CN1204923C - 局部用无水皮肤制剂 - Google Patents
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Abstract
本发明提供一种用于局部传递一种或多种药物的无水组合物,该组合物含:(A)渗透增强剂/溶剂,选自醇、丙二醇或它们的混合物;(B)保湿剂/溶剂,选自聚乙二醇、甘油、山梨醇、木糖醇、或它们的任意组合;和(C)无水载体。在另一实施例中,本发明提供的用于局部传递一种或多种药物的无水组合物含:(A)渗透增强剂/溶剂,选自醇、丙二醇或它们的混合物;(B)保湿剂/溶剂,选自聚乙二醇、甘油、山梨醇、木糖醇、或它们的任意组合;(C)无水载体;和(D)一种或多种药物。本发明还提供一种向需要治疗的动物局部传递药物的方法,所述方法包括局部给予动物本发明组合物。
Description
发明领域
本发明涉及局部用无水皮肤制剂,它疗效高,毒性低,并能引导或加强活性药物向皮肤的传递,从而得到更好、更高的治疗指数。本发明还涉及制造和使用上述组合物的方法。
发明背景
已知,醇、多元醇(例如丙二醇)、表面活性剂(例如十二烷基硫酸钠)、防腐剂(例如对羟基苯甲酸酯,如对羟基苯甲酸甲酯)、酸(例如山梨酸)和溶剂单独使用或在局部制剂中使用会导致刺激、过敏或变应性皮肤反应,及/或成为皮肤渗透增强剂。保湿剂(例如甘油)、溶剂(例如聚乙二醇)、防晒剂(例如氧化锌)和表面活性剂属于妨碍活性药物渗入皮肤的物质。参见,Angleini,G.Contact Dermatitis 7,1981;Belmonte,J.Pham Sci.67:517,1978;Catanzaro,J.M.J.Am.Acad.Dermatol24(1),1981;Cooper,J.Pharm Sci.73:1153,1984;Faucher,J Am Oil Chem Soc56:776,1979;Lahti,A.Contact Dermatitis 29,1993;Trancik,R.J.,ContanctDermatitis 8,1982;Wahlberg,J.E.Acta Derm Venereol 64,1984;Zatz,J.L.J SocCosmet Chem 34:327,1983。
Patel等的美国专利4,855,294公开了一种含甘油组合物和一种降低透皮(即,通过药物实际通过皮肤或黏膜组织来传递)药物增强剂组合物对皮肤刺激的方法。
自40年代起,基于糖皮质类固醇的组合物被用于治疗皮肤炎症。国际专利申请WO92/18113公开一种用于漱口的液体溶液,其中含抗真菌药物和类固醇。Hogi,F.Mykosen 23(8):426,1980报道了酮康唑在曲安奈德存在下的活性。最近显示,酮康唑组合物能有效治疗真菌感染。
皮肤病一般有炎症与真菌感染相伴发生的特点,因为,皮肤发炎的过程为致病微生物的生长和繁殖创造了适宜的条件。所以,单用消炎药或抗真菌药治疗,往往不足以治愈各种皮肤病。
美国专利5,654,293和EP专利公开0680328描述一种局部用水包油乳液和药物组合物,分别含酮康唑和丙酮化糖皮质类固醇,pH在2.5以上6以下。
但是,从美国专利5,002,938和5,110,809可知道,将17-酯类固醇与咪唑类抗真菌药混合存在稳定性问题。因为类固醇在酮康唑存在下不稳定,无法制备同时含酮康唑和糖皮质类固醇的制剂。至今,仍未获得针对皮肤、用于治疗皮肤病、局部用稳定、有效且无毒的疗法。因此需要有关制造这类组合物的新方法。
发明概述
本发明实施例之一提供了一种用于局部传递一种或多种药物的无水组合物。这类组合物含有:
(A)渗透增强剂/溶剂,选自醇、丙二醇或它们的混合物;
(B)保湿剂/溶剂,选自聚乙二醇、甘油、山梨醇、木糖醇、或它们的任意组合;和
(C)无水载体。
本发明另一实施例提供的用于局部传递一种或多种药物的无水组合物含有:
(A)渗透增强剂/溶剂,选自醇、丙二醇或它们的混合物;
