CN1753674A - 泰妥拉唑在治疗胃食管反流性疾病中的应用 - Google Patents
泰妥拉唑在治疗胃食管反流性疾病中的应用 Download PDFInfo
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
本发明涉及泰妥拉唑的新颖治疗应用。泰妥拉唑及其盐可用于生产治疗胃食管反流、胃出血和消化不良的非典型食管症状的药物。
Description
本发明涉及与胃食管反流、消化性出血(digestive bleeding)和消化不良有关的疾病的治疗,尤其是泰妥拉唑(tenatoprazole)在制造治疗与胃食管反流、消化性出血和消化不良有关的疾病的药物中的应用。
泰妥拉唑或称5-甲氧基-2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]亚磺酰基]咪唑并[4,5-b]吡啶描述在欧洲专利号254588中。该化合物属于治疗胃和十二指肠溃疡用的被认为是质子泵抑制剂的药物族。其它质子泵抑制剂包括奥美拉唑(omeprazole)、雷贝拉唑(rabeprazole)、喷妥拉唑(pantoprazole)和兰索拉唑(lansoprazole),这些化合物均结构类似并属于吡啶基-甲基-亚磺酰基-苯并咪唑族。上述化合物是在硫原子级别上具有不对称性的亚砜,因此通常为两种对映体的外消旋混合物形式。
该系列中的第一个已知衍生物是在欧洲专利号005.129中所述的奥美拉唑,该化合物具有抑制胃酸分泌的性能,并被广泛用作人体治疗中的抗溃疡药剂。
也有设想将奥美拉唑用于治疗胃食管反流性疾病,但其对此适应症的活性并不完全令人满意。实际研究表明,奥美拉唑的持效期与其它质子泵抑制剂一样,并不足以有效治疗夜发性反流。
胃食管反流被认为主要是由于运动性紊乱,其特征在于频率异常,瞬时松弛和下部食管的括约肌发声丧失。上述异常的结果是胃中内含物反流进入食管。此外,在胃食管反流患者中,反流物酸度的消去通常比正常人慢约50%,同时食管壁的耐酸性显著降低。因此,在胃食管反流患者中,胃酸分泌在食管粘膜受损的发生和持续中起重要作用。
各种研究表明,胃食管反流患者的症状严重程度与食管粘膜暴露于酸的持续时间成正比(Howden CW,Burget DW,Hunt RH“Appropriate acid suppression for optimal healing of duodenal ulcer andgastroesophageal reflux disease”,Scand.J.Gastroenterol,Suppl(1994)201:79-82)。因此,无症状受验者具有约1%的暴露(1天中暴露于酸的时间的百分数),而患偶发性胃食管反流的受验者具有接近2%的暴露比率,每天都具有该症状的受验者具有3%的暴露比率,而内窥镜检查受损的患者具有6%至12%的暴露,这取决于受损的严重程度。通过使患者食管暴露于pH低于4的异常低的酸中进行上述研究,而正常pH值通常为5至7。
研究表明,暴露于酸的时间越长,症状和食管粘膜的受损越严重。
此外,研究还表明由合适药物治疗而产生的酸的抑制与损伤的恢复速率有关,而该恢复速率是酸抑制持续时间与幅度的重要参数。因此,对胃食管反流病患者通常给出的药方是抗酸剂,组胺受体拮抗剂或质子泵抑制剂,目的在于帮助其减轻症状。然而,所用多数药物并不完全令人满意,这是由于它们仅仅部分减轻症状或持效期太短,因此需重复服药。
类似地,对治疗消化不良的研究表明,质子泵抑制剂仅能提供一定程度的减轻,很少能达到有效的治疗。机能性消化不良由一系列与饮食有关的各种变化症状构成,并且在其不同程度与上腹的疼痛或不适、早饱(early satiety)感或消化慢、恶心、呕吐等相关联。机能性消化不良的病理生理学仍然不是很清楚。
研究表明,在某些患者中尤其是假溃疡型机能性消化不良或酷似胃食管反流症状的患者中,通过服用诸如奥美拉唑或兰索拉唑的治疗类质子泵抑制剂药物能减轻症状。在上述研究过程中,主要在对食管酸的暴露增加的患者中观察治疗效果。然而,在胃酸度抑制中存在质子泵抑制剂的排除半衰期(elimination half-life)较短的问题,从而就不能以质子泵抑制剂开出药方,用以确保机能性消化不良的有效减轻。
已开发了多种技术以得到可能具有改进性能的含质子泵抑制剂的药剂。例如,WO 02.072070公开了通过喷雾-冷冻技术得到的具有高奥美拉唑或埃索美拉唑镁(esomeprazole magnesium)含量的微粒,可将该微粒用肠溶衣包衣以避免与酸性胃液接触。WO 99.59544描述了含细微颗粒的口服可崩解片剂,该细微颗粒包含用肠溶衣层包衣的组合物。所述组合物含酸不稳定活性物质如兰索拉唑。人们设想将上述专利中所述微粒和含细微颗粒的片剂用于与胃酸有关的疾病的常规治疗,但没有给出临床结果。Adis R&D Profile(2002:3(4)276-277)涉及了泰妥拉唑的某些性质并提及泰妥拉唑已于2002年4月在日本注册为治疗反流食管炎的药物,但上述信息是错误的,这是由于那时还没有证明泰妥拉唑的此种可能用途,因此不会获得上述注册。
