CN1116897C - 甲状旁腺激素药物组合物 - Google Patents
甲状旁腺激素药物组合物 Download PDFInfo
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- CN1116897C CN1116897C CN94194608A CN94194608A CN1116897C CN 1116897 C CN1116897 C CN 1116897C CN 94194608 A CN94194608 A CN 94194608A CN 94194608 A CN94194608 A CN 94194608A CN 1116897 C CN1116897 C CN 1116897C
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- parathyroid hormone
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Abstract
本发明涉及含有被赋形剂和缓冲剂稳定的甲状旁腺激素的制剂。优选的制剂包括人PTH(1-84)、作为赋形剂的甘露醇以及作为缓冲剂的柠檬酸盐，并以冻干粉末形式装入小瓶中以用于重配而治疗骨质疏松症。
Description
发明领域
本发明涉及含有甲状旁腺激素的药物组合物，更具体地说，涉及提高了储存稳定性的甲状旁腺激素的药物组合物。
发明背景
甲状旁腺激素(PTH)是含有84个氨基酸的哺乳动物甲状旁腺的分泌产物。它通过对多种组织(包括骨组织)的作用来控制血液中钙的水平。有关某些形式的甲状旁腺激素在人体中的研究证明它有促进骨骼合成的作用，提示可将其运用于骨质疏松症及相关骨类疾病的治疗。
以牛与人类的PTH的N端34个氨基酸(具有整个激素的全部的生物学活性)为例，已证明当以皮下和静脉交互给药时，在人体中甲状旁腺激素能显著地促进骨组织生长。另一种稍微不同形式的PTH，人PTH(1-38)也有相似的结论。因为仅仅在最近才得到重组形式的全长人类激素，即人PTH(1-84)，关于它还没有在人体中的研究结果，但在大鼠中的研究显示在某些方面多少能促进骨组织生长。
以上实验中所用的PTH制剂由新鲜或冻干的激素及各种形式的载体和赋形剂构成。大多数制成水剂例如用盐水，或乙酸酸化的水来溶解激素。大部分已报道的配方中还将白蛋白作为载剂(见Reeve et al，Br.Med.J，1980，280：6228；Reeve et al，Lancet，1976，1：1035；Reeve et al，Calcif Tissue Res，1976，21：469；Hodsman et al，Bone Miner，1990，9(2)：137；Tsai et al，J.Clin.Endocrinol Metab，1989，69(5)：1024；Isaac et al.，Horm Metab Res，1980，12(9)：487；Law et al，J Clin Invest，1983，72(3)：1106；Hulter et al，J Clin Hypertens，1986，2(4)：360)。其它已见报道的配方中以甘露醇作为赋形剂(在冻干的激素及用于重配的载体中都存在)。在人体内研究中所用的具代表性的配方包括一种人PTH(1-34)制剂，由甘露醇、热失活人血清白蛋白、以及用来促进吸收的己酸(一种蛋白酶抑制剂)重新配成。(见Reeve et al，1976，Calcif Tissue Res，21，Suppl.，469-477)；还有一种人PTH(1-38)制剂，由盐水载体重配(见Hodsman et al，1991，14(1)，67-83)；以及一种加有白蛋白并用乙酸调节pH的制成水剂的牛PTH(1-34)制剂。还有一种国际参考的配方，对于人PTH是由100ng激素、250微克人血清白蛋白及1.25mg乳糖组成，封成安瓿；对于牛PTH是将10微克冻干的激素溶在0.01M乙酸及0.1％(w/v)的甘露醇中(见Martindale，The Extra Pharmacoepia，ThePharmaceutic Press，London，29th Edition，1989 at p.1338)。
