲头的Korsch压制机上将该混合物压成标定重量为100mg的100000个扁平片。实施例2
遵循实施例1的湿成粒方法，制得了具有下述配方的另外两种硝酸双氯苯咪唑缓释颊含片。
                      1mg片        5mg片硝酸双氯苯咪唑(微粉)      1mg          5mg转鼓干燥的蜡状玉米淀粉    91.8mg       87.8mgCarbopol 974P             5mg          5mg胶态无水硅石              0.2mg        0.2mg硬脂酰富马酸钠            2mg          2mg乙醇*                    适量         适量
*乙醇不出现在最终产品中(对每克最终干制剂使用大约0.1克乙醇)。实施例3：曲安西龙1mg缓释颊含片微粉曲安西龙                           1mg转鼓干燥的蜡状玉米淀粉                 91.8mg硬脂酰富马酸钠                         2mgCarbomer 974P                          5mg胶态无水硅石                           0.2mg
遵循小规模湿成粒方法和前面实施例中所述的工业干燥加压法，制备若干批曲安西龙1mg缓释颊含片。实施例4：一次和多次口服施药后在健康志愿者的唾液中咪康唑的浓度
    (μl/ml)
  治疗     天   时间    中值   平均值    标准差     n
  A     18   0h15分30分45分60分90分2h3h4h6h8h12h0h15分30分45分60分90分2h3h4h6h8h12h    NQ2.53.620.512.122.421.833.937.824.77.3NQNQNQ4.77.28.013.823.033.917.814.013.1NQ   NQ5.614.220.818.728.124.035.336.325.314.7NQNQ4.216.620.424.531.229.735.724.315.916.9NQ    -7.525.520.828.625.515.120.516.916.016.3--6.734.732.932.834.218.719.518.116.618.4-     121212121212121212121212121212121212121212121212
  治疗    天   时间    中值    平均值     标准差     n
   B    18   0h5分15分30分45分60分90分2h3h4h0h5分15分30分45分60分90分2h3h4h    NQ41.36.21.5NQNQNQNQNQNQNQ56.93.21.1NQNQNQNQNQNQ    NQ60.28.31.9NQNQNQNQNQNQNQ75.95.31.7NQNQNQNQNQNQ     -53.29.81.8-------64.64.42.3------     1212121212121212121212121212121212121212
治疗A：10mg硝酸双氯苯咪唑(用湿成粒法制备的实施例1的改进配
   方)作为生物粘着颊含片每日一次共8天。治疗B：60mg咪康唑制成3g口服制剂给药(20mg/g)，每日四次，8
   天NQ：用GC方法不能定量(＜1.0μg/ml)实施例5
以实施例1的改进片剂进行体外溶解研究。介质是在37℃，在Apparatus 2(USP 23，<711>Dissolution，pp.1791 1793)(叶片，每分钟50转)中的600ml 2-丙醇/水(60/40)的混合物。在每次溶解试验中使用3片10mg(给的总剂量30mg)硝酸双氯苯咪唑；于规律的时间间隔从溶解介质中取出3ml样品，并测定在UV 260-300mm波长范围处的吸收来确定溶于其中的咪康唑的浓度。在下表中，溶于介质中的咪康唑的量以总剂量的(％w/w)表示。A.湿成粒法制得的片剂
                      活性剂量的计算浓度(％w/w)
 时间(分)    样品1   样品2    样品3   样品4   样品5    样品6    平均值
    01530601201802403604801440    0.008.2616.1621.5431.4137.7049.3755.6564.6295.14   0.008.9814.3620.6431.4139.4951.1658.3466.4295.14    0.009.8716.1622.4435.9038.5950.2660.1468.2198.73   0.008.8913.4621.5434.1138.5948.4758.3466.4298.73   0.009.8715.2620.6432.3140.3950.2658.3467.3297.83    0.0012.5715.2621.5432.3139.4949.3760.1465.5296.04    0.009.7415.1121.3932.9139.0449.8158.4966.4296.94
B.干压法制得的片剂
                       活性剂量的计算浓度(％w/w)
 时间(分)   样品1    样品2   样品3    样品4   样品5   样品6  平均值
   0306090180240   0.0018.8543.0858.3483.47100.53    0.0018.8533.2153.8575.3985.27   0.0017.9535.0052.0680.7885.27    0.0015.2632.3151.1683.4796.94   0.0021.5439.4954.7578.0986.16   0.0018.7635.9050.2676.2982.57   0.0018.5336.5053.4079.5889.46
应该指出，上述溶解数据是在不常用的介质2-丙醇/水(60/40)中获得的，目的是为了加速溶解速率。改变所加的压力和压实的力量也得到比上表中显示的数据或慢或快的溶解速率。简言之，上面的数据达到了证明按本发明制备的片剂的缓释性能的目的，但是，自然不能用来显示湿成粒法和干压实法之间的任何可识别的确切的特征。实施例6：体外测定生物粘着力
按照前述的方法(S.Bouckaert，J.P.Remon，缓释咪康唑颊含片的体外粘着力，药品药理学杂志(J.Pharm.Pharmacol.)45：504-507(1993))评价含片的生物粘着力。分离力和粘着功，由该力对拉伸长度作图的曲线高和曲线下的面积来决定。仪器由装有20N负载传感测力器的拉力试验机(型号L1000R，Lloyd Instruments，Segenworth，Fareham，UK)组成。猪龈从屠宰场获得，屠宰后直接切出来。将粘膜(±100mm2)于-20℃贮存于pH7.4的等渗缓冲盐水中(将2.38gNa2HPO4H2O，0.19g KH2PO4，8.0g NaCl用脱矿物质水加至1000ml)。
将猪龈组织用氰基丙烯酸酯胶液(Loctite，Belgium)附着在下面的特氟隆支撑上，同时将药片附着在上面的铝冲头上。用15μl等渗磷酸盐缓冲盐水水合粘膜后，施加0.5N力5分钟使药片固定在粘膜上。初次接触后，用125ml pH7.4的等渗缓冲盐水充满烧杯。然后，用5mm/分速度将药片和粘膜拉开，直至药片-粘膜连结完全断开。
其结果以个体值和平均值(±SD)形式列于下表中。A：10mg咪康唑片(用湿成粒法制备的实施例1的改进配方)。B：10mg咪康唑片(用干压法制备的实施例1的改进配方)。C：实施例3的1mg曲安西龙片，用湿成粒法制备。
                                    分离力(N)
   样品1    样品2    样品3   样品4   样品5   平均值   标准差
  ABC    1.2191.2852.08    1.0861.4662.684    1.0681.5812.998   1.3531.3733.068   1.1261.5242.265   1.17041.44582.619   0.11760.11830.437
                          粘着功(mJ)
  样品1   样品2   样品3   样品4   样品5    平均值   标准差
  ABC   0.0920.2630.570   0.1150.1420.662   0.1310.1160.658   0.2080.1020.634   0.1220.1580.498    0.13360.15620.604   0.0440.06360.070

