CN88101379A - 实现避孕的方法及组合物 - Google Patents
实现避孕的方法及组合物 Download PDFInfo
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- CN88101379A CN88101379A CN88101379.XA CN88101379A CN88101379A CN 88101379 A CN88101379 A CN 88101379A CN 88101379 A CN88101379 A CN 88101379A CN 88101379 A CN88101379 A CN 88101379A
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- melatonin
- progestogen
- estrogen
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Abstract
本发明公开了一种实现妇女避孕的方法。该方法包括施用有效量的褪黑激素来抑制排卵。可任意地将褪黑激素同孕激素和/或雌激素结合用药。本发明还公开了一种通过施用褪黑激素来预防妇女乳房癌的方法。
Description
本发明涉及抑制妇女排卵的方法。更具体地说,本发明涉及通过施用能抑制排卵的有效量的褪黑激素来抑制排卵的方法。可任意地将褪黑激素同孕激素和/或雌激素结合起来施用。
在人体避孕领域中的研究和发展一直都集中在用物理及化学的方法来阻挡精子的转移,例如,一般采用阴道泡沫材料、隔膜、子宫内避孕器和避孕套,以及集中在含一种或多种类固醇激素的口服避孕药方面。目前已研制出能有效实现避孕的口服避孕药。全世界大约有5千万妇女使用口服避孕药。一般,口服避孕药采取孕激素与雌激素相结合的形式。在这种称之为结合程序的大多数人中的一些人,在整个投药期内,每天以雌激素和孕激素的连贯剂量用药。在其他称之为连续程序的大多数人中,在月经周期内,雌激素或孕激素的量,或两者的量,或多或少。某些连续程序提供两期的抑制。(例如见美国专利3,969,502。)其他的程序提供三期或三种成分结合。(见美国专利4,628,051和4,390,531。)第三种类型程序也是已知的,是在整个月经周期每天施用一种或多种孕激素。
口服避孕药中的激素在中框神经系统和泌尿生殖道的组织中起作用,抑制生殖功能。这种作用的重要位置是下丘脑和垂体,从而阻止黄体激素(LH)的中期高潮,阻止排卵。口服避孕药后,抑制了使用者的LH与促卵泡成熟激素(FSH)的基本浓度和雌二醇与孕酮的血浆水平。实际上,避孕药是通过激素水平的变化而发生作用的,这类变化模拟由于怀孕而引起的变化。避孕效果由剂量所决定。一般,在一个妇女周期的最少的21天里,施用这些普通的口服避孕药,某些情况下,在周期的整个28~30天的时间里服用。
口服避孕药还对泌尿生殖道产生直接影响。这类药改变了子宫内膜的结构和物理化学组成,改变了颈粘液的稠度,从而改变了子宫使卵子植入的能力。
已经证明,口服避孕药所带来的好处决不单单是防止怀孕。同未使用者相比,使用口服避孕药的妇女患盆腔炎疾病(PID)、异位怀孕、子宫癌和良性乳房疾病的危险性较小。最显著的是,目前的结合型避孕药还可降低卵巢癌的发生率。口服避孕药还可解除常见的月经紊乱、包括月经无规则、经前紧张、过量失血和痛性痉挛。
然而,使用普通的口服避孕药也伴随一定的危险。这些危险包括较有可能患上静脉血栓塞、局部缺血的心脏病、脑血管病和高血压。一般认为,这些病主要是由于避孕药中的雌激素成分(一般为炔雌醇或炔雌醇甲醚)造成的。患这些症状的可能性较大的妇女主要是35岁以上的,尤其是35岁以上的吸烟妇女。接受了雌激素的妇女还可能受到其他副作用的影响,这些副作用包括胃肠失调、噁心和体重增加。
为了避免由于含有雌激素的口服避孕药造成的副作用,研制出了仅含一种或多种孕激素(作活性成分)的口服避孕药。然而,这类避孕药的效力低于同时含雌激素和孕激素的避孕药。口服仅含孕激素的避孕药所产生的一个主要的副作用是在月经周期里出现突破性的出血。
鉴于普通口服避孕药存在的缺陷和副作用,必须寻求一种新的避孕药。因而,本发明的一个目的在于提供一种高效的避孕方法,该方法具有若干优点,可避免目前所用的避孕药会产生的副作用。本发明的另一目的是提供一种降低妇女乳房癌发生率的方法。
