CN101001610A - 防止药物转向的陶瓷结构 - Google Patents
防止药物转向的陶瓷结构 Download PDFInfo
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Abstract
本发明涉及提供递药的组合物,同时提供抵抗转向的方法。这些组合物为药物与陶瓷结构的组合。可以使用任意合适的药物,但该药物一般为阿片样物质激动剂。所述的陶瓷结构通常为金属氧化物并且通常为具有空心的近球形形状。
Description
发明领域
本发明一般涉及防止药物转向(drug diversion)的方法。更具体地说,本发明涉及提供递药的药物/陶瓷结构组合,同时提供阻止转向的方法。
发明背景
药物转向是未被开据处方药的人使用处方药。这类应用在美国占药物滥用的30%,并且代表了接近对可卡因成瘾的挑战。大部分滥用者为无在先药物滥用史的人,它们在因合法的医学原因而使用处方药后变成瘾。
众所周知处方药的滥用者在药物转向时以两个参数为目标-剂量和快速给药的剂型。转向者通常可以获得药物、将其压碎且然后通过鼻内递送。另一种给药方式包括将药物溶于水或醇且然后通过鼻内递送。每种递送方式各自提供了将药物快速导入血流。
已经研发了几种抑制药物转向的方法。一种这类方法包括将靶药物掺入聚合物基质。这种构思在于使药物吸附在聚合物基质内,这样仅使其在导入溶剂时缓慢释放。换句话说,即使使用萃取方法,也不能直接获得掺入的药物。然而,当转向者发现他们可以简单压碎聚合物基质而提供便于直接获得吸附的药物时,这一策略最终失败了。
因此,存在对用于抑制或防止药物转向的新方法的需求。这就是本发明的目的。
发明概述
本发明涉及药物/陶瓷结构组合,它提供药物递送,同时提供阻止转向的方法。所述的陶瓷结构一般包括金属氧化物,其中氧化物是钛、锆、钪、铈或钇。任意合适的药物都可以用于该组合,但优选阿片样物质激动剂,尤其是羟考酮。
在本发明的组合物方面中,提供了包括陶瓷结构和药物的组合物。陶瓷结构为近球形和空心的。将药物涂敷在陶瓷结构的空心部分内并且该结构的平均直径在10nm-100μm。平均粒径通常在如下范围:10nm-100nm;101nm-200nm;201nm-300nm;301nm-400nm;401nm-500nm;501nm-600nm;601nm-700nm;701nm-800nm;801nm-900nm;901nm-1μm;1μm-10μm;11μm-25μm;和26μm-100μm。粒经的变异一般低于平均粒径的10.0%,优选低于平均粒径的7.5%,且更优选低于平均粒径的5.0%。
陶瓷结构一般包括二氧化钛或氧化锆。包括的药物一般为选自羟考酮、可待因、氢可酮、氢吗啡酮、左啡诺、哌替啶、美沙酮(methandone)和吗啡的阿片样物质激动剂。本发明的陶瓷结构/药物组合表现出可测定的机械强度。至少50%的颗粒在5kg/cm2、7.5kg/cm2、10.0kg/cm2、12.5kg/cm2、15.0kg/cm2、17.5kg/cm2或20kg/cm2的力施加于其上时可维持总体完整性(例如形状。大小、孔隙度等)。
详细描述
本发明涉及药物/陶瓷结构组合,它提供药物递送,同时提供阻止转向的方法。