(B)保湿剂/溶剂,选自聚乙二醇、甘油、山梨醇、木糖醇、或它们的任意组合;
(C)无水载体;和
(D)一种或多种药物。
本发明另一实施例提供向需要治疗的哺乳动物或人患者等动物局部传递一种或多种药物的方法。所述方法包括局部给予动物上述组合物。
本发明详细描述
本发明的组合物通常是乳膏、凝胶、软膏、洗液或液剂。这些组合物无水,因为不需要加水。但是,组合物可能含有与各组分一定量的结合水。通常,这些水少于组合物总重量的10%。较好的是,本发明组合物完全无水。
适用于本发明的渗透增强剂/溶剂是醇类,包括但不限于:乙醇、丙二醇、或它们的混合物。本发明合适的保湿剂/溶剂包括但不限于:聚乙二醇、甘油、山梨醇、木糖醇或它们的各种形式的组合。合适的无水载体包括但不限于与醇类渗透增强剂相同或不同的醇。这类醇包括异丁醇和异丙醇等。
可以本发明组合物局部传递的药物包括但不限于:抗真菌药、抗菌剂、抗病毒药、抗痤疮药、抗衰老药、止痒药、防晒剂、肤色调节剂、生发剂、生发抑制剂、脱毛剂、去屑剂、抗脂溢剂、抗牛皮癣剂、蜕皮剂、愈创剂、抗寄生虫药、皮脂调节剂、免疫调节剂、激素、植物性药物、湿润剂、收敛剂、清洁剂、增敏剂、抗生素、抗刺激药、麻醉剂、镇痛剂、类固醇、消炎药、组织愈伤剂、组织再生剂、维生素A等维生素、氨基酸、肽、矿物质、包括α羟基酸和β羟基酸的羟基酸,或以上所述的任意组合。
类固醇例如糖皮质类固醇等,尤其是地奈德。抗真菌药例如酮康唑等。抗生素例如红霉素等。
本发明组合物可包含的其他成分包括但不限于:润滑药、螯合剂、pH调节剂、抗氧化剂、胶凝剂、增稠剂、色素、香料、UV稳定剂、防晒剂,或以上所述的任意组合。
pH调节剂例如苹果酸、乳酸、柠檬酸、乙二酸、苯甲酸、抗坏血酸、或以上所述的任意组合,等等。抗氧化剂例如没食子酸丙酯、抗坏血酸、棕榈酸抗坏血酸酯、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、例如α生育酚的生育酚,或以上所述的任意组合,等等。增稠剂例如羟基丙基纤维素。
本发明组合物中各组分的含量就是足以实现该组分功用的量。例如,渗透增强剂的量一般即渗透增强有效量。较好的是,以组合物总重为100份,组合物含约1.0-50wt%渗透增强剂/溶剂,约10-80wt%保湿剂/溶剂,润滑剂和外观改善剂共约0-10wt%,螯合剂和pH调节剂共约0-2wt%,约0-2wt%抗氧化剂,胶凝剂和增稠剂共约0-5wt%,和无水载体。
较好的是,羟丙基纤维素胶凝剂约占组合物总重的0-3%。
以组合总重为100份,具体药物的含量优选:约0.0001-20%,约0.5-3%更好,最好约2%的抗真菌,特别是剂酮康唑;约0.0001-10%,约0.01-2.0%更好,最好约0.05%糖皮质类固醇,特别是地奈德;约0.001-0.5%,最好约0.02-0.1%维生素,特别是全反式维生素A酸(维A酸);约0.01-10%,最好约0.1-3%抗生素,特别是红霉素。
渗透增强剂、溶剂和载体的含量可相互平衡,以使药物增溶。
根据所含药物的治疗有效量,局部给予本发明组合物。
可在一主容器内将渗透增强剂/溶剂、保湿剂/溶剂和无水载体混合均匀,制备成本发明的组合物。然后加入药物或活性物质,混合均匀。然后,加入各种螯合剂、pH调节剂、抗氧化剂、润滑剂、外观改善剂、香料、UV稳定剂、防晒剂、色素等,混合均匀。然后加入增稠剂和胶凝剂,混合均匀。然后,包装最终产物。
优选实施例的描述
以下实施例说明本发明,但不限制本发明。若非另作说明,所有含量都是基于组合物总重的百分数。
实施例1
制备用于局部给予的酮康唑和地奈德的无水组合物,配方为表1。
表1 | |
酮康唑/地奈德制剂 | |
成分 | %(w/w) |
酮康唑 | 0-2 |
地奈德 | 0.0-0.05 |
丙二醇 | 20 |
聚乙二醇 | 20 |
甘油 | 20 |
PPG-15硬脂基醚 | 0-2 |
羟丙基纤维素 | 1.5-2.0 |
抗坏血酸 | 0.0-0.3 |