甲状旁腺激素的商业开发要求发展可稳定储存并易于配制和重配成制剂的组合物。因其是一种蛋白质，比传统的小分子药物具有更大的易变性，因而，甲状旁腺激素的配制过程中遇到了不同于一般制药工业生产中的挑战。而且，与其它已成功配制成药剂的蛋白质不同，PTH对氧化作用极其敏感，并且要求保持其N端序列的完整以保存其生物活性。
本发明的目的就是提供一种由全长形式的人PTH作为活性组分的、可用作药物的PTH制剂。
发明概述
现提供一种药物可接受的PTH制剂。根据本发明的一个方面，激素制剂由冻干的组分组成，包括医学有效剂量的甲状旁腺激素，与甲状旁腺激素一起冻干以形成不定形粉块的赋形剂，以及其量足以调节制剂的pH至生理可接受pH的不挥发的缓冲剂。在本发明的一个优选实施方案中，制剂中的激素是人甲状旁腺激素，赋形剂是甘露醇，缓冲剂是柠檬酸缓冲体系。
根据本发明另一方面，提供了得到PTH制剂的方法，它包括使PTH、缓冲剂、赋形剂在水中结合及将得到的溶液冻干最后得到水分不到2％(重量)的产品的步骤。
根据本发明再一方面，提供了一种用于非肠胃给药的甲状旁腺激素制剂的制备方法，包括将本发明冻干状态的制剂在无菌水中重配的步骤。
根据本发明又一方面，还提供了一种临床使用的药盒，其包括一含经过消毒的本发明的冻干粉的小瓶，一份适于重配的载体，以及一份关于重配和注射(任选的)的说明书。该药盒还可为最终的用户配备一套注射重配制剂的器械。
以下将结合附图详细描述本发明。
附图的简要描述
图1和图2显示了分别在pH4和pH6，以及4℃及37℃条件下PTH制剂的储存稳定性。稳定性由生物活性分析(图1)及SDS-PAGE电泳分析(图2)结果显示。
本发明的详细描述
本发明涉及甲状旁腺激素制剂，该制剂表现出激素在化学组成及生物活性方面的储存稳定性。
作为活性组分，本制剂加有全长形式的含84个氨基酸的人甲状旁腺激素，该激素来源于多肽合成的重组体或人体液的提取物。在本说明书中，这种形式的人PTH简写为hPTH(1-84)，其氨基酸序列见Kimura et al的报道(Biochem Biophys Res Comm，114(2)：493).作为全序列人PTH的替代品，制剂中也可加入那些人PTH的同源物、片段、或突变体。这些替代品已在切除了卵巢的大鼠模型中证明对于骨质增生症具有人PTH的活性(见Kimmel et al，Endocrinology，1993，32(4)：1577，引入本文作参考)。
甲状旁腺激素还可以用别的形式如牛或猪PTH(见Keutmann et al，Current Research on CalciumRegulating Hormones，Cooper，C.W.(Ed)，1987，University of Texas Press，Austin，pp57-63)，或者是成熟PTH同源物的片段或突变体。可加入的替代性PTH片段至少得含有PTH的N端27个氨基酸残基，理想的是至少34个N端残基，例如PTH(1-34)、PTH(1-37)、PTH(1-38)和PTH(1-41)。在PTH突变体形式的替代品中，1-5位的氨基酸发生了替换以提高PTH的稳定性和半寿期。例如8和/或18位的甲硫氨酸替换为亮氨酸或其它疏水氨基酸可提高PTH的抗氧化稳定性。又如将25-27位氨基酸替换为胰蛋白酶不敏感的氨基酸如组氨酸或其它氨基酸可增加PTH抗蛋白酶的稳定性。这些形式的PTH都包括在本文通用的术语″甲状旁腺激素″。
本发明提供了一种水含量不超过2％(重量)的粉末形式的PTH制剂。它由经选择的甲状旁腺激素、不挥发的缓冲剂以及赋形剂混合得到的无菌激素水溶液冻干而成。
本制剂中加入的赋形剂用来作为冻干过程的低温保护剂和使配药过程易行的膨化剂。在药物中可使用的赋形剂中，本发明未选用糖类如乳糖和麦芽糖，而挑选了那些在冻干过程中能与缓冲剂结合，形成非晶体的无定形粉块的赋形剂。由于使用了据此挑选的赋形剂，冻干后的粉块在快速重配的过程中能保证理想的品质。本文优选的是多醇类赋形剂，对多醇类赋形剂成块性质的估测表明甘露醇是首选的赋形剂，因为它不仅能制成高质量的粉块，而且在溶液中能使PTH稳定。