可以将任意合适的药物掺入本发明的组合,不过,优选阿片样物质激动剂。这类激动剂包括,但不限于下列药物:阿芬太尼、烯丙罗定、阿法罗定、阿尼利定、苄吗啡、贝齐米特、丁丙诺啡、布托啡诺、氯尼他秦、可待因、二氢去氧吗啡、吗散痛、地佐辛、地恩丙胺、海洛因、双氢可待因、双氢吗啡、地美沙朵、地美庚醇、二甲噻丁、吗苯丁酯、地匹哌酮、依他佐辛、依索庚嗪、乙甲噻丁、乙基吗啡、依托尼秦、埃托啡、二氢埃托啡、芬太尼、氢可酮、氢吗啡酮、羟哌替啶、异美沙酮、凯托米酮、左啡诺、左芬啡烷、洛芬太尼、哌替啶、美普他酚、美他佐辛、美沙酮、美托酮、吗啡、麦罗啡、罂粟碱、尼可吗啡、去甲左啡诺、去甲美沙酮、烯丙吗啡、纳布啡、去甲吗啡、诺匹哌酮、阿片、羟考酮、羟吗啡酮、阿片全碱、喷他佐辛、苯吗庚酮、非诺啡烷、非那佐辛、苯哌利定、匹米诺定、哌腈米特、propheptazine、三甲利定、丙哌利定、右丙氧芬、舒芬太尼、替利定、曲马多、其药物上可接受的盐、其立体异构体、其醚类、其酯类及其混合物。
可以掺入陶瓷结构的其它药物的实例包括,但不限于下列药物:醋托啡、阿醋美沙朵、阿法美罗定、阿法芳沙朵、阿法罗定、aenzethidine、倍醋美沙朵、倍他美罗定、倍他美沙朵、倍他罗定、蟾蜍特宁、卡芬太尼、二醋吗啡、二乙噻丁、地芬诺辛、双氢可待因酮、羟蒂巴酚、乙环利定、依托利定、乙色胺(etryptanrine)、依托利定、氢吗啡醇(hydromoiphinol)、左美沙芬、左吗拉胺、醋美沙朵、甲地索啡、甲二氢吗啡(methyldihydroniorphine)、吗哌利定、诺美沙朵、哌替啶、苯吗庚酮、非那丙胺、苯环利定、裸头草辛、消旋甲啡烷、消旋吗拉胺、消旋啡烷、咯环利定、替诺环定、醋氢可酮、二甲基吗啡、胺苯环己乙酯、三甲利定、醋氢可待因、苯丙胺、格鲁米特、来苯胺、甲氯喹酮、甲喹酮、甲卡西酮、去氧麻黄碱、哌甲酯、甲苯比妥、尼可待因、烟氢可待因(nicodicodinc)、去甲可待因、芬美曲秦、福尔可定、丙吡兰、齐培丙醇、阿普唑仑、阿米雷司、benzphetarnine、溴西泮、溴替唑仑、卡马西泮、去甲伪麻黄碱、卡西酮、ehlordiazepoxide、对氯苯丁胺、氯巴占、elonazeparn、氯氮草、氯噻西泮、氯噁唑仑、地洛西泮、右丙氧芬、地西泮、安非拉酮、艾司唑仑、乙氯维诺、炔己蚁胺、氯氟卓乙酯、芬坎法明、苯丙胺乙茶碱、芬普雷司、氟地西泮、氟硝西泮、氟西泮、哈拉西泮、卤沙唑仑、凯他唑仑、氯普唑仑、劳拉西泮、氯甲西泮、马吲哚、美达西泮、美芬雷司、美芬丁胺、甲丙氨酯、双苯斯酮胺、甲乙哌啶酮、咪达唑仑、尼美西泮、硝西泮、去甲西泮、奥沙西泮、奥沙唑仑、匹莫林、苯甲曲秦、芬特明、匹那西泮、pipadrol、普拉西泮、吡咯戊酮、替马西泮、四氢西泮、三唑仑、N-乙基苯异丙胺、阿他美坦、勃雄二醇、勃拉睾酮、勃拉嗪、勃地酮、勃来诺、勃金刚酯、卡普睾酮、4-氯甲烷二烯酮(chloromethandienone)、氯司替勃、屈他雄酮、依奈替勃、环硫雄醇、乙基雌烯醇、氟甲睾酮、甲酰勃龙、夫拉扎勃、美勃嗪、美雄烷、美沙勃龙、美睾酮(mestarolone)、美睾酮、美雄酮、美雄醇、美替诺龙、美曲勃龙、米勃酮、诺龙、诺勃酮、诺司替勃、诺乙雄龙、卵雄酮、羟勃龙、氧雄龙、羟甲睾酮、羟甲烯龙、普拉睾酮、普罗雄醇、奎勃龙、罗昔勃龙、硅雄酮、二氢睾丸酮、司坦唑醇(stanozolo)、司腾勃龙、其药物上可接受的盐、其立体异构体、其醚类、其酯类及其混合物。
本发明的陶瓷结构一般包括钛、锆、钪、铈和钇的氧化物,它们为单独的或作为混合物。优选所述的陶瓷结构为二氧化钛或氧化锆,尤其优选二氧化钛。陶瓷的结构特征为通过合成方法或分离技术很好控制的。可控特征的实例包括:1)结构为近球形和空心的,还是彼此结合成近球形的小颗粒集合;2)结构大小的范围(例如粒经);3)结构的表面积;4)壁厚,其中结构是空心的;5)孔径范围;和6)结构整体的强度。