柠檬酸 | 0.0-0.1 |
丁基化羟基甲苯 | 0.0-0.1 |
乙醇 | 补足100 |
比较实施例1A-C
制备表2-4配方的组合物。
表2 | |
酮康唑/地奈德制剂 | |
成分 | %(w/w) |
酮康唑 | 0-2 |
地奈德 | 0-0.05 |
丙二醇 | 10 |
硬脂醇 | 4 |
十六烷基醇 | 4 |
脱水山梨糖醇单硬脂酸酯 | 2 |
聚山梨酯60 | 1.5 |
矿物油 | 1 |
磷酸氢钠 | 0.25 |
柠檬酸 | 0.24 |
苯甲酸 | 0.2 |
丁基化羟基苯甲醚 | 0.005 |
纯水 | 100 |
表3 | |
酮康唑/地奈德制剂 | |
成分 | %(w/w) |
酮康唑 | 0-2 |
地奈德 | 0-0.05 |
丙二醇 | 20 |
聚乙二醇 | 10 |
甘油 | 30 |
PPG-15硬脂基醚 | 2 |
羟丙基纤维素 | 1.5-2.0 |
抗坏血酸 | 0-0.3 |
柠檬酸 | 0-0.1 |
丁基化羟基苯甲醚 | 0-0.1 |
乙醇 | 补足100 |
表4 | |
酮康唑/地奈德制剂 | |
成分 | %(w/w) |
酮康唑 | 0-2 |
地奈德 | 0.0-0.05 |
丙二醇 | 20 |
N-甲基-2-吡咯烷酮 | 20 |
甘油 | 20 |
PPG-15硬脂基醚 | 2 |
羟丙基纤维素 | 1.5-2.0 |
抗坏血酸 | 0.0-0.3 |
柠檬酸 | 0.0-0.1 |
丁基化羟基甲苯 | 0.0-0.1 |
乙醇 | 补足100 |
实施例2
制备用于局部给予的全反式维生素A酸(维A酸)的无水组合物,配方见表5。
表5 | |
维甲酸制剂 | |
成分 | %(w/w) |
维A酸 | 0.05 |
丙二醇 | 20 |
聚乙二醇 | 20 |
甘油 | 20 |
PPG-15硬脂基醚 | 0-2 |
羟丙基纤维素 | 1.5-2.0 |
柠檬酸 | 0-0.15 |
丁基化羟基甲苯 | -0.1 |
乙醇 | 补足100 |
实施例3
局部给予红霉素的无水组合物,配方见表6。
表6 | |
红霉素制剂 | |
成分 | %(w/w) |
红霉素 | 2 |
丙二醇 | 20 |
聚乙二醇 | 20 |
甘油 | 20 |
PPG-15硬脂基醚 | 0-2 |
羟丙基纤维素 | 1.5-2.0 |
柠檬酸 | 0-0.5 |
乙醇 | 补足100 |
实施例4和比较实施例4A:皮肤炎症试验
已知局部涂以佛波酯可诱导皮肤炎症。已知皮质类固醇以剂量依赖性方式高效减轻佛波酯(例如TPA)诱导的炎症。所以,用该模型评价皮质类固醇的相对消炎活性。
用实施例1(实施例4)和比较实施例1A(比较实施例A4)进行减轻皮肤炎症(TPA耳水肿小鼠模型)的剂量效应研究。结果见表7。
表7皮肤消炎活性 | ||||
%地奈德 | 实施例4 | 比较实施例4 | ||
%抑制 | ED50(%) | %抑制 | ED50(%) | |
0.0000 | 0 | 0.0015 | 0 | 0.0054 |
0.0003 | 30.40 | 15.36 | ||
0.003 | 57.43 | 39.05 | ||
0.03 | 87.08 | 74.79 |
实施例1(实施例4)组合物(ED50=0.0015%)的局部皮肤消炎活性和效力比比较实施例1A(比较实施例4A)(ED50=0.0054%)高3倍。
实施例5和比较实施例5A和5B:皮肤抗真菌试验
以实施例1(实施例5)、比较实施例1A(比较实施例5A)的化合物和NIZORAL乳膏(2%酮康唑乳膏)(Janssen Pharmaceutica)(比较实施例5B)在尸体皮肤上进行体外微生物抑制实验,测定抗真菌活性,并证明在人皮肤上的活性。
结果见表8。
表8皮肤抗真菌活性 | ||
没有P.ovale的区域 | 没有T.rubrum的区域 | |
实施例5 | 11mm | 13mmm |