本发明的制剂中加入的缓冲剂，除了符合药物可接受的需要外，还必须是非挥发性的。不挥发才能使冻干过程中pH值的降低不超过0.4个pH单位这个范围。以前在PTH制剂中所使用的缓冲剂，例如乙酸，已被发现在冻干过程中有不同程度的挥发，结果导致不仅产品不均一，而且由于缓冲剂的损失，重配后产品的pH值也不一致。本发明中所选用的缓冲剂是在生理上可接受的pH范围内具有缓冲能力的缓冲剂。所谓生理上可接受的pH指的是在给药时不或极少引起患者不适，并适于不同注射方式的pH。对于在给药之前需要稀释的制剂，如溶解在储用的输注液中的制剂的pH变化范围较广，从约pH3到约pH9。作为在重配后直接注射的制剂，PTH制剂理想的缓冲范围是在pH3.5～7.5之间。合适的非挥发性缓冲剂因此应是那些药物上可接受且能将制剂的pH值缓冲在目标pH值范围之内的，包括磷酸盐缓冲剂等，优选的是柠檬酸缓冲剂，如柠檬酸钠/柠檬酸。
在本发明中，为了提供储存稳定的甲状旁腺激素制剂，所选用的不挥发性缓冲剂是在加入后能得到最终pH范围为3.5～6.5的缓冲剂，而赋形剂是加入后能得到终浓度为2％～10％(w/v)范围的赋形剂。在本发明的具体实施方案中，缓冲剂产生的pH范围是3.8～6.2，赋形剂的终浓度是3～7％，如4～6％(w/v)。首选的缓冲剂使用柠檬酸类如柠檬酸二氢钠/柠檬酸，赋形剂使用5％(w/v)的甘露醇。
本发明的PTH制剂中所加入的PTH是医学有效剂量的。该术语指的是其量既足以用于临床治疗又适于医学诊断。根据所选用的PTH的类型及制剂的预期最终用途，制剂中加入的甲状旁腺激素的特定量可以预先确定。在一种应用中，开发的制剂是用于治疗目的，尤其是对于骨质增生症的治疗。骨质增生症的治疗这个目的限定了重配后的制剂的给药方式是通过注射，最好是皮下注射，根据治疗方案，对于人PTH(1-84)的单位剂量是，每个患者25微克PTH/ml～500微克PTH/ml注射液，注射体积范围是0.3～1.3ml。因此，经过纯化并无菌过滤后的PTH与缓冲剂和赋形剂混合后形成PTH浓度为25微克PTH/ml～500微克PTH/ml，优选50微克/ml～150微克/ml的水溶液。如果需要，可以通过加入等当量的PTH的同源物，如PTH(1-84)的突变体或片段来代替人PTH(1-84)。
本发明的一个实施方案中，提供的制剂的单位剂量是在大约1ml(0.8～1.2ml)重配溶剂中加入50～150微克的人PTH(1-84)，每个小瓶中加入约1ml液体PTH制剂，随后冻干。
在本发明的一个优选实施方案中，每份冻干形式的PTH制剂包括25～250微克/ml的人PTH(1-84)，2～8％(重量)的甘露醇，以及在无菌水中能将重配的制剂的pH缓冲到3.5～6.5范围的柠檬酸类缓冲剂。在本发明的具体实施方案中，加入的柠檬酸缓冲剂将足以使pH缓冲在6.0±0.4的范围。
当把制剂制备成含有所需数量及浓度的缓冲剂、赋形剂及PTH的水溶液的形式后，在每个小瓶中注入所需体积的溶液，然后将小瓶集中进入冻干过程。
作为现有的传统技术，冻干过程中要求严格的温度控制以保证冻干这一程序的均一性及完全性，如要求得到的干粉中水的重量比不超过2％，最好不超过1.5％。将小瓶中的PTH制剂溶液冻干成PTH粉剂至少要经过两个不同的干燥步骤：第一步要除去溶液制剂中的非结合水而不引起粉块的损毁。首先将小瓶中的PTH制剂溶液冷却到低于-30℃(最好是约-50℃)使其结冰，然后将温度升高并保持在-10℃左右，同时减压，使压力不超过350微巴如260微巴，直到所有非结合水基本上都被除掉。在本文具体的实施例的条件下，合适的干燥时间是16小时。第二步是设法除去粉块中的结合水，同样要避免损坏粉块。该过程在低于使PTH的生物活性受损的温度下进行，在更低的压力(＜50微巴)下在-10℃保持3小时，然后加热并保持在25℃直到几乎所有的结合水(＜2％)都被除去。该过程至少需要12小时，最好16小时或更长时间。完成之后，小瓶可以用例如自动加塞机密封，离开冻干机后加盖。
最终的使用者仅需将制剂重配在无菌水中配成可供注射的针剂这一点上，本发明中的PTH制剂可说是完满的。为了这一目的，根据本发明的另一方面，提供了一种医用药盒，包括至少一个含本发明的冻干的PTH粉的小瓶，至少一瓶重配制剂所需的无菌水，以及一份指导如何将干粉重新溶解的说明书。药盒中还可以包括一套供最终的使用者注射重配药剂的器械。在本发明的一个具体实施方案中，注射器械是皮下注射用针头，如25号针头和一个能容纳0.5～5ml，例如1或2ml溶液的针筒。另外，一套药盒还可以包括一个内装多个单位剂量的PTH的小瓶，以及一瓶附带的足以溶解多单位剂量粉剂的无菌水。
