CN1071835A - 含有反胺苯环醇物质和可待因、氧可酮或氢可酮任意之一的组合物及其用途 - Google Patents
含有反胺苯环醇物质和可待因、氧可酮或氢可酮任意之一的组合物及其用途 Download PDFInfo
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- CN1071835A CN1071835A CN92111382A CN92111382A CN1071835A CN 1071835 A CN1071835 A CN 1071835A CN 92111382 A CN92111382 A CN 92111382A CN 92111382 A CN92111382 A CN 92111382A CN 1071835 A CN1071835 A CN 1071835A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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Abstract
本发明涉及含有一种反胺苯环醇物质和可待因,
氧可酮或氢可酮中的任一种的组合物及其用途。组
合物在治疗疼痛、腹泻和咳嗽上有药理效用。与纯鸦
片剂组合物相比,本发明组合物产生的副作用要小,
例如药物依赖性,耐药性、便秘和呼吸压抑。更进一
步说,当组合物的成分,即一种反胺苯环醇物质和可
待因,氧可酮或氢可酮中的任一种,在一定的比例范
围内,组合物的药用效果是超加和(增效)作用的。
Description
美国专利3,652,589号中公开了一类镇痛的环烷环上具有碱性胺基的环烷醇取代苯酚酯,其中具体公开了化合物(1RS,2RS)反-2-[(二甲基胺基)-甲基]-1-(3-甲氧苯基)环己醇,通用名:反胺苯环醇。有关反胺苯环醇的药理;毒理和临床研究的一系列文章可见于Arzneim.Forsch(Drug Res.)28(1),114(1978)。Driessen等人在Arch.Pharmacol,341,R104(1990)中公开了反胺苯环醇通过一种既不完全与鸦片样物质相似也不与非鸦片样物质相似的机制产生镇痛效果。《第6届病痛世界大会文摘》(1990年4月1-6日)中揭示了反胺苯环醇盐酸盐是一种口服活性的纯兴奋剂鸦片样物质镇痛药。然而,临床试验表明,反胺苯环醇不具鸦片样兴奋剂的许多典型副作用,例如,呼吸压抑(W.Vogel等Arzneim.Forsch.(Drug Res.),28(1),183(1978)),便秘(I.Arend等Arzneim.Forsch.(Drug Res.),28(1),199(1978),耐药性(L.Flohe等Arzneim.Forsch.(Drug Res.),28(1),213(1978)),和药物依赖性(T.Yanagita,Arzneim.Forsch.(Drug Res.),28(1),158(1978)。然而,反胺苯环醇以50mg的剂量快速静脉注射时,要产生包括脸色潮红和出汗等对反胺苯环醇来说是独特的某些副作用。尽管有这些副作用,反胺苯环醇与非鸦片样物质和鸦片样物质活性的组合使得反胺苯环醇成为一种非常独特的药剂。反胺苯环醇最近被德国Grunenthal GMBH作为镇痛药推上市场。
鸦片样物质许多年来被用作镇痛药治疗严重病痛。然而,它们产生的不良副作用限制了其使用范围,这些副作用问题在文献中做了详尽描述。可见于,Jaffe,J著的Goodman and Gilman′s The Pharmacological Basis of Therapeutics,第8版;Gilman等Peragamon出版社,纽约,1990;第22章,522-573页,文中阐述了吗啡及其同类物,例如,可待因、氢可酮和氧可酮是鸦片样兴奋镇痛药,它们具有诸如呼吸压抑、便秘、耐药性和药物依赖性等副作用。