由于上述原因,今天仍需要能有效治疗并缓解胃食管反流和消化不良患者的症状的药物。
本申请人进行的研究和试验工作预料不到的表明,泰妥拉唑能有效用于治疗与胃食管反流和消化不良相关的疾病,而奥美拉唑和其它具有类似结构的质子泵抑制剂对这些适应症并不能产生令人满意的治疗效果。
因此,本发明的目的在于泰妥拉唑在治疗胃食管反流、消化性出血和消化不良的非典型食管症状中的应用,以及泰妥拉唑在制造治疗胃食管反流、消化性出血和消化不良的非典型食管症状的药物中的应用。
与奥美拉唑和其它具有类似结构的亚砜相似,泰妥拉唑包含不对称结构,因此以外消旋混合物或以其对映体的形式存在。
与其它诸如奥美拉唑或埃索美拉唑的质子泵抑制剂不同,泰妥拉唑因其7倍长的半衰期而具有明显更长的持效期。因此,收集到的医学数据表明,泰妥拉唑确保了优于用其它同属治疗类质子泵抑制剂的药物所观察到的症状减轻和受损恢复程度,由此确保其有效用于治疗胃食管反流、消化性出血和消化不良的非典型食管症状。
本发明使用泰妥拉唑以更大程度地减轻胃食管反流的非典型症状,尤其是目前用诸如奥美拉唑的标准质子泵抑制剂难以治疗的夜发性非典型症状。同样,本发明在胃食管反流非典型症状的偶然性治疗(occasional treatment)中取得了明显的进步,其中药物的摄入量视治疗效果的持续时间而定。
本发明的另一优点在于泰妥拉唑也可有效作用于巴雷特(Barrett)食管或内短食管,所述巴雷特(Barrett)食管或内短食管定义为下食管或胃食管连接处存在的肠型粘膜(圆柱形)。这种状况是消化性食管炎的并发症,并在某些情况下恶化成腺癌。
巴雷特食管患者通常经受比一般更为严重的胃食管反流,而且反酸程度对细胞分化和增殖产生有害影响,从而容易产生发育不良。因此,减少带有与巴雷特食管相关的胃食管反流和组织受损症状的患者的酸分泌是很重要的。
在巴雷特食管的情况下治疗必须最大程度地抑制胃食管反流酸度,而服用泰妥拉唑确实做到了这一点,尤其是避免了夜发性胃灼热的发作,而目前药物即便是标准质子泵抑制剂也不能做到这一点。
如下所示,泰妥拉唑可与其它的质子泵抑制剂区分开来,这是由于其令人吃惊的更长排除半衰期,以及如本申请人进行的实验所证明的相当大的组织暴露程度。
在口服单剂量和持续7天日剂量的情况下,在高加索人个体(n=8/组)中进行的I期研究可以证明泰妥拉唑的不同剂量对药物代谢动力学参数的影响。
泰妥拉唑的测试剂量为10、20、40和80mg。
所得结果列在下表1中。
表1
单剂量 | 重复剂量(7天) | |||||||
10mg | 20mg | 40mg | 80mg | 10mg | 20mg | 40mg | 80mg | |
Cmax(μg/ml) | 0.9 | 2.4 | 5.3 | 8.3 | 1.6 | 3 | 5.5 | 11.8 |
Tmax(h) | 4 | 4 | 3 | 3 | 3 | 2 | 3 | 2 |
T1/2(h) | 5 | 6 | 6 | 7 | 5 | 8 | 9 | 9.2 |
AUC0-t | 8 | 24 | 43 | 97 | 13 | 36 | 75 | 218 |
上表所用缩略语具有如下含义:
Cmax 最大浓度
Tmax 达到最大浓度所需时间
T1/2 排除半衰期
AUC0-t 零时至最后测量浓度之间曲线下的面积
上表1所示结果证明,依赖于剂量,平均排除半衰期在服用单剂后为5-6小时,而服药7天后为5-9.5小时。泰妥拉唑还表现出高AUC值(曲线下面积),这提供了经由口服途径的低代谢速率和/或高生物利用率的证据。此外,无论何种服药情况,是1次还是多次服药,Cmax、AUC0-t和AUC0-inf值均以线性方式增加。通过外推法计算AUC0-inf值。
Tolman等人比较了两种质子泵抑制剂兰索拉唑和奥美拉唑的AUC值(
J,Clin.Gastroenterol.,24(2),65-70,1997),但这并不能判断一种产品优于另一产品。事实上,必须把不同标准考虑在内,即泵再生所需时间和抑制质子泵所需最小浓度以上的时间段。对于泵再生时间,观察到泵通常具有30-48小时的半衰期,因此每72-96小时就会全部更新。
由于上述的药物代谢动力学性质,泰妥拉唑能够通过保持抑制浓度并持续足够长时间来满足前述的两个标准而对抗质子泵再生现象。
如此,与泰妥拉唑的长半衰期相关的长时暴露(由AUC确定)使其在活性位点上的存在时间延长,并因此产生时间延长的药效作用。试验由此表明,泰妥拉唑具有明显高于其它质子泵抑制剂的血浆半衰期/泵再生时间比,从而可将其用于治疗目前可用治疗效果较差的疾病,尤其是胃食管反流、消化不良和巴雷特食管的非典型食管症状。