比较实施例5A | 3mm | 0* |
比较实施例5B | 3 | 0* |
*对此微生物只有部分抑制,微生物继续生长的区域;没有得到无菌区。
已知T.rubrum是引起体癣、股癣、足癣等皮肤真菌病的一种主要微生物。结果显示:实施例1(实施例5)组合物对常见皮肤真菌T.rubrum有显著的皮肤抗真菌活性(无菌区)。比较实施例1A(比较实施例5A)和NIZORAL乳膏(比较实施例5B)的组合物在该研究中,没有表现出抗真菌T.rubrum活性的无菌区。
已知P.ovale在例如脂溢性皮炎等皮肤病的病因中起着重要作用。实施例1(实施例5)组合物对酵母菌P.ovale也表现出显著的抗真菌活性,而比较实施例1A(比较实施例5A)和NIZORAL乳膏(比较实施例5B)的组合物则只表现出很小的活性。
实施例6和7和比较实施例6A-E和7A:引导和增强向皮肤传递的测定
用实施例1(实施例6和7)、NIZORAL乳膏(比较实施例6A、6C和6E)、DesOwen乳膏(0.05%地奈德乳膏)(Galderma)(比较实施例7B、7C和7E)、实施例1A(比较实施例6B和7A)和比较实施例1B(比较实施例6D和7D)的组合物,在人尸皮肤上进行Franz池扩散研究,测定酮康唑和地奈德等药物的皮肤生物利用度。
结果见表9和10。
表9 | ||||
酮康唑引导的向皮肤的传递 | ||||
实施例 | 制剂 | 表皮 | 真皮 | 接受液 |
6B | 2%酮康唑,0.05%地奈德 | 0.33±0 | 0.55±0 | 0.2±0 |
6C | 2%酮康唑乳膏 | 0.64±0.0 | 1.18±0.0 | 0.12±0.0 |
试验2 | ||||
6 | 2%酮康唑,0.05%地奈德 | 2.44±0.65 | 1.24±.0.78 | 0.5±0.05 |
6A | (2%酮康唑乳膏) | 0.205±0.01 | 0.371±0.10 | 1.017±0.24 |
试验3 | ||||
6D | 2%酮康唑,0.05%地奈德) | 1.83±0.37 | 1.77±1.01 | 0.950±0.43 |
6E | (2%酮康唑乳膏) | 0.112±0.03 | 0.195±0.08 | 0.428±0.15 |
表10 | ||||
地奈德引导的向皮肤的传递 | ||||
实施例 | 制剂 | 表皮 | 真皮 | 接受液 |
7A | 2%酮康唑,0.05%地奈德) | 2.64±0 | 1.85±0 | 1.6±0 |
7B | (0.05%地奈德乳膏) | 2.57±0 | 2.03±0 | 2.99±0 |
试验2 | ||||
7 | 2%酮康唑,0.05%地奈德) | 1.222±1.35 | 1.125±0.88 | 0.677±0.06 |
7C | (0.05%地奈德乳膏) | 1.372±0.21 | 0.718±0.43 | 12.49±1.83 |
试验3 | ||||
7D | 2%酮康唑,0.05%地奈德) | 1.359±0.44 | 1.905±1.09 | 0.516±0.1 |
7E | (0.05%地奈德乳膏) | 0.853±0.03 | 1.104±0.31 | 3.677±1.24 |
实施例1的组合物表现出酮康唑和地奈德向表皮室的定向传递。据信,与NIZORAL乳膏相比,酮康唑更多地传递到表皮和真皮,而到达接受液的则较少。与DesOwen乳膏相比(比较实施例7B、7C和7E),实施例1组合物中相当量的地奈德传递到表皮和真皮,而到达接受液的则较少。实施例1组合物中的酮康唑和地奈德在接受液区室内的含量减少,可在临床上降低药物全身性吸收低和所致的药物全身性毒性低。与NIZORAL乳膏和DesOwen乳膏相比,比较实施例1A组合物向表皮和真皮传递的酮康唑较少,而向接受液传递的则比NIZORAL乳膏多。