为减少副作用,将鸦片样物质与其它非鸦片样镇痛剂组合以减少产生等同镇痛作用所需的鸦片样物质的量。鸦片样物质量的减少一般来说减少副作用的数量和程度。据称,某些这类组合产品还具有产生协同镇痛效果的优点。例如,A.Takemori在Annals New York Acad.Sci.281,262(1976)中揭示了包括鸦片样镇痛药和非镇痛药剂组合的组合物显示出各种效果,即是,亚加和(拮抗),加和,或超加和等。R.Taber等在J.Pharm.Expt.Thera.,169(1)29(1969)中公开了吗啡和美沙酮(另一种鸦片样镇痛药)的组合显示出仅有加和效果。美国专利4,571,400号公开了另一种鸦片样镇痛药二氢可待因和一种非鸦片样镇痛药布洛芬的组合,当其成分在一定的比例范围内产生超加和效果。A.Pircio等在Arch.Int.Pharma-codyn.,235,116(1978)报道了另一种鸦片样镇痛药环丁甲二羟吗南和一种非鸦片样镇痛药扑热息痛(APAP)1∶125混合物的超加和镇痛作用,而它的1∶10混合物却不显示任何统计意义的超加和镇痛作用。
然而,现有技术中并未提示或公开反胺苯环醇,一种非典型的鸦片样镇痛药,可以或应当与其它镇痛药,特别是一种鸦片样镇痛药组合,以减少各自的副作用,或者产生一种显示出超加和镇痛作用的组合物。
业已发现,包括如后文中所定义的反胺苯环醇的各种形式的反胺苯环醇物能与一些鸦片样物质,可待因、氧可酮和氢可酮组合产生镇痛效果。这些鸦片样物质均为一类具有同样核心结构的鸦片样物质的一员,即是,每一种都在芳基部分有一个3-甲氧基取代基。组合物用的反胺苯环醇和鸦片样物质两者的量要比单独使用每种成分,产生同样镇痛效果所需的量要少。由于两种药用量减少,与每种药相关联的副作用在数量和程度上减少。令人惊奇的是,包含反胺苯环醇物和可待因,氧可酮或氢可酮中的任一种的组合物业已发现在一定的比例组合时显示协同镇痛效果。根据本发明的组合物在治疗咳嗽和腹泻上也有作用。
参考下列的附图能更容易理解本发明:
图1为等辐射热图,显示反胺苯环醇盐酸盐和可待因磷酸盐组合物的小鼠尾动反应潜伏时间(tail-flick latency)试验的镇痛效果;和
图2为等辐射热图,显示反胺苯环醇盐酸盐和氧可酮盐酸盐组合物的小鼠尾动反应潜伏时间试验的镇痛效果。
本发明涉及包含一种反胺苯环醇物质和可待因、氢可酮或氢可酮任一种的组合物及其混合物。
根据本发明,反胺苯环醇原料是指(1R,2R或1S,2S)-(二甲胺基甲基)-1-(3-甲氧苯基)-环己醇(反胺苯环醇),它的N-氧化衍生物(“N-氧化反胺苯环醇”),和它的O-脱甲基衍生物(“O-脱甲基反胺苯环醇)之一种或 其混合物。它还包括各种立体异构体,包括外消旋体的立体异构体混合物,药学上可接受的胺盐,诸如盐酸盐,溶剂化物和其多晶型物。反胺苯环醇可从Grunenthal公司购买或可通过在此列为参考的美国专利3,652,589号中所描述的方法制备。
N-氧化反胺苯环醇的制备在有机溶剂,例如甲醇或异丙醇中,加热(但优选不加热)的条件下,用氧化剂,例如过氧化氢(30%)处理作为游离碱的反胺苯环醇。见“Reagents For Organic Synthesis”,1,471,Fieser & Fieser编,Wiley N.Y;(1987)和B.Kelentey等Arzneim.Forsch.7,594,(1957)。若加热,反应花费约1小时,而不加热反应时间为约3天。氧化之后,混合物接着用试剂,例如PtO2或优选Pt/C处理约1天,分解掉过剩的过氧化氢。将混合物过滤,接着蒸发滤液,残留物从有机溶剂混合物(例如二氯甲烷/乙酸乙酯)中重结晶。