Claims (13)

1.生物粘着药物组合物，含有药物有效量活性组分，80％至98.8％(w/w)预胶质化淀粉，和1％至10％(w/w)生成亲水基质的聚合物，其特征在于该组合物还含0.2％至5％(w/w)碱金属C16-22烷基富马酸盐作为润滑剂。
2.按照权利要求1的组合物，其中润滑剂是微粉化硬脂酰富马酸钠。
3.按照权利要求1的组合物，含2.5至7.5％(w/w)生成亲水基质的聚合物。
4.按照权利要求3的组合物，其中聚合物是聚丙烯酸(Carbomer)、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、聚乙烯醇或其混合物。
5.按照权利要求1的组合物还含有助流剂。
6.按照权利要求5的组合物，其中助流剂是胶态无水硅石。
7.按照权利要求1的组合物，含有以总重量为基础的：0.001％至10％活性组分；80％至99.8％预胶质化淀粉；1％至10％生成亲水基质的聚合物；0.2％至5％硬脂酰富马酸钠；和0％至1％助流剂。
8.适于口内、鼻内、直肠内或阴道内给药的剂型，含有权利要求1至7之任一的组合物并且它被成形为片剂。
9.按照权利要求8的颊含片，含有以该片总重量为基础的：10％微粉硝酸双氯苯咪唑；82.8％转鼓干燥的蜡状玉米淀粉；2％硬脂酰富马酸钠；5％Carbomer 974P；和0.2％胶态无水硅石。
10.按照权利要求8的颊含片，含有以该片总重量为基础的：1％微粉曲安西龙；91.8％转鼓干燥的蜡状玉米淀粉；2％硬脂酰富马酸钠；5％Carbomer 974P；和0.2％胶态无水硅石。
11.制备片剂或胶囊的干制法，包括下述步骤：-将活性组分，预胶质化淀粉和生成亲水基质的聚合物在干燥状态紧密混合；-将这样得到的混合物压实为薄片；-将该片破碎为颗粒；-将该颗粒与润滑剂和任意地与助流剂一起混合；并且-将该混合物压成片。
12.按照权利要求11的方法得到的产品。
13.使用0.2％至5％(w/w)硬脂酰富马酸钠作润滑剂和80％至98.8％(w/w)预胶质化淀粉和1％至10％生成亲水基质的聚合物制备生物粘着剂型。
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CN105073099A (zh) * 2013-03-06 2015-11-18 诺华股份有限公司 有机化合物的制剂
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CZ298690B6 (cs) 2007-12-27
SI0869772T1 (en) 2002-04-30
CZ199298A3 (cs) 1998-09-16
HU228350B1 (hu) 2013-03-28
AU1308597A (en) 1997-07-28
KR100459029B1 (ko) 2006-03-27
HK1015680A1 (en) 1999-10-22
JP2000502691A (ja) 2000-03-07
DE69615704T2 (de) 2002-07-11
EA199800350A1 (ru) 1998-10-29
NZ325844A (en) 1999-06-29
NO320015B1 (no) 2005-10-10
CY2269B1 (en) 2003-07-04
WO1997024109A1 (en) 1997-07-10
HUP9802913A3 (en) 2000-06-28
ZA9610886B (en) 1998-06-23
CA2232152A1 (en) 1997-07-10
BR9612291A (pt) 1999-07-13
ES2164940T3 (es) 2002-03-01
HUP9802913A2 (hu) 1999-06-28
DE69615704D1 (de) 2001-11-08
ATE206304T1 (de) 2001-10-15
US6303147B1 (en) 2001-10-16
IL123636A0 (en) 1998-10-30
DK0869772T3 (da) 2002-01-21
KR19990067112A (ko) 1999-08-16
PT869772E (pt) 2002-03-28
EA000818B1 (ru) 2000-04-24
SK88798A3 (en) 1998-11-04
PL186278B1 (pl) 2003-12-31
SK283370B6 (sk) 2003-06-03
NO981027D0 (no) 1998-03-09
AU713849B2 (en) 1999-12-09
EP0869772B1 (en) 2001-10-04
NO981027L (no) 1998-06-15
CA2232152C (en) 2007-02-06
PL326196A1 (en) 1998-08-31
CN1146401C (zh) 2004-04-21
IL123636A (en) 2001-04-30
JP4317264B2 (ja) 2009-08-19
EP0869772A1 (en) 1998-10-14

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