一般通过将金属盐溶液喷雾水解成颗粒来生产陶瓷,将其收集并且加热处理。喷雾水解最初得到非晶体的空心球。这些球的表面由非晶形玻璃样金属氧化物或混合的金属氧化物薄膜组成。煅烧或加热处理这些材料使薄膜结晶,从而形成雏晶的互连骨架。煅烧产品一般为空心的多孔刚性结构。
各种近球形陶瓷材料通过某些参数的变异产生:a)改变金属组成或原始溶液的混合物;b)改变溶液浓度v;和c)改变煅烧条件。此外,可以按照大小,使用众所周知的空气分类和筛分技术给所述的材料分类。
就近球形的空心结构而言,粒经一般在10nm-100μm的范围。平均粒径通常在如下范围:10nm-100nm;101nm-200nm;201nm-300nm;301nm-400nm;401nm-500nm;501nm-600nm;601nm-700nm;701nm-800nm;801nm-900nm;901nm-1μm;1μm-10μm;11μm-25μm;和26μm-100μm。
整个样品中粒经的变异一般是充分可控的。例如,粒经的变异一般低于平均直径的10.0%,优选低于平均直径的7.5%,且更优选低于平均直径的5.0%。
陶瓷结构的表面积依赖于几个因素,包括颗粒形状、颗粒大小和颗粒孔隙度。一般来说,近球形颗粒的表面积在0.1m2/g-100m2/g的范围。然而,通常的表面积在0.5m2/g-50m2/g的范围。
空心颗粒的壁厚趋向于在10nm-5μm的范围,一般为50nm-3μm。这类颗粒的孔径进一步在1nm-5μm,且通常属于5nm-3μm范围。
本发明的陶瓷结构表现出显著的机械强度。至少50%的颗粒在被施加以如下力时可维持其总体完整性(例如形状、大小、孔隙度等):5kg-力/cm2(45牛顿/cm2),7.5kg-力/cm2(67.5牛顿/cm2),10.0kg-力/cm2(90牛顿/cm2),12.5kg-力/cm2(112.5牛顿/cm2),15.0kg-力/cm2(135牛顿/cm2),17.5kg-力/cm2(157.5牛顿/cm2),20kg-力/cm2(180牛顿/cm2),35kg-力/cm2(315牛顿/cm2),50kg-力/cm2(450牛顿/cm2),75kg-力/cm2(675牛顿/cm2),100kg-力/cm2(900牛顿/cm2)乃至125kg-力/cm2(1125牛顿/cm2)。一般来说,至少60%的颗粒可维持其总体完整性。优选至少70%的颗粒可维持其总体完整性,更优选至少80%的颗粒可维持其总体完整性,且尤其优选至少90%的颗粒可维持其总体完整性。
不经进一步处理,本发明的陶瓷结构为亲水性的。然而,可以使用公知技术对亲水性程度进行化学改变。这类技术包括,但不限于用含有镁、铝、硅、银、锌、磷、锰、钡、镧、钙、铈和PEG聚醚或冠醚结构的盐或氢氧化物处理所述的结构。这类处理影响结构将药物,特别是亲水性药物吸收和掺入其空心空间的能力。
或者,可以通过使用合适类型的化学试剂处理来制备相对疏水性的结构。疏水性试剂包括,但不限于有机硅烷类、氯-有机硅烷、有机-烷氧基-硅烷类、有机聚合物和烷基化试剂。这些处理使得所述的结构更适合于掺入亲脂性或疏水性药物。另外,可以使用化学蒸汽淀积、金属蒸汽淀积、金属氧化物蒸汽淀积或碳蒸汽淀积处理多孔空心结构来修饰其表面特性。
应用于陶瓷结构上的药物可以任选包括赋形剂。赋形剂的实例包括,但不限于下列物质:柠檬酸乙酰基三乙酯;acetyltrin-n-butylcitrate;阿司帕坦;阿司帕坦和乳糖;藻酸盐;碳酸钙;卡巴普;角叉藻聚糖;纤维素;纤维素和乳糖组合;交联羧甲基纤维素钠;交聚维酮;葡萄糖;癸二酸二丁酯;果糖;吉兰糖胶;甘油二十二烷酸酯;硬脂酸镁;麦芽糖糊精;麦芽糖;甘露糖醇;羧甲基纤维素;聚乙烯乙酸酯邻苯二甲酸酯;聚维酮;羟基乙酸淀粉钠;山梨醇;淀粉;蔗糖;三醋精;柠檬酸三乙酯;和黄原胶。