在使用时，最终使用者将水瓶中的水抽到注射器中，然后加入到装有PTH的小瓶中，与PTH冻干粉混合并使之重新溶解。需要的话可以用注射器抽打几次直到可见粉末完全溶解为止。本PTH制剂的优点是混合极为迅速，1分钟，更通常的是30秒内混合完毕。混合之后，使用者立即可以按医嘱剂量和方式注射PTH。若所提供的是多剂量小瓶，还附带一份抗菌剂，每次注射之后剩下的制剂可以冷藏保存继续使用数天。
除了在临床治疗上使用之外，本PTH制剂还可用于医学诊断目的，尤其是辅助诊断低钙血患者的甲状旁腺机能减退与假性甲状旁腺机能减退。除了PTH的剂量之外，上述用于治疗目的的PTH制剂的组成成分都维持不变。为诊断目的，较为合适的是静脉注射相当于200IU的人PTH(1-84)或PTH的等效物。依靠确定注射PTH对尿液中cAMP水平的影响可作出诊断结论。cAMP水平提高表示甲状旁腺机能减退，反之则是假性甲状旁腺机能减退。
实施例
在冻干之前首先制备液体PTH制剂，即混合作为激素的人PTH(1-84)、作为赋形剂的甘露醇及作为缓冲剂的柠檬酸盐。
生产制剂的第一步，是用可注射使用的20％(w/v)无菌甘露醇溶液(British Pharmacopeia)配成两种混合液：在20％的甘露醇溶液中加入：(1)柠檬酸溶液以得到含10mM柠檬酸和5％甘露醇的混合液；(2)柠檬酸钠一水合物溶液得到第二份含10mM柠檬酸盐和5％甘露醇的混合液，将两种混合液以合适的体积比混溶，以得到pH分别为4(±0.2)和6(±0.2)的5％甘露醇溶液。
然后在5％的甘露醇溶液(pH分别为4和6)中加入一定数量的冻干的人PTH(1-84)。PTH是由微生物发酵生产的，在冻干之前需经过纯化、灭菌等处理。定量的PTH加入到pH4和pH6的5％甘露醇溶液中得到储存液，将其以1.1ml的体积分装到小瓶中，每个小瓶中分别含有如下数量的PTH：100，250，500，1000和2500微克。
冻干之前，各种浓度的PTH溶液在无菌条件下以手工或自动分装机按1.1ml体积分装到5ml的玻璃小瓶中(USP Type I)，然后装盘并在一个无菌的、充氮的冻干机中预冷至-50℃。在装盘及预冷4小时后，抽去冻干室的空气，1小时后使压力降至0。26毫巴。然后执行第一个干燥步骤：加热30余分钟，使温度从-50℃上升到-10℃，并保持16小时。再执行第二个干燥步骤：从-10℃继续加热至25℃，并继续减压3小时以上使压力降至0.05毫巴，保持此温此压16小时。在第二步结束时，冻干室充上氮气，压力为0.85～0.95巴。箱子上移，给药瓶塞上橡皮塞，然后移走瓶，在压力平衡后封上铝瓶帽。
装有各浓度的pH4或pH6的冻干的PTH制剂的小瓶随后储存在4℃和37℃。于储存1，2，3，6和9个月后进行分析。作稳定性分析时要将制剂重配在1.1毫升的无菌水中。将水透过橡皮塞注入瓶中，1分钟后药粉溶解，再抽取溶液进行分析。
下面依次介绍各种稳定性实验的结果：
PTH的生物活性分析是在大鼠卵巢肉瘤细胞(UMR106)中分析PTH刺激的腺苷酸环化酶的产生。这种PTH分析可见Rodan et al(J Clin Invest，1983，72：1511)和Rabbani et al(Endocrinol，1988，123：2709)的报道。在储存九个月后，无论温度为4℃或37℃，也无论pH是4还是6，PTH的生物活性均末发现有明显降低。在图1中，PTH浓度为1000微克/剂量，用一条最接近平均值的直线表示了这一结果。
使用传统方法，对重配后的PTH制剂进行的SDS-PAGE电泳分析同样表明，储存后的纯度，在各种pH、温度及储存温度下都没有明显降低。见图2所示。RP-HPLC分析表明，重配后的制剂的纯度有些降低，但仅限于较高的37℃储存时的情况(每过一月纯度降低0.7％)。在4℃储存时，反相HPLC分析表明没有明显的纯度降低的情况发生。免疫分析(Allego)同样表明，完整的PTH在各种浓度、pH和温度下在储存时间内是恒定的。