O-脱甲基反胺苯环醇的制备通过在O-脱甲基化反应条件,例如加热回流的条件下用强碱诸如NaH或KH,苯硫酚和二甘醇(DEG)与作为游离碱的反胺苯环醇反应。见,Wildes等J.Org.Chem.,36,721(1971)。反应时间约为1小时,接着冷却和在水中骤冷反应混合物。将骤冷的混合物酸化,用有机溶剂如乙醚萃取,碱化,再用卤代有机溶剂如二氯甲烷再萃取。干燥萃取物,蒸发溶剂得O-脱甲基化产品,可再将其短路蒸馏,转化成相应的盐,例如用酸性溶液(HCl/乙醇)处理,从有机溶剂混合物例如乙醇/乙醚中重结晶。
可待因、氧可酮和氢可酮包括它们基本的形态和制药上可接受的盐。诸如磷酸盐,硫酸盐,盐酸盐和酒石酸盐等。可待因、氧可酮和氢可酮的制备分别公开于Goto等的Proc.Japan Acad.30,769(1954)Freund等的J.Prakt.Chem.,94,135(1916)和美国专利2,715,626号。
通常给出的反胺苯环醇物质和鸦片样物质的重量比为约200∶1至1∶20。在所公开范围内的比例变化依据组合物特定的成分而定。在此范围内的某些比例的组合物显示协同镇痛效果。例如,包含反胺苯环醇和可待因,成分比例为约20∶1至1∶20,优选的为2∶1至1∶2,更优选的为2∶1至1∶1的组合物;包含反胺苯环醇和氧可酮,成分比例为从约200∶1至1∶1,更优选的为从约20∶1至2∶1的组合物。
含有反胺苯环醇物质和可待因,氧可酮或氢可酮之任一种作为活性成分,与药用载体紧密掺合的组合物,可采用惯常的制药配合技术来制备。依据所需给药形式,例如静脉,口服或肠道外给药,载体可以采用多种形式。组合物也可用气雾剂的方法给药。制备口服剂组合物时,可采用任何常见的制药介质。例如,若配制口服液剂(诸如悬浮剂,酏剂和溶液液),可采用水、甘醇、油、醇、芳香剂、防腐剂、着色剂等等。若配制口服固体剂(诸如粉剂、胶囊剂和片剂),可采用诸如淀粉、糖、稀释剂、颗粒化剂、润滑剂、粘合剂,崩解剂等等。片剂和胶囊剂由于便于服用而成为最便利的口服单位剂量形式,在这种情况中常采用固体药剂载体。如果需要,片剂可以由标准技术裹糖衣或肠衣。对于肠道外给药,载体除可包括其它成分外通常还包含帮助溶解或为保存目的的无菌水。也可制备可注射悬浮剂,在此情况下,可采用适当的液体载体、助悬剂等。药用组合物通常以剂量单位的形式存在,例如,片剂、胶囊剂、粉剂、针剂、匙剂等等,其量从约0.001至约50.0mg/Kg,优选从约0.003至约25.0mg/Kg活性成分。
下列试验例对本发明作更具体的描述,只是一种说明问题的方法而非限制本发明。
例1 反胺苯环醇和可待因合剂的制备
为药剂组合试验(表1)中采用的各种药的每一种比例,根据两倍于每种药的剂量来制备贮液,该浓度以mg药/5ml蒸馏水表示。如,若反胺苯环醇∶可待因比为1∶20时,则9.1mg反胺苯环醇盐酸盐(等于当反胺苯环醇以碱形式存在时为8.0mg)和217.1mg可待因磷酸盐(等于可待因游离碱160.0mg)各自溶解在5ml管瓶蒸馏水中构成各自的储液。将每种储液等体积合并制备最终所需的各10ml蒸馏水的药剂组合物。例如,5ml反胺苯环醇储液与5ml可待因储液合并得10ml水中1∶20的剂量(即是8mg反胺苯环醇∶160mg可待因)。然后将10ml/Kg的储液注射小鼠。见表1,用同样的方式分别制备每一种比例,以每只小鼠10ml/Kg的体积药量注射。
例2 反胺苯环醇和氧可酮合剂的制备
反胺苯环醇/氧可酮组合的不同比例的制剂是通过配制以mg药/10ml溶解水浓度表示的储液来完成的。例如,80mg反胺苯环醇游离碱和4mg氧可酮游离碱溶于10ml水得每10ml水反胺苯环醇/氧可酮组合(80mg∶4mg)的储液。再将药物组合物的储液用足量的蒸馏水稀释,制备每10ml溶解水较低剂量的药物组合物。例如,5ml 20∶1反胺苯环醇/氧可酮组合物储液用等体积的蒸馏水稀释,得较低的20∶1剂量,即是每10ml水(40mg∶2mg)组合物。每一种比例按同样的方法分别制得,按每只小鼠10ml/Kg的体积药量注射。
例3 反胺苯环醇和氢可酮合剂的制备