更特别地,根据本发明,可采用泰妥拉唑治疗胃食管反流的非典型症状,例如哮喘和哮喘类型的呼吸困难发作、咽炎、发声困难、假咽峡炎、发作性咳嗽和夜发性咳嗽。在治疗假溃疡性消化不良方面也特别有效。而且,如上所示,也可成功用于治疗巴雷特食管。
在治疗胃食管反流、尤其因溃疡的消化性出血、和消化不良的非典型食管症状时,泰妥拉唑可以与所选服药方式相适应的常规剂型服用,例如经由口服或肠胃外途径,但优选为口服或静脉途径。例如,可使用含泰妥拉唑作活性成分的片剂或胶囊,或使用含泰妥拉唑盐与可药用的标准基质的可饮用溶液或乳液或者肠胃外使用溶液。泰妥拉唑盐可选自钠、钾、镁或钙盐。
作为实施例,含20mg泰妥拉唑并结合有可药用的载体和赋形剂的片剂的合适配方如下所示:
泰妥拉唑 20.0mg
乳糖 32.0mg
氢氧化铝 17.5mg
羟丙基纤维素 12.1mg
滑石 4.5mg
二氧化钛 3.2mg
硬脂酸镁 1.0mg
常规赋形剂 q.s.p.160mg
剂量作为患者状态和疾病严重程度的函数由医生确定。剂量通常为每天10-120mg泰妥拉唑,优选20-40mg,例如在初期或维持治疗的情况下,对应于每天服用1-2片,每片含20或40mg活性物质,持续4-12周的时间。对于适合小孩的儿童配方,诸如可饮用溶液,可降低单位剂量至如2或5mg。对于严重的疾病情况,最初可通过静脉内途径给药,而后通过口服途径而有效给药。此外,本发明具有可通过每周服用含20或40mg泰妥拉唑的单一片剂的简单给药进行有效、连续治疗的优点。
下面给出了一些临床实例,这些实例说明了通过口服泰妥拉唑治疗胃食管反流或消化不良患者的效果。
表2
患有胃食管反流症状的患者的治疗
年龄/性别 | 主要症状 | 疗程 | 症状发展 | 安全性 |
47/女38/男35/女34/男45/男30/男49/女42/男38/女25/女28/男39/女41/男36/女 | n.h.h.n.h.h.n.h.n.h.r.h.n.h.h.n.h.n.h.h.r. | 8周8周4周8周8周8周8周8周8周12周4周4周8周8周 | ++++++++++++++++++++++++++++++++++++ | ++++++++++++++++++++++++++++++++++++++++ |
h.:胃灼热
n.h.:夜发性胃灼热
r.:反胃
符号+至+++表示症状的变化和从中等到很高的安全性。
通过每天服用含20mg泰妥拉唑的片剂进行治疗。上表表明14位患者中12位对治疗有出色的耐受性,另外两位也有较好的耐受性,同时观察到的症状发展普遍令人满意。
表3
患有胃食管反流的非典型症状的患者的治疗
年龄/性别 | 主要症状 | 与GERD的联系 | 疗程 | 症状发展 | 安全性 |
44/男36/男34/女45/男29/女27/男33/男34/女36/女26/男49/男31/女 | 咽炎发声困难发声困难假咽峡炎夜发性咳嗽牙龋哮喘咽炎夜发性咳嗽哮喘假咽峡炎咽炎 | ++++++++++++++++++++++ | 4周5周4周8周7周12周12周8周8周12周12周8周 | +++++++++++++0++++++++++++++ | ++++++++++++++++++++++++++++++++++ |
GERD:胃食管反流疾病。
上表结果表明,与胃食管反流联系最明确的患者的症状发展尤其令人满意。
表4
患有机能性消化不良症状的患者的治疗
年龄/性别 | 主要症状 | 疗程 | 症状发展 | 安全性 |
47/女38/男35/女34/男45/男30/男49/女42/男38/女25/女28/男39/女41/男36/女44/女 | n.g.f.h.e.s.e.p.n.h.n.e.s.e.p.e.d.d.e.p.h.e.d.n. | 4周8周8周8周6周8周8周6周8周12周4周4周6周8周10周 | ++++++++++++++++++++++++++++++++++++++ | +++++++++++++++++++++++++++++++++++++++++ |
h.:胃灼热
n.h.:夜发性胃灼热
n.:恶心
g.f.:胃胀感
e.s.:早饱
e.p.:上腹部疼痛
e.d.:上腹部不适
d.:肿胀
上述结果证实了根据本发明服用的泰妥拉唑治疗消化不良的效力。
进行了两次公开标记的研究以评价泰妥拉唑治疗胃食管反流的效力和安全性。第一次研究中的22位和第二次研究中的24位年龄大于20岁的侵蚀和/或溃疡型反流食管炎(内窥镜诊断)患者服用了含肠衣颗粒的片剂,该片剂中含10mg泰妥拉唑。
每天早饭后口服1次片剂,疗程为8周,某些情况下连续治疗长达12周。距第1次服药4周和8周后或研究停止时通过内窥镜检查掌握治愈情况,根据Savary和Miller分级评价疾病等级,当确信治愈时停止治疗。将确信侵蚀消失时的状况评为痊愈。
根据以下6级评价内窥镜改善等级:“痊愈”、“明显减少”、“中度减少”、“稍微减少”、“无变化”和“恶化”。
与研究初期观察到的相比,根据以下6个等级评价主观和客观症状的改善等级:“明显改善”、“中度改善”、“轻微改善”、“无改善”、“恶化”和“自研究开始无症状”。