使用标准的Karl-Fischer技术分析PTH的残存湿度，结果指出，在所有冻干并经历储存期的PTH制剂中，水的含量低于2％(重量)，典型的是在1％(重量)左右。
经历冻干与储存过程后重新溶解表明pH没有明显的改变，说明在冻干时缓冲剂没有挥发。缓冲到pH4的制剂保持pH4±0.2，缓冲到pH6的制剂保持在pH6±0.4。
对冻干制剂溶解的速度与程度也进行了检验。在室温下所有样品都能在1分钟之内溶解于1.1毫升无菌水中。最快的溶解时间是0.5分钟(pH4)和0.4分钟(pH6)。此外，无论那种pH或那种储存温度下，冻干粉重新溶解后都未发现有不溶颗粒存在。
Claims (15)
1、一种甲状旁腺激素制剂，其包括：
(a)医学有效剂量的人1-84甲状旁腺激素；
(b)可与所述激素共同冻干形成不定形粉块的多元醇类赋形剂；
(c)其量足够调节制剂的pH使其保持在生理可接受pH范围之内的不挥发性缓冲剂；以及
(d)水。
2、根据权利要求1所述的甲状旁腺激素制剂，其包括浓度在25微克/毫升～2500微克/11毫升范围内的人1-84甲状旁腺激素。
3、根据权利要求1所述的甲状旁腺激素制剂，其中的人1-84甲状旁腺激素的浓度在25微克/毫升～500微克/毫升范围内。
4、根据权利要求1所述的甲状旁腺激素制剂，其中的人1-84甲状旁腺激素的浓度在25微克/毫升～250微克/毫升范围内。
5、根据权利要求1所述的甲状旁腺激素制剂，其中的人1-84甲状旁腺激素的浓度在50微克/毫升～150微克/毫升范围内。
6、根据权利要求1至5中任意一项所述的甲状旁腺激素制剂，其中所述的赋形剂是甘露醇。
7、根据权利要求1至5中任意一项所述的甲状旁腺激素制剂，其中所述的缓冲剂是柠檬酸盐类。
8、根据权利要求1所述的甲状旁腺激素制剂，包括：
(a)浓度在25微克/毫升～250微克/毫升范围内的人1-84甲状旁腺激素；
(b)浓度范围为3～7％(重量/体积)的甘露醇；
(c)其量足以调节制剂的pH在pH3.5～pH6.5范围内的柠檬酸盐缓冲剂；以及
(d)水。
9、根据权利要求8所述的甲状旁腺激素制剂，其中所述的甘露醇的浓度为4～6％。
10、根据权利要求8或9所述的甲状旁腺激素制剂，其中所述的柠檬酸盐缓冲剂的量足以调节制剂的pH到pH6±0.4。
11、根据权利要求1至10中任意一项所述的甲状旁腺激素制剂，以含水量小于2％(重量)的冻干粉末形式存在。
12、装有根据权利要求1至11中任意一项所述的甲状旁腺激素制剂的小瓶。
13、根据权利要求12所述的小瓶，其进一步含有一种抑菌剂。
14、用于配制可注射PTH溶液的药盒，包括如前述任意一项权利要求所述的甲状旁腺激素制剂，并独立地含有用于重新溶解所述制剂以配制可注射溶液的无菌水，和一份关于其制剂配制方法的说明书。
15、根据权利要求14所述的药盒，其中进一步包括一种用来注射重新配制的PTH溶液的器械。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/172,206 US5496801A (en) | 1993-12-23 | 1993-12-23 | Parathyroid hormone formulation |
| US08/172,206 | 1993-12-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1142772A CN1142772A (zh) | 1997-02-12 |
| CN1116897C true CN1116897C (zh) | 2003-08-06 |
Family
ID=22626763
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94194608A Expired - Lifetime CN1116897C (zh) | 1993-12-23 | 1994-12-16 | 甲状旁腺激素药物组合物 |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US5496801A (zh) |
| EP (2) | EP1880732A1 (zh) |
| JP (1) | JP3065662B2 (zh) |