总的结果表明,实施例1的组合物实现了药物向皮肤的定向传递,与比较实施例1A、NIZORAL乳膏和DesOwen乳膏相比,传递到表皮和真皮内目标位置的药更多。数据证明,实施例1组合物向皮肤传递的定向性更好,药理活性更高。而且,实施例1组合物透过皮肤向接受液的渗透显然较少,因此在临床上的全身性毒性较低。相比之下,比较实施例1A组合物使较多的酮康唑渗透到接受液中,这可能表现为不良的临床毒性全身性效应。
实施例8和比较实施例8A和8B:累积刺激试验
对白兔进行实施例1组合物(实施例8)、比较实施例1B(比较实施例8A)和比较实施例1C(比较实施例8B)的皮肤刺激试验,用红斑和水肿平均计分来评定相对刺激作用。结果见表11。
如表11所示,实施例1组合物的刺激性低于比较实施例1B和1C(p<0.05)。单用甘油没有明显降低刺激作用。
此外,实施例1组合物刺激性降低,而且效力增强,因此提高了治疗指数。
表11累积刺激试验(合计每日的红斑和水肿计分) | |||||
日 | 0 | 5 | 10 | 15 | 19 |
实施例8 | 0 | 1.6 | 2.6 | 1.8 | 0.7 |
比较实施例8A | 0 | 2.4 | 3.5 | 3.1 | 1.3 |
比较实施例8B | 0 | 2.5 | 3.9 | 3.1 | 1.5 |
实施例9:贴剂反复损伤试验
评价实施例1的载体组合物,即不含酮康唑或地奈德的组合物,诱导人皮肤接触性致敏的能力。
对总共216名男性和女性进行了6周的评价。挑选后,用测试材料贴剂半封闭敷贴,在3周内反复敷贴了9次。经一段休整期后,观察测试部位,进行激发试验。
在诱导阶段,3名受试者表现出低水平的反应。2名受试者只表现出干燥。原来的测试部位在测试阶段和刺激时,没有表现出反应。只有2名受试者在刺激期表现出低水平的反应。
以上临床结果表明,实施例1的载体组合物在重复使用后不对人诱导接触性皮肤致敏。
本文参考引用了文中提到的各专利、出版物、专利申请和试验方法。
根据以上详细描述,本发明的变通形式对本领域熟练技术人员来说是显而易见的。这类明显的变通形式都属于本发明权利要求书的范围内。
Claims (25)
1.一种用于局部传递一种或多种药物的无水组合物,按组合物总重计,包含:
(A)1-50wt%丙二醇;
(B)10-80wt%聚乙二醇和甘油;
(C)醇;和
(D)药物,包括酮康唑和地奈德。
2.根据权利要求1所述组合物,所述药物被增溶。
3.根据权利要求1所述组合物,还包含其它药物,所述其它药物选自:抗真菌药、抗菌剂、抗病毒药、抗痤疮药、抗衰老药、止痒药、防晒剂、肤色调节剂、生发剂、生发抑制剂、脱毛剂、去屑剂、抗脂溢剂、抗牛皮癣剂、蜕皮剂、愈创剂、抗寄生虫药、皮脂调节剂、免疫调节剂、激素、植物性药物、湿润剂、收敛剂、清洁剂、增敏剂、抗生素、抗刺激药、麻醉剂、镇痛剂、类固醇、消炎药、组织愈伤剂、组织再生剂、维生素、氨基酸、肽、矿物质、羟基酸,或以上所述的任意组合。
4.根据权利要求3所述组合物,其中所述的其它药物选自:抗真菌药、维生素A类、抗生素、糖皮质类固醇,或以上所述的任意组合。
5.根据权利要求4所述组合物,其中所述的药物是维A酸。
6.根据权利要求4所述组合物,其中所述的药物是红霉素。
7.根据权利要求1所述组合物,还含有:
(E)润滑剂;
(F)螯合剂;
(G)pH调节剂;
(H)抗氧化剂;
(I)胶凝剂;
(J)增稠剂;
(K)色素;
(L)香料;
(M)UV稳定剂;
(N)防晒剂;或
(O)以上所述的任意组合。
8.根据权利要求7所述组合物,其中所述pH调节剂选自苹果酸、乳酸、柠檬酸、乙二酸、苯甲酸、抗坏血酸,或以上所述的任意组合。
9.根据权利要求7所述的组合物,其中所述抗氧化剂选自没食子酸丙酯、抗坏血酸、棕榈酸抗坏血酸酯、丁基化羟基苯甲醚、丁基化羟基甲苯、生育酚,或以上所述的任意组合。
10.根据权利要求7所述的组合物,其中所述增稠剂是羟丙基纤维素。