在第1次研究中的20个病例和第2次研究中的23个病例中,于第4周观察治愈情况并在该阶段终止服用泰妥拉唑。治疗8周后只有1位患者没有痊愈。
结果列在下表5和6中。
表5
内窥镜改善等级
A | B | C | D | E | F | 总计 | |
第一次研究 | |||||||
4周 | 20 | 1 | 0 | 0 | 1 | 0 | 22 |
8周 | 21 | 0 | 0 | 0 | 1 | 0 | 22 |
最终 | 21 | 0 | 0 | 0 | 1 | 0 | 22 |
第二次研究 | |||||||
4周 | 23 | 2 | 0 | 0 | 0 | 0 | 25 |
8周 | 24 | 0 | 0 | 0 | 0 | 0 | 24 |
12周 | 24 | 0 | 0 | 0 | 0 | 0 | 24 |
最终 | 24 | 0 | 0 | 0 | 0 | 0 | 24 |
A:痊愈
B:明显减少
C:中度减少
D:轻微减少
E:无变化
F:恶化
表6
症状的改善等级
A | B | C | D | E | 总计 | |
第一次研究 | ||||||
1周 | 16 | 6 | 0 | 3 | 0 | 25 |
2周 | 21 | 1 | 0 | 1 | 0 | 23 |
4周 | 23 | 0 | 1 | 0 | 0 | 24 |
6周 | 10 | 0 | 1 | 0 | 0 | 11 |
8周 | 9 | 0 | 1 | 0 | 0 | 10 |
10周 | 2 | 0 | 0 | 0 | 0 | 2 |
最终 | 21 | 0 | 1 | 0 | 0 | 22 |
第二次研究 | ||||||
1周 | 19 | 2 | 1 | 1 | 0 | 23 |
2周 | 21 | 1 | 1 | 0 | 0 | 23 |
4周 | 20 | 1 | 1 | 0 | 0 | 22 |
6周 | 10 | 0 | 1 | 0 | 0 | 11 |
8周 | 10 | 1 | 0 | 0 | 0 | 11 |
10周 | 0 | 1 | 0 | 0 | 0 | 1 |
12周 | 0 | 1 | 0 | 0 | 0 | 1 |
最终 | 19 | 2 | 0 | 0 | 0 | 21 |
A:明显改善
B:中度改善
C:轻微改善
D:无变化
E:恶化
上述结果表明,与用标准质子泵抑制剂治疗8周所得到的令人不满意的结果相比,用泰妥拉唑治疗4周就痊愈了,因此本发明的泰妥拉唑在治疗胃食管反流性疾病方面是很有效的。
Claims (10)
1.泰妥拉唑在制造用于治疗胃食管反流、消化性出血和消化不良的非典型食管症状的药物中的应用。
2.根据权利要求1的应用,其中泰妥拉唑经由口服途径给药。
3.根据权利要求1的应用,其中泰妥拉唑经由肠胃外途径给药。
4.根据前述任一项权利要求的应用,其中泰妥拉唑以每天10-120mg的比率给药。
5.根据权利要求4的应用,其中泰妥拉唑以单位剂型提供,所述单位剂型含20-40mg活性物质并结合有一种或多种可药用的赋形剂和基质。
6.根据权利要求1-5任一项的应用,其中药物是用于治疗巴雷特食管。
7.根据权利要求1-5任一项的应用,其中药物是用于治疗夜发性反流。
8.根据权利要求1-5任一项的应用,其中药物是用于治疗假溃疡性消化不良。
9.根据权利要求1-5任一项的应用,其中药物是用于治疗哮喘、类似哮喘的急性呼吸困难、咽炎、发声困难、假咽峡炎、突发性咳嗽和夜发性咳嗽。
10.根据权利要求1-5任一项的应用,其中药物是以钠、钾、镁或钙盐的形式提供。
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FR2845916B1 (fr) * | 2002-10-21 | 2006-07-07 | Negma Gild | Composition pharmaceutique associant le tenatoprazole et un antagoniste des recepteurs h2 a l'histamine |
FR2845917B1 (fr) * | 2002-10-21 | 2006-07-07 | Negma Gild | Composition pharmaceutique associant le tenatoprazole et un anti-inflammatoire |
FR2848555B1 (fr) * | 2002-12-16 | 2006-07-28 | Negma Gild | Enantiomere(-)du tenatoprazole et son application en therapeutique |