| KR (1) | KR100398461B1 (zh) |
| CN (1) | CN1116897C (zh) |
| AT (1) | ATE374621T1 (zh) |
| AU (1) | AU681737B2 (zh) |
| BR (1) | BR9408398A (zh) |
| CA (1) | CA2179207C (zh) |
| CZ (1) | CZ184296A3 (zh) |
| DE (1) | DE69435033T2 (zh) |
| DK (1) | DK0735896T3 (zh) |
| ES (1) | ES2293637T3 (zh) |
| FI (1) | FI120291B (zh) |
| HK (1) | HK1010336A1 (zh) |
| HU (1) | HUT74381A (zh) |
| LV (1) | LV11731B (zh) |
| NO (1) | NO324905B1 (zh) |
| NZ (1) | NZ277463A (zh) |
| PL (1) | PL315158A1 (zh) |
| PT (1) | PT735896E (zh) |
| SK (1) | SK82896A3 (zh) |
| WO (1) | WO1995017207A1 (zh) |
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-
1993
- 1993-12-23 US US08/172,206 patent/US5496801A/en not_active Expired - Lifetime
-
1994
- 1994-12-16 KR KR1019960703288A patent/KR100398461B1/ko not_active IP Right Cessation
- 1994-12-16 PL PL94315158A patent/PL315158A1/xx unknown
- 1994-12-16 AU AU12698/95A patent/AU681737B2/en not_active Expired
- 1994-12-16 EP EP07019169A patent/EP1880732A1/en not_active Withdrawn
- 1994-12-16 CA CA002179207A patent/CA2179207C/en not_active Expired - Lifetime
- 1994-12-16 DE DE69435033T patent/DE69435033T2/de not_active Expired - Lifetime
- 1994-12-16 CZ CZ961842A patent/CZ184296A3/cs unknown
- 1994-12-16 CN CN94194608A patent/CN1116897C/zh not_active Expired - Lifetime
- 1994-12-16 ES ES95903732T patent/ES2293637T3/es not_active Expired - Lifetime
- 1994-12-16 PT PT95903732T patent/PT735896E/pt unknown
- 1994-12-16 AT AT95903732T patent/ATE374621T1/de active
- 1994-12-16 DK DK95903732T patent/DK0735896T3/da active
- 1994-12-16 HU HU9601721A patent/HUT74381A/hu unknown
- 1994-12-16 JP JP7517064A patent/JP3065662B2/ja not_active Expired - Lifetime
- 1994-12-16 EP EP95903732A patent/EP0735896B1/en not_active Expired - Lifetime