反胺苯环醇/氢可酮组合的不同比例的制剂是通过配制以mg药/10ml溶解水浓度表示的储液来完成的。例如,160mg反胺苯环醇游离碱和160mg氢可酮游离碱溶解于10ml水中得每10ml水(160mg∶160mg)反胺苯环醇/氢可酮组合的储液。再将药物组合的储液用足量的蒸馏水稀释得每10ml溶解水较低剂量的药物组合。例如,5ml 1∶1反胺苯环醇/氢可酮组合储液用等体积蒸馏水稀释,得较低的1∶1剂量即每10ml水(80mg∶80mg)组合。
例4 N-氧化反胺苯环醇其合成及与一种鸦片样物质合剂的制备
首先,按下文所述制备N-氧化反胺苯环醇。将反胺苯环醇盐酸盐(0.5ml)在碱化水(pH>9)中转化成游离碱,然后用乙醚萃取。将乙醚蒸发得反胺苯环醇结晶水合物。该固体在高真空中用蒸气加热尽可能多的去除水,得约131.5g物质。将此物溶于(500ml)甲醇中,加入65g30%的H2O2。将溶液搅拌3小时,然后再加入65g 30%的H2O2。反应在室温下搅拌2.5天。加约10mg炭载P+O2(使用P+/C是因其容易去除),这时慢慢产生泡沫。再加另一份10mg PtO2,反应混合物搅拌过夜,然后加助滤剂过滤。在加热温度<40℃,真空条件下浓缩滤液。残留物用二氯甲烷处理。因为该二氯甲烷溶液含有一些胶态铂,因此该溶液用乙酸乙酯稀释至1升,经尼龙滤膜(0.45μ孔径)过滤得清彻的无色滤液。浓缩滤液至600ml,然后在加热该溶液时连续添加乙酸乙酯,保持800ml体积直至蒸气温度达到74℃。将溶液冷却至室温。过滤收取固体,用乙酸乙酯洗涤,真空干燥得126.6g N-氧化反胺苯环醇(mp.159.5-160℃)。
C16H25NO3理论值 C,68.78;H,9.27;N,5.01
实测值 C,68.65;H,9.22;N,4.99
N-氧化反胺苯环醇/鸦片样物质组合的不同比例的制剂通过配制相应N-氧化反胺苯环醇/鸦片样物质组合的特定比例的最高剂量的储液来实现,该浓度以mg药/10ml蒸馏水表示。例如,160mg N-氧化反胺苯环醇游离碱和160mg鸦片剂氧可酮游离碱溶于10ml蒸馏水得最高剂量的1∶1 N-氧化反胺苯环醇/氧可酮组合物,每10ml蒸馏水(160mg∶160mg)。该药物组合的储液再用足量的蒸馏水稀释制备每10ml溶解水较低剂量的药物组合。例如,5ml 1∶1 N-氧化反胺苯环醇/氧可酮组合储液用等体积蒸馏水稀释得较低的1∶1剂量,即是每10ml水(80mg∶80mg)组合。以同样的方式分别制备每一种比例,以每只小鼠10ml/Kg的体积药量注射。
例5 O-脱甲基反胺苯环醇的(-)和(+)对映体:
其合成和O-脱甲基反胺苯环醇与一种鸦片样物质合剂的制备
首先,按下文所述制备O-脱甲基反胺苯环醇。将二甘醇(125ml)在加以冷却,温度保持在<50℃的条件下加入KH(9.5g)中。于该溶液中加入溶于二甘醇(25ml)的苯硫酚(10ml),然后加入溶于二甘醇(50ml)的(-)反胺苯环醇游离碱(9.3g)。最终反应混合物缓慢加热回流45分钟。将混合物冷却,用水骤冷。将pH调至约为3,用乙醚萃取混合物。将pH再调至约为8,再将此混合物用二氯甲烷萃取5次。将萃取液干燥,蒸发二氯甲烷得4.6g标题化合物。馏出(Kugelrohr)标题化合物(4.6g),溶于四氢呋喃,用乙醇/HCl溶液处理得2.3g其盐酸盐。用乙醇/乙醚重结晶该盐,干燥,得1.80g O-脱甲基反胺苯环醇(-)对映体的盐(mp.242-3℃),[α]25 D=-32.9(C=1,EtOH)。
C15H23NO2·HCl 理论值 C,63.04;H,8.46;N,4.90
实测值 C,63.00;H,8.51;N,4.94
制备标题化合物的(+)对映体,除了用(+)-反胺苯环醇游离碱代替(-)-反胺苯环醇外,该反应在同样条件下进行,产生2.48g的O-脱甲基反胺苯环醇(+)对映体(mp.242-3℃),[α]25 D=+32.2(C=1,EtOH)。C15H23NO2·HCl 理论值 C,63.04;H,8.46;N,4.90