FR2871800B1 (fr) * | 2004-06-17 | 2006-08-25 | Sidem Pharma Sa Sa | Sel de sodium monohydrate du s-tenatoprazole et application en therapeutique |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE7804231L (sv) | 1978-04-14 | 1979-10-15 | Haessle Ab | Magsyrasekretionsmedel |
JPH0643426B2 (ja) | 1986-07-25 | 1994-06-08 | 東京田辺製薬株式会社 | イミダゾ〔4,5−b〕ピリジン誘導体、その製造法及びそれを含有する抗潰瘍剤 |
SE9603725D0 (sv) * | 1996-10-11 | 1996-10-11 | Astra Ab | New teatment |
PT2263660T (pt) * | 1998-05-18 | 2017-12-19 | Takeda Pharmaceuticals Co | Comprimidos de desintegração oral |
CA2362930C (en) * | 1999-02-26 | 2010-10-05 | Nitromed, Inc. | Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use |
SE0100823D0 (sv) * | 2001-03-09 | 2001-03-09 | Astrazeneca Ab | Method I to obtain microparticles |
SE9903831D0 (sv) * | 1999-10-22 | 1999-10-22 | Astra Ab | Formulation of substituted benzimidazoles |
WO2003097011A1 (en) * | 2002-05-17 | 2003-11-27 | Eisai Co., Ltd. | Compositions and methods using proton pump inhibitors |
FR2845916B1 (fr) * | 2002-10-21 | 2006-07-07 | Negma Gild | Composition pharmaceutique associant le tenatoprazole et un antagoniste des recepteurs h2 a l'histamine |
FR2845917B1 (fr) * | 2002-10-21 | 2006-07-07 | Negma Gild | Composition pharmaceutique associant le tenatoprazole et un anti-inflammatoire |
FR2848555B1 (fr) * | 2002-12-16 | 2006-07-28 | Negma Gild | Enantiomere(-)du tenatoprazole et son application en therapeutique |
FR2871800B1 (fr) * | 2004-06-17 | 2006-08-25 | Sidem Pharma Sa Sa | Sel de sodium monohydrate du s-tenatoprazole et application en therapeutique |
-
2002
- 2002-10-21 FR FR0213113A patent/FR2845915B1/fr not_active Expired - Fee Related
-
2003
- 2003-10-21 DK DK03778427T patent/DK1553943T3/da active
- 2003-10-21 EP EP08000893A patent/EP2014290B1/fr not_active Expired - Lifetime
- 2003-10-21 SI SI200331298T patent/SI1553943T1/sl unknown
- 2003-10-21 JP JP2004546114A patent/JP2006508083A/ja active Pending
- 2003-10-21 AT AT03778427T patent/ATE395060T1/de active
- 2003-10-21 CN CN2012102653624A patent/CN102920705A/zh active Pending
- 2003-10-21 ES ES03778427T patent/ES2306905T3/es not_active Expired - Lifetime