- 1994-12-16 BR BR9408398A patent/BR9408398A/pt not_active Application Discontinuation
- 1994-12-16 WO PCT/CA1994/000693 patent/WO1995017207A1/en active IP Right Grant
- 1994-12-16 SK SK828-96A patent/SK82896A3/sk unknown
- 1994-12-16 NZ NZ277463A patent/NZ277463A/en not_active IP Right Cessation
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1996
- 1996-06-20 NO NO19962634A patent/NO324905B1/no not_active IP Right Cessation
- 1996-06-20 FI FI962593A patent/FI120291B/fi not_active IP Right Cessation
- 1996-07-19 LV LVP-96-283A patent/LV11731B/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| HUT74381A (en) | 1996-12-30 |
| KR100398461B1 (ko) | 2004-03-20 |
| JPH09506869A (ja) | 1997-07-08 |
| US5496801A (en) | 1996-03-05 |
| WO1995017207A1 (en) | 1995-06-29 |
| FI962593A (fi) | 1996-08-19 |
| DE69435033D1 (de) | 2007-11-15 |
| LV11731A (lv) | 1997-04-20 |
| NO324905B1 (no) | 2007-12-27 |
| CA2179207C (en) | 2000-11-14 |
| CA2179207A1 (en) | 1995-06-29 |
| ATE374621T1 (de) | 2007-10-15 |
| CN1142772A (zh) | 1997-02-12 |
| BR9408398A (pt) | 1997-08-12 |
| AU1269895A (en) | 1995-07-10 |
| EP1880732A1 (en) | 2008-01-23 |
| JP3065662B2 (ja) | 2000-07-17 |
| DE69435033T2 (de) | 2008-05-29 |
| PL315158A1 (en) | 1996-10-14 |
| PT735896E (pt) | 2007-12-07 |
| NO962634D0 (no) | 1996-06-20 |
| DK0735896T3 (da) | 2008-02-04 |
| AU681737B2 (en) | 1997-09-04 |
| HK1010336A1 (en) | 1999-06-17 |
| EP0735896B1 (en) | 2007-10-03 |
| SK82896A3 (en) | 1997-01-08 |
| CZ184296A3 (en) | 1997-01-15 |
| EP0735896A1 (en) | 1996-10-09 |
| HU9601721D0 (en) | 1996-08-28 |
| NO962634L (no) | 1996-06-20 |
| FI962593A0 (fi) | 1996-06-20 |
| NZ277463A (en) | 1997-03-24 |
| LV11731B (en) | 1997-08-20 |
| ES2293637T3 (es) | 2008-03-16 |
| FI120291B (fi) | 2009-09-15 |
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