11.根据权利要求7所述的组合物,以组合物总重为100%计,含1-50%丙二醇,10-80%聚乙二醇和甘油,0.0001-20%药物,润滑剂和色素共0-10%,螯合剂和pH调节剂共0-2%,0-2%抗氧化剂,胶凝剂和增稠剂共0-5%,和醇。
12.根据权利要求11所述的组合物,所述胶凝剂为组合物总重1.5-2.0%的羟丙基纤维素。
13.根据权利要求11所述的组合物,含组合物总重0.05-3%的酮康唑。
14.根据权利要求11所述的组合物,含组合物总重0.5-3%的酮康唑。
15.根据权利要求11所述的组合物,含组合物总重2%的酮康唑。
16.根据权利要求11所述的组合物,含组合物总重0.0001-10%的地奈德。
17.根据权利要求11所述的组合物,含组合物总重0.01-2%的地奈德。
18.根据权利要求11所述的组合物,含组合物总重0.05%的地奈德。
19.根据权利要求11所述的组合物,含组合物总重0.001-0.5%的维生素。
20.根据权利要求11所述的组合物,含组合物总重0.02-0.1%的维A酸。
21.根据权利要求11所述的组合物,含组合物总重0.01-10%的抗生素。
22.根据权利要求11所述的组合物,含组合物总重0.1-3%的红霉素。
23.根据权利要求1所述的组合物,其中丙二醇和甘油的合计含量大于组合物总重的10%。
24.根据权利要求1所述的组合物,按组合物总重计,包含:
(A)20wt%丙二醇;
(B)20wt%聚乙二醇;和
(C)20wt%甘油。
25.权利要求1所述组合物用于制造局部传递型药物的用途。
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-
1998
- 1998-12-04 US US09/205,474 patent/US6238683B1/en not_active Expired - Lifetime
-
1999
- 1999-12-03 DE DE69930004T patent/DE69930004T2/de not_active Expired - Lifetime
- 1999-12-03 EP EP99961929A patent/EP1051193B1/en not_active Expired - Lifetime
- 1999-12-03 WO PCT/US1999/028661 patent/WO2000033877A1/en active IP Right Grant
- 1999-12-03 KR KR1020007008442A patent/KR100619228B1/ko active IP Right Grant
- 1999-12-03 PT PT99961929T patent/PT1051193E/pt unknown
- 1999-12-03 AU AU18412/00A patent/AU778524B2/en not_active Expired
- 1999-12-03 AR ARP990106172A patent/AR021539A1/es unknown
- 1999-12-03 BR BR9907666-7A patent/BR9907666A/pt not_active Application Discontinuation
- 1999-12-03 EP EP05077996A patent/EP1645287A3/en not_active Withdrawn
- 1999-12-03 AT AT99961929T patent/ATE318148T1/de active
- 1999-12-03 CN CNB998036560A patent/CN1204923C/zh not_active Expired - Fee Related
- 1999-12-03 CA CA002319515A patent/CA2319515C/en not_active Expired - Lifetime
- 1999-12-03 DK DK99961929T patent/DK1051193T3/da active