- 2003-10-21 PT PT03778427T patent/PT1553943E/pt unknown
- 2003-10-21 US US10/531,900 patent/US20070066659A1/en not_active Abandoned
- 2003-10-21 KR KR1020057006851A patent/KR101186034B1/ko not_active IP Right Cessation
- 2003-10-21 AU AU2003285426A patent/AU2003285426A1/en not_active Abandoned
- 2003-10-21 EP EP03778427A patent/EP1553943B1/fr not_active Expired - Lifetime
- 2003-10-21 CA CA2503212A patent/CA2503212C/fr not_active Expired - Fee Related
- 2003-10-21 DK DK08000893.1T patent/DK2014290T3/da active
- 2003-10-21 CN CNA2003801071998A patent/CN1753674A/zh active Pending
- 2003-10-21 DE DE60321025T patent/DE60321025D1/de not_active Expired - Lifetime
- 2003-10-21 ES ES08000893T patent/ES2412395T3/es not_active Expired - Lifetime
- 2003-10-21 BR BR0315458-0A patent/BR0315458A/pt not_active Application Discontinuation
- 2003-10-21 WO PCT/FR2003/003122 patent/WO2004037255A1/fr active IP Right Grant
-
2008
- 2008-08-11 CY CY20081100837T patent/CY1108248T1/el unknown
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2011
- 2011-02-25 US US13/035,547 patent/US20110152314A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
US20110152314A1 (en) | 2011-06-23 |
KR20050090374A (ko) | 2005-09-13 |
DK1553943T3 (da) | 2008-09-15 |
WO2004037255A1 (fr) | 2004-05-06 |
EP2014290B1 (fr) | 2013-01-23 |
CA2503212C (fr) | 2012-03-13 |
CY1108248T1 (el) | 2014-02-12 |
EP2014290A2 (fr) | 2009-01-14 |
BR0315458A (pt) | 2005-08-23 |
US20070066659A1 (en) | 2007-03-22 |
KR101186034B1 (ko) | 2012-09-25 |
CA2503212A1 (fr) | 2004-05-06 |
PT1553943E (pt) | 2008-08-20 |
EP1553943A1 (fr) | 2005-07-20 |
EP1553943B1 (fr) | 2008-05-14 |
ATE395060T1 (de) | 2008-05-15 |
FR2845915B1 (fr) | 2006-06-23 |
EP2014290A3 (fr) | 2009-03-04 |
SI1553943T1 (sl) | 2008-12-31 |
AU2003285426A8 (en) | 2004-05-13 |
ES2306905T3 (es) | 2008-11-16 |
DK2014290T3 (da) | 2013-05-06 |
CN102920705A (zh) | 2013-02-13 |
DE60321025D1 (de) | 2008-06-26 |
FR2845915A1 (fr) | 2004-04-23 |
AU2003285426A1 (en) | 2004-05-13 |
JP2006508083A (ja) | 2006-03-09 |
ES2412395T3 (es) | 2013-07-11 |
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