本发明公开了一种实现育令妇女避孕的方法,即:通过施用有效剂量的褪黑激素来阻止排卵。可任意地将褪黑激素同孕激素和/或雌激素结合施用。在最佳实施例中,以口服剂量形式施用本发明的避孕药。本发明还公开了通过施用有效剂量的褪黑激素来防止乳房癌的方法。
褪黑激素(N-乙酰基-5-甲氧色胺)是由松果腺合成及分泌的激素。激素的确切作用目前还未确定。研究表明,在一天的特定时间给Syrian金色仓鼠注射褪黑激素,可对其生殖腺的发展、雄性鼠睾丸的重量和雌性鼠的排卵产生抑制作用。然而,对其他哺乳动物注射褪黑激素后,却未显示出类似的结果。具体地说,对羊施用褪黑激素(Kenneway,D.J.et al,J.Reproauctive Fertility 73∶859〔1985〕及对灵长目动物施用褪黑激素(Reppert,S.M.,et al,Endocrin.104∶295〔1979〕),未直接改变其生殖机能。结合如下一种假说,并联系睡醒节律和由于时区变化造成的飞行后生理节奏破坏的现象,以药物动力学角度,来研究施用外源的褪黑激素对人体的影响。所述的假说是:不规则的褪黑激素节律与内源抑制相关联(Waldhauser,F.Neuroendocrinology 39∶307,313〔1984〕)。
本发明是基于这样的发现,即:有选择地将生理上适宜的日剂量的褪黑激素施用于妇女,可抑制其正常月经中期的黄体激素高潮,足以阻止排卵。本发明旨在提供一种实现育令妇女避孕的方法,即:在其排卵日前,通过每天对其施用有效量的褪黑激素,来抑制黄体激素高潮,进而阻止排卵。
本发明的目的还在于提供一种防止妇女乳房癌发生的方法。已经发现,施用生理上适宜的褪黑激素可在各种啮齿动物中防止7,12-二甲基苯并蒽(DMBA)引起的腺癌。还发现,患有雌激素受体阳性乳房癌的妇女的夜间褪黑激素浓度减低(Tamarkin,D.et al.,Science216∶1003~1005(1982))。虽然不能指望从推测来说明,但可以相信,施用生理上可接受剂量的褪黑激素,能够阻止月经周期中发生的乳房组织中细胞的集结。一般认为,这种细胞集结如果持续时间较长,就会导致发展成肿瘤,而施用褪黑激素则能使细胞的生长趋于稳定,从而在每一生殖周期中使乳房组织的细胞数得到平衡。
本说明书中所采用的术语“褪黑激素”还包括施用于妇女时具有抑制排卵作用的褪黑激素类似物。这类褪黑激素类似物包括6-氟褪黑激素、5-羟色胺、5-甲氧基吲哚和5-甲氧色胺。其他这类褪黑激素类似物包括美国专利4,087,444和美国专利4,614,807中所公开的那些,本说明书中将此用作引证。
以日剂量施用褪黑激素(或褪黑激素类似物)可充分抑制使用者的正常黄体激素高潮,从而阻止排卵。一般情况下,对服用褪黑激素的妇女而言,每70kg体重施用2mg至1000mg褪黑激素;较理想的是,每日施用褪黑激素30mg至5mg特别好是7.5-3mg。
在整个妇女月经周期可每天服用褪黑激素。然而,已发现,在妇女的正常排卵日之前,于其周期内的1~14天里施用褪黑激素,可达到避孕的效果。排卵一般发生于第十四个周期日,或者说,发生于妇女月经周期的第九至第十七日之间。利用这个程序服用褪黑激素,效果最佳。程序类型的选择,会影响褪黑激素的日施用量。同样,每次提供的日剂量随选择的给药方式的不同而不同。
可以按口服、非肠道或植入的形式向妇女提供褪黑激素。如果褪黑激素呈口服剂量形式,如胶囊、片剂,悬浮液或溶液,则给药最方便。胶囊或片剂最为理想。可根据常规的步骤,将化合物同药物上可接受的赋形剂混合、然后用混合物填充明胶胶囊,制备出胶囊剂。或者,可把褪黑激素同一种或多种润滑剂如硬脂酸或硬脂酸镁、调味剂、崩解剂如包括土豆淀粉、藻酸、粘合剂,例如明胶和玉米淀粉和/或片剂基质混合,压制成片;所述片剂基质包括乳糖、玉米淀粉和蔗糖。
作为口服给药的另一方式,可经非肠道或呈固体植入的方式提供褪黑激素。就非肠道给药而言,可采用溶于生理上可接受的稀释液、与药物上可接受的载体结合的激素的溶液或悬浮液,以注射剂量的形式提供褪黑激素。所述的载体可包括水或油,并且还可任意地含表面活性剂或其他药物上可接受的佐剂。适宜的油类包括动物油、植物油、石油或经加工而成的油类,包括花生油、大豆油、玉米油、芝麻油、蓖麻油和矿物油。最佳的液体载体包括水、盐水、糖水溶液和甘醇,如1,2-丙二醇或聚乙二醇。