- 1999-12-03 CN CNB2005100650867A patent/CN100341578C/zh not_active Expired - Lifetime
- 1999-12-03 JP JP2000586367A patent/JP4610741B2/ja not_active Expired - Lifetime
- 1999-12-03 ES ES99961929T patent/ES2258347T3/es not_active Expired - Lifetime
-
2000
- 2000-01-21 TW TW088121127A patent/TW590777B/zh not_active IP Right Cessation
-
2001
- 2001-03-28 HK HK01102266A patent/HK1031342A1/xx not_active IP Right Cessation
-
2005
- 2005-03-09 AU AU2005201042A patent/AU2005201042A1/en not_active Abandoned
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2006
- 2006-04-13 CY CY20061100516T patent/CY1105450T1/el unknown
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WO2000033877A1 (en) | 2000-06-15 |
TW590777B (en) | 2004-06-11 |
CN1292707A (zh) | 2001-04-25 |
CN100341578C (zh) | 2007-10-10 |
AU778524B2 (en) | 2004-12-09 |
CN1714869A (zh) | 2006-01-04 |
EP1051193A1 (en) | 2000-11-15 |
PT1051193E (pt) | 2006-06-30 |
AU2005201042A1 (en) | 2005-04-07 |
ES2258347T3 (es) | 2006-08-16 |
CA2319515A1 (en) | 2000-06-15 |
HK1031342A1 (en) | 2001-06-15 |
KR100619228B1 (ko) | 2006-09-04 |
EP1645287A2 (en) | 2006-04-12 |
DE69930004D1 (de) | 2006-04-27 |
JP2002531526A (ja) | 2002-09-24 |
CA2319515C (en) | 2009-10-13 |
EP1051193B1 (en) | 2006-02-22 |
EP1645287A3 (en) | 2006-06-07 |
BR9907666A (pt) | 2000-12-19 |
DE69930004T2 (de) | 2006-10-12 |
US6238683B1 (en) | 2001-05-29 |
DK1051193T3 (da) | 2006-06-12 |
CY1105450T1 (el) | 2010-04-28 |
AR021539A1 (es) | 2002-07-24 |
AU1841200A (en) | 2000-06-26 |
KR20010040573A (ko) | 2001-05-15 |
JP4610741B2 (ja) | 2011-01-12 |
ATE318148T1 (de) | 2006-03-15 |
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