实测值 C,63.14;H,8.49;N,4.86
O-脱甲基反胺苯环醇/鸦片样物质组合物的不同比例的制剂通过配制相应O-脱甲基反胺苯环醇/鸦片样物质组合物的特定比例的最高剂量储液来实现,该浓度以mg药/10ml蒸馏水表示。例如,160mg O-脱甲基反胺苯环醇游离碱和80mg鸦片剂氢可酮游离碱溶于10ml蒸馏水得最高剂量的2∶1 O-脱甲基反胺苯环醇/氢可酮组合物,即每10ml蒸馏水(160mg∶80mg)。该药物组合的储液再用足量的蒸馏水稀释制备每10ml溶解水较低剂量的药物组合。例如,5ml 2∶1 O-脱甲基反胺苯环醇/氢可酮组合储液用等体积蒸馏水稀释得较低剂量的2∶1组合,即是每10ml水(80mg∶40mg)。以同样的方式分别制备每一种比例,以每只小鼠10ml/Kg的体积药量注射。
例6 镇痛活性
采用雄CD1小鼠(体重为18-24g)测定与本发明组合物相关的镇痛效果。一些小鼠口服剂1中制备的组合物,示于表Ⅰ,另一些小鼠口服例2中制备的组合物,示于表Ⅱ,剂量体积为10ml/Kg。
镇痛活性采用F.D′Amour等在J.Pharmacol.Exp.Ther.,72,74(1941)所描述的尾动试验来评估。该试验包括将小鼠的尾巴对准聚焦的热刺激源,检测其应答,即尾巴从刺激源抽动(移开)。首先在未服任何药物组合物时测试应答的反应时间(反应潜伏期),服用本发明组合物15分钟后重复测试一次,其中组合物成分为各种比例。每只小鼠只作一次给药前和给药后测试。
对每一种固定比例的组合物的可能的超加和作用的分析测定采用R.J.Tallarida等在Life Sci.,45,947(1989)中发表的方法。这种方法涉及测定要求产生特定的效果水平的混合物总量,如50%(ED50mix)效果,和相应的所预期的简单加和(ED50add)效果的总量,对于一种具体的固定比例,如果ED50mix<ED50add则这种组合比例就为超加合。ED50mix和ED50add都是随机变量。ED50mix是从特定比例剂量应答曲线估计的,ED50add是由两种药剂相加效果的ED50合并估算而得。ED50mix通过t-试验与ED50add比较。单独的反胺苯环醇盐酸盐ED50值(95%置信区间)为76.8(59.2-99.7)mg/Kg。单独的可待因磷酸盐ED50值(95%置信区间)为71.3(52.0-99.7)mg/Kg,对于氧可酮其ED50为4.2(3.0-5.8)。
反胺苯环醇和可待因或氢可酮之间的相互作用用反胺苯环醇盐酸盐和可待因或氧可酮的准确剂量比例测定。采用一种保证各分开的剂量形式试验完全随机的试验设计,15分钟后,对每种选择的组合的重复(典型的4-6次)编码剂量研究其镇痛效果。
表Ⅰ和表Ⅱ的数据以及图Ⅰ和图Ⅱ的Loewe等辐射热图(有关等辐射热图的制作和基础见S.Loewe,Pharm.Rev.,9;237(1957))分别表示反胺苯环醇盐酸盐和可待因磷酸盐或氧可酮硫酸盐在小鼠尾动潜伏时间试验中的相互作用。在附图中,连结两种给定药物的ED50值的斜线代表以不同成分比例构成的组合物效果的简单加和。与斜线相邻的两条虚点线限定95%置信区间。落于曲线之下(该线和原点之间)的ED50值表示有超加和作用,即预料之外的增效。由原点处放射状伸出的短横斜线代表小鼠服用的组合药物剂量中用的反胺苯环醇盐酸盐与可待因磷酸盐(图Ⅰ)或氧可酮硫酸盐(图Ⅱ)的剂量比例。通过反胺苯环醇和可待因或氧可酮组合物ED50点的短线代表ED50的95%置信区间。