还可以植入的形式施用褪黑激素。对此,配制时须保证褪黑激素将延迟持续释放。可按照常规的植入技术,将褪黑激素压制成小圆柱体,置于生理上可接受的壳体材料(如可生物降解的或多孔的聚合物)内。
在本发明的一个最佳实施例中,将褪黑激素与孕激素结合在一起施用。加入孕激素是为了引起类似周期月经出血的周期性出血,并提供含孕激素的传统口服避孕药的优点。任何具孕激素性质的活性化合物都适于用作本发明的孕激素组分。适宜的孕激素包括孕酮及其衍生物。目前,最佳的孕激素是炔诺酮(19-去甲-17α-乙炔-17β-羟基-4-雄烯-3-酮)和甲基炔诺酮(13β-乙基-17α-乙炔基-17β羟基gon-4-烯-3-酮)。其他雌激素包括氯地孕酮(6-氯-17-羟基-娠-4,6-二烯-3,20-二酮乙酸酯)、异炔诺酮(17α-乙炔基-17-羟基-酯-5(10)-烯)、甲孕酮(17α-乙酰氧基-6α-甲基-娠-4-烯-3,20-二酮)、甲地孕酮(17α-乙酰氧基-6-甲基-娠-4,6-二烯-3,20-二酮)、炔雌烯醇(17α-乙炔基-17β-羟基-酯-4-烯)、3-环戊氧孕-3,5-二烯-20酮(3-环戊氧基-娠-3,5-二烯-20-酮)、醋炔诺酮(17β-乙酰氧基-17α-乙炔基-酯-4-烯-3-酮)、醋炔诺醇(3β,17β-二乙酰氧基-17α-乙炔基-酯-4-烯)、二甲炔睾酮〔17β-羟基-6α-甲基-17(1-丙炔基)-雄(甾)-4-烯-3-酮和左旋甲基炔诺酮。
适宜于结合施用褪黑激素和孕激素的程序有若干种。例如,假定28天为一个周期,则可同时提供褪黑激素和孕激素,持续21天,然后,施用褪黑激素而不用孕激素,持续7天。第二种程序是提供褪黑激素和孕激素,持续21天,然后停止施用两者,持续7天。
第三种程序是:施用褪黑激素5~14天,接着施用孕激素7~14天,全部结合用药时间为24天最好21天。在这个周期的剩余7天里,既不施用褪黑激素,也不施用孕激素。第四种程序包括:在开始的五天中施用安慰剂,然后在3~7天里施用褪黑激素;在用药的全部21天中,提供孕激素。同样,在该周期的剩余7天时间里,既不施用褪黑激素,也不施用孕激素。
另一种程序是施用孕激素21天。在中期,于用者的正常的排卵日前,将褪黑激素与孕激素结合施用1~12天(最好是3~5天)。在21天结束后,停止施用孕激素7天。如上所述,逮常为21~128天的剂量、仅采用孕激素的避孕药效果不很理想。加入褪黑激素就弥补了单单施用孕激素的不足。
每天所施用的避孕药中的孕激素成分一般为约7.5μg至约2500μg,较理想的是约7.5至800μg,最理想的是7.5μg至250μg。每次所提供的孕激素的实际日剂量取决于所选择的特定孕激素、其相对效力和选择的给药方式。例如,采用数量较少、效力较高的孕激素,可达到与采用数量较多、效力较低的孕激素所取得的同样效果。如上所述,所采用的孕激素的量随着给药方式的不同而变化。与口服给药相比,植入给药或静脉注射给药所需的剂量一般较低。
在上述推荐的任何一种程序中,在同时施用褪黑激素和孕激素的哪些天里,虽然它们可以分别施用,较有益的是,将这两种活性成分结合起来施用。
在本发明的另一个实施例中,将少量雌激素补充上述褪黑激素或褪黑激素-孕激素的用药程序。若需要,可加进雌激素,以便防止在缺乏雌激素情况下施用褪黑激素时可能发生的期外排卵,从而使褪黑激素稳定。任何普通的雌激素均可用作本发明的适用的避孕药物组合物成分。目前较理想的雌激素是炔雌醇(17α-乙炔基3.17β-二羟基-雌-1,3,5(10)-三烯)和炔雌醇甲醚(17α-乙炔基-17β-羟基-3-甲氧基-雌-1,3,5(10)三烯)。其他合适的雌激素包括雌二醇(3,17β-二羟基-雌-1,3,5(10)-三烯)、雌三醇(3,-16α,17β-三羟基-雌-1,3,5(10)-三烯)、雌酮(3-羟基-雌-1,3,5(10)-三烯-17-酮)、己烯雌酚、雌三醇环戊醚(3-环戊氧基-16α,17β-二羟基-雌-1,3,5-(10)-三烯)和硫酸雌酮。可根据上述给药程序中的任一种,在28天周期中的全部21天里每天施用雌激素,但最好是在正常排卵日之前给药。一般每天施用的雌激素的量为约2μg至约100μg,最好是约10μg至约50μg。当与孕激素一起使用时,日剂量中的雌激素量取决于所选择的特定的雌激素及其相对效力。例如,炔雌醇的生物效力两倍于炔雌醇甲醚。由于雌激素会带来有害的副作用,所以最好采用最低量的所需雌激素来稳定褪黑激素。可根据上面推荐用药程序,将雌激素同褪黑激素和/或孕激素结合起来施用。根据另一种用药规律,在正常排卵日前,于妇女周期开始时施用雌激素,持续约5~13天,接着给褪黑激素,持续约1~7天(最好是3~5天);在整个用药期的21天施用孕激素。