使用任意合适的方法将药物与本发明的陶瓷结构合并,不过优选溶剂涂布/蒸发和药物熔化。为了溶剂涂布/蒸发,将选择的药物溶于合适的溶剂。这类溶剂包括,但不限于下列物质:水、缓冲水、醇、酯类、醚类、氯化溶剂、氧化溶剂、有机-胺类、氨基酸、液体糖类、糖类混合物、超临界液体流体或气体(例如二氧化碳)、烃类、聚氧化溶剂、天然存在或衍生的流体和溶剂、芳族溶剂、聚芳族溶剂、液体离子交换树脂和其它有机溶剂。将溶解的药物与多孔空心陶瓷结构混合,并使用变压技术或超声给所得混悬液脱气。在搅拌该混悬液的同时,使用合适的方法(例如在低分压或大气压下进行真空、喷雾干燥并且冻干)进行溶剂蒸发。
或者,过滤上述混悬液并且任选用溶剂洗涤涂敷的陶瓷颗粒。按照标准方法干燥收集的颗粒。另一种备选方法包括过滤所述的混悬液并且使用诸如真空干燥、气流干燥、微波干燥和冷冻干燥这类技术干燥湿滤饼。
就药物熔化涂敷方法而言,将所需药物的熔化物与多孔空心陶瓷结构在低分压条件(即脱气条件)下混合。将该混合物在大气压下平衡并且在搅拌下冷却。该方法得到在结构内部和外部含有药物的粉末。
在压片前通过使用合适的溶剂简单洗涤颗粒表面且随后干燥而从颗粒表面除去药物。
一般给陶瓷结构内部涂敷10nm-10μm厚度,优选50nm-5μm的药物。药物与颗粒的相应重量比通常在1.0-100的范围,优选2.0-50。
涂敷的药物可以以晶体或非晶(非晶体)形存在。晶体物质因其原子、离子或分子的排列而表现出形成称作晶格的确定模式的特征形状和裂解面。非晶体物质不具有分子晶格结构。这种差异可以在物质的粉末衍射研究中观察到。在晶体物质的粉末衍射研究中,峰加宽开始在约500nm粒径。这种加宽随着晶体物质变小而持续,直至峰在约5nm时消失。当峰加宽至在5nm或5nm以下出现的与本底噪声无法区分的点时,通过XRD将物质定义为″非晶形″。
颗粒上涂敷的药物基本上为纯的形式。一般来说,该药物至少为95.0%纯度,优选至少97.5%的纯度值并且尤其优选至少99.5%的纯度值。换句话说,药物降解物(例如水解产物、氧化产物、光化降解产物等)分别保持在低于0.5%、2.5%或5.0%。
本发明的药物/陶瓷结构组合在通过各种方法,一般是通过口服给药时可提供药物递送。一般来说,该组合可提供至少25%的包含的药物,优选至少50%包含的药物,并且更优选至少75%包含的药物的释放。
本发明的药物/陶瓷结构组合在对患者给药时,一般可对患者提供受控的药物递送。通常在37℃下使用LISP桨式方法以100rpm在900ml含水缓冲液(pH为1.6-7.2)中测试本发明主题的组合时,提供下列溶出特性:1小时后释放5.0%-50.0%的药物;2小时后释放10.0%-75.0%的药物;4小时后释放20.0%-85.0%的药物;和6小时后释放25.0%-95.0%的药物。通常从1小时开始到4、5或6小时为止观察到遵从零级动力学的药物释放。
本发明的药物/陶瓷结构组合特别耐转向尝试。如上所述,所述的陶瓷结构表现出显著的机械强度,也可对该组合提供完整性。一般来说,当所述的组合经受5.0、7.5、10.0、12.5、15.0、17.5或20.0kg/cm2的力且然后如上所述使用USP桨式法测试时,受力后与受力前溶出速率之比小于2.0。优选该值小于1.7,更优选小于1.5,且最优选小于1.3。