图Ⅰ中表示的试验数据表明,反胺苯环醇 与可待因的比例为1∶20至20∶1(由曲线表示)的组合物具有预料之外的增高活性,因为ED50mix小于ED50add。图Ⅱ中表示的试验数据同样表明,反胺苯环醇与氧可酮为200∶1至1∶1的组合物也具有预料之外的增高活性。更进一步说,由于氢可酮与氧可酮具同样的活性形式和化学结构,可以预料在组合物中采用氢可酮会得到一种与含有氧可酮组合物相同活性的组合物。
Claims (16)
1、一种药用组合物,它包括一种反胺苯环醇物质和一种选自由可待因、氧可酮和氢可酮组成的组群的鸦片样物质。
2、权利要求1的药用组合物,其中反胺苯环醇物质和鸦片样物质的配比为足以产生协同药用效果的比例。
3、权利要求2的药用组合物,其中的鸦片样物质为可待因。
4、权利要求3的药用组合物,其中的反胺苯环醇物质为反胺苯环醇盐酸盐。
5、权利要求4的药用组合物,其中的反胺苯环醇盐酸盐为外消旋体。
6、权利要求5的药用组合物,其中的比例为约1∶20至20∶1的重量比。
7、权利要求6的药用组合物,其中的重量比为约1∶2至2∶1。
8、权利要求7的药用组合物,其中的重量比为约1∶1至2∶1。
9、权利要求2的药用组合物,其中的鸦片样物质为氧可酮。
10、权利要求9的药用组合物,其中的反胺苯环醇物质为反胺苯环醇盐酸盐。
11、权利要求10的药用组合物,其中的反胺苯环醇盐酸盐为外消旋体。
12、权利要求11的药用组合物,其中的比例为约200∶1至1∶1的重量比。
13、权利要求12的药用组合物,其中的重量比为药20∶1至1∶1。
14、权利要求1的药用组合物还含有一种药学上可接受的载体。
15、一种治疗哺乳动物药理学病态的方法,它包括给哺乳动物施用有效量的权利要求1的药用组合物。
16、权利要求15的方法,其中的药理学病态是疼痛。
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US75592391A | 1991-09-06 | 1991-09-06 | |
US755,923 | 1991-09-06 |
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DE69215316T2 (de) | 1997-03-20 |
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CA2077637A1 (en) | 1993-03-07 |
AU2218592A (en) | 1993-03-11 |
EP0534628B1 (en) | 1996-11-20 |
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GR3022515T3 (en) | 1997-05-31 |
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CN1051705C (zh) | 2000-04-26 |
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HU217584B (hu) | 2000-02-28 |
ZW14392A1 (en) | 1994-05-11 |
IL103070A (en) | 1996-10-16 |
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NO923453L (no) | 1993-03-08 |
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CA2077637C (en) | 2007-01-09 |
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DE69215316D1 (de) | 1997-01-02 |
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