根据本发明的另一个实施例,可作为“早饭后”的药片,单独施用褪黑激素,或将褪黑激素与雌激素和/或孕激素结合在一起施用。在此实施例中,于性交后的1~5天期间,以约100mg至约10000mg、最好是至少为2000mg的日剂量施用褪黑激素。若将褪黑激素与孕激素和/或雌激素合在一起施用,则最好以约10mg至20mg日用量给出孕激素,以约2.5至25mg的日用量给出雌激素。
在本发明的最佳实施例中,以口服剂量形式,最好是丸剂或胶囊,施用本发明的避孕药组合物。可根据适于交货及使用的特点包装丸剂或胶囊剂。较理想的是,以药袋或药盒的形式包装该药物组合物,该药袋或药盒上具有日剂量形式;或者按顺序连结来排列丸粒,以便妇女在其生殖期的适当时间根据适当的处方服用。适用的药袋或药盒包括普通的含21或28颗丸粒(根据所选择用药制度的不同来选择)具单个分开的气泡、呈柔性塑料片的气泡塑料药盒。气泡由塑料纸密封,压气泡时,气泡破裂,放出丸粒。用药的第一天一般为从她的月经周期最后开始停止出血后的第一天。在这一天,将按顺序排列的第一颗丸粒(不管是含避孕药还是含安慰剂)从单个的槽里取出并服用。第二天服用按顺序排列的第二颗,以后如此进行,直至分配器变空。在其下一个周期的第七天,开始采用新的分配器。可在分配箱上附上标记或说明,以引导或指示使用者恰当地使用口服避孕药。
如上所述,还发现,按上述公开的用药程序中的量来施用褪黑激素,可有效地防止乳房癌。这一发现,给使用褪黑激素或本发明的含褪黑激素的组合物来避孕的育令妇女带来了显著的益处。此外,褪黑激素或本发明的含褪黑激素的组合物可用于绝经后的妇女,作为预防乳房癌的方法。较理想的是,如上所述,以2mg至约1000mg的日剂量,将褪黑激素施用于绝经后的妇女。可根据上述用药程序和用药量,将孕激素和/或雌激素同褪黑激素结合用药。
本发明由下述实施例一步说明。这些实例仅为说明之用,不构成对发明的限制。
实施例Ⅰ
这里,就一个在1950年9月21日出生的病人S.B.的情况,来研究褪黑激素的避孕效果。图IA、IB、IC、ID中分别显示了其周期(平均为连续5个周期)内每天的血液中的黄体激素(LH)、促卵泡成熟激素(FSH)、孕酮和雌二醇等的浓度。如图所示,该病人具有正常的排卵前期的LH高潮和FSH峰,接着出现的是排卵期后的孕酮上升曲线。图中的PHC代表血浆激素浓度。
分别在三个周期中,从其周期的第9天开始连续6天静脉注射300mg溶于葡萄糖生理盐水溶液的褪黑激素。图ⅡA、ⅡB、ⅡC和ⅡD显示了在第一个周期(1983年1月)内注射褪黑激素后的结果。这些图显示了经注射后的排卵停止期。图ⅢA~ⅢD显示了第二个周期(1983年5月)中所取得的施用褪黑激素后的结果;图ⅣA~ⅣD显示了在第三个周期(1984年11月)注射褪黑激素后的结果。这些图同样说明,注射了褪黑激素后,产生排卵停止期。
这些资料表明,在三个周期中,施用褪黑激素后,抑制了病人的正常排卵前期的LH高潮。这些资料还说明,用药后,一定程度地抑制了FSH和排卵后期的雌二醇,并且显著降低了孕激素水平。抑制LH的效果很明显,在施用了褪黑激素的三个月内,病人未排卵。
实施例Ⅱ
在病人的整个三个月经周期中,每天测定病人血浆中的LH、FSH、孕酮和雌二醇的浓度。在一个周期中,确定每一天的各种激素的平均浓度。病人的LH峰的平均浓度为295ng/ml,她的FSH峰的平均浓度为410ng/ml,其周期中黄体期峰处的平均孕激素水平为14.5ng/ml,其雌二醇峰的平均浓度为0.6ng/ml。病人的LH峰在其周期的第十五天出现。
在病人周期的第7至12天中,每天静脉注射500mg溶于葡萄糖盐水溶液的褪黑激素。如前所述,在整个周期中测定其血浆中四种激素的浓度。结果发现,施用褪黑激素后,改变了激素浓度,即:
峰PHC LH110ng/ml
FSH295ng/ml
雌二醇.4ng/ml
孕酮.3ng/ml
这些资料表明,在该周期内,病人未排卵。研究表明,排卵所必需的LH峰浓度至少为250ng/ml。
实施例Ⅲ
从某一病人周期的第8天开始,连续7天向其静脉注射350mg在葡萄糖生理盐水溶液中的褪黑激素。该病人具有正常的28天的月经周期,其中有3~5天的中等程度的月经出血(失血±50ml)。在其周期的第14至28天,每天口服0.75mg炔诺酮。在其整个周期内,每天测定其血液中的LH、FSH、孕酮和雌二醇的浓度。在该周期中,她未排卵(峰PHC LH为115ng/ml),月经出血最少(±15ml)。
实施例Ⅳ
在病人周期的第7至第10天,每天向其静脉注射200mg在葡萄糖生理盐水溶液中的褪黑激素。在该周期内,她未排卵,虽然其血中LH水平未被均匀地抑制,但在50ng/ml至180ng/ml之间相当不规则地变化。在该周期内,其FSH的PHC正常,其孕酮PHC一定程度地受到抑制,在整个周期中,雌二醇PHC始终正常。
实施例Ⅴ
在一个连续的研究中,给四名女子服用呈胶囊剂的褪黑激素。以日剂量30mg至1000mg施用褪黑激素。初步评价表明,由胃肠道吸收褪黑激素,不产生副作用(如腹泻或噁心)。
Claims (8)
1、一种制备实现预防妇女乳房癌的组合物的方法,该方法包括将避孕有效量的褪黑激素与孕激素、雌激素或它们的混合物相结合施用。
2、按权利要求1的方法,其中孕激素选自包括炔诺酮、18-乙基炔诺酮、chlormadinone-acetate、异炔诺酮、安宫黄体酮、甲地孕酮、炔雌烯醇、3-环戊氧孕-3,5-二烯-20-酮、醋炔诺酮、醋炔诺醇、levonorgestrel和二甲炔睾酮。
3、按权利要求1的方法,其中雌激素选自包括炔雌醇、mestronol、雌二醇、雌酮、雌三醇、己烯雌酚、雌三醇环戊醚和雌酮硫酸盐。
4、按权利要求1的方法,其中的组合物为单剂量形式,含有约2毫克至约1000毫克褪黑激素和约7.5μg至约2500μg孕激素。
5、按权利要求4的方法,其中单剂量形式含有约5mg至约500mg,褪黑激素和约7.5μg至约800μg孕激素。
6、按权利要求1的方法,其中组合物是单剂量形式,含有约2mg至约1000mg褪黑激素和约2μg至约100μg雌激素。
7、按权利要求6的方法,其中的单剂量形式含有约5mg至约500mg褪黑激素和约10μg至约50μg雌激素。
8、按权利要求7的方法,其中的单剂量形式含有约7.5μg至800μg孕激素。
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US029,229 | 1987-03-23 | ||
US07/029,229 US4855305A (en) | 1987-03-23 | 1987-03-23 | Compositions and methods of effecting contraception utilizing melatonin |
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RU (1) | RU2114621C1 (zh) |
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1987
- 1987-03-23 US US07/029,229 patent/US4855305A/en not_active Expired - Lifetime
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1988
- 1988-03-22 BR BR888807426A patent/BR8807426A/pt not_active Application Discontinuation
- 1988-03-22 PH PH36671A patent/PH26709A/en unknown
- 1988-03-22 DE DE3855606T patent/DE3855606T2/de not_active Expired - Fee Related
- 1988-03-22 HU HU883281A patent/HU208487B/hu not_active IP Right Cessation
- 1988-03-22 EP EP88904025A patent/EP0354921B1/en not_active Expired - Lifetime
- 1988-03-22 RU SU4742272A patent/RU2114621C1/ru not_active IP Right Cessation
- 1988-03-22 AT AT88904025T patent/ATE143807T1/de not_active IP Right Cessation
- 1988-03-22 IL IL85814A patent/IL85814A/xx not_active IP Right Cessation
- 1988-03-22 WO PCT/US1988/000971 patent/WO1988007370A1/en active IP Right Grant
- 1988-03-22 CA CA000562109A patent/CA1322527C/en not_active Expired - Fee Related
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- 1988-03-22 JP JP63503744A patent/JP2965160B2/ja not_active Expired - Fee Related
- 1988-03-23 ZA ZA882079A patent/ZA882079B/xx unknown
- 1988-03-23 CN CN88101379A patent/CN1041383C/zh not_active Expired - Fee Related
- 1988-03-23 ES ES8800883A patent/ES2009251A6/es not_active Expired
- 1988-03-23 EG EG166/88A patent/EG18583A/xx active
- 1988-03-23 GR GR880100177A patent/GR1002146B/el not_active IP Right Cessation
- 1988-03-23 PT PT87053A patent/PT87053B/pt not_active IP Right Cessation
- 1988-03-23 DD DD88313924A patent/DD269557A5/de not_active IP Right Cessation
- 1988-03-23 NZ NZ223989A patent/NZ223989A/xx unknown
- 1988-03-28 IN IN197/MAS/88A patent/IN166946B/en unknown
- 1988-11-23 KR KR1019880701526A patent/KR890700349A/ko not_active Application Discontinuation
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1989
- 1989-09-19 FI FI894423A patent/FI894423A/fi not_active Application Discontinuation
- 1989-09-19 OA OA59646A patent/OA09134A/xx unknown
- 1989-09-25 BG BG89841A patent/BG51075A1/xx unknown
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1991
- 1991-10-31 AU AU86938/91A patent/AU8693891A/en not_active Abandoned
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1994
- 1994-02-14 AU AU55134/94A patent/AU676523B2/en not_active Ceased
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1998
- 1998-02-12 JP JP10044264A patent/JPH1171276A/ja active Pending
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