一般来说,当将阿片样物质激动剂用于本发明的组合中时,包括75ng-750mg的激动剂。确切量取决于具体的阿片样物质激动剂并且可以使用众所周知的方法确定。还进行了研究以便概括出各种阿片样物质的等效剂量,它们有助于确切剂量的确定,包括如下剂量:羟考酮(13.5mg);可待因(90.0mg);氢可酮(15.0mg);氢吗啡酮(3.375mg);左啡诺(1.8mg);哌替啶(135.0mg);美沙酮(9.0mg);和吗啡(27.0mg)。
可以任选通过包含额外的非-阿片样物质激动剂,诸如NSAID或COX-2抑制剂来减少阿片样物质激动剂的剂量。NSAIDs的实例包括,但不限于下列药物:布洛芬;双氯芬酸;萘普生;苯噁洛芬;氟比洛芬;非诺洛芬;氟布芬;酮洛芬;吲哚洛芬;piroprofen;卡洛芬;奥沙普秦;普拉洛芬;muroprofen;trioxaprofen;舒洛芬;aminoporfen;噻洛芬酸;氟洛芬;布氯酸;吲哚美辛;舒林酸;托美丁;佐美酸;硫平酸;齐多美辛;阿西美辛;芬替酸;环氯茚酸;oxpinac;甲芬那酸;甲氯芬那酸;氟芬那酸;尼氟酸;托芬那酸;二氟尼柳;氟苯柳;吡罗昔康;舒多昔康;和伊索昔康。COX-2抑制剂包括,但不限于塞来考昔、氟舒胺、moloxicam、6-甲氧基-2萘乙酸(na phtylacetic acid)、万络、萘丁美酮和尼美舒利。上述NSAIDs和COX-2抑制剂的有用剂量为本领域众所周知的。
所述的药物/陶瓷结构组合在许多条件下均表现出有益的稳定性。换句话说,包含的药物在合理的时间期限内基本上不会分解。例如,在25℃下2周期限内,药物纯度一般降解小于5%。通常小于4%、3%、2%或1%的降解率(例如水解、氧化、光化反应)。
下列实施例的含义在于解释本发明,而并不意味着以任何方式限制本发明。
具体实施方式
实施例1
以12升/小时的速率将含有15g/l Ti和55g/l Cl的氯氧化钛和HCl的水溶液注射在钛喷雾干燥器中。从该喷雾干燥器中的出口温度为250℃。使用滤袋回收由非晶形球组成的固体中间产物。在500℃下的烘炉中煅烧该中间产物8小时。通过使煅烧的物质通过一组旋风除尘器进一步对其进行分级。筛选15-25μm大小的部分以便消除任何不作为球体存在的颗粒。X-射线衍射显示产物主要由TiO2金红石与约1%锐钛矿构成。通过将统计数量的这些颗粒置于位于另一金属平板上部的平坦金属表面上且逐步施加压力,直到颗粒开始断裂为止来测定平均机械强度。煅烧产物的扫描电子显微照片显示它由彼此作为薄膜结构结合的金红石晶体构成。该薄膜的厚度约为500nm并且孔具有约50nm大小。
实施例II
在500-900℃范围内的不同温度下重复实施例I的实验,其中使用不同浓度的氯化物和钛溶液与不同的喷嘴大小。钛浓度在120-15g/l Ti之间改变。一般来说,温度越高,则产生的颗粒越大且越强硬,较低的Ti浓度趋向于减小球体的大小,增加壁的厚度并且增加颗粒的机械强度。
实施例III
条件与实施例I的那些条件相同,但在喷雾步骤前向溶液中加入等同于25%的TiO2存在量的Li、Na和K的氯化物盐的低共熔混合物并且在煅烧步骤后添加洗涤步骤。在洗涤步骤中,在水中洗涤煅烧的产物且由此从终产物中除去碱盐。使用添加盐的优点在于终产物的球体具有较厚的壁。
实施例IV
条件与实施例I的那些条件相同,但在喷雾步骤前向溶液中加入等同于3%的TiO2存在量的磷酸钠Na3PO4的量。这种添加可以确保产物在煅烧过程中较为快速地金红石化(rutilization)。在本实施例中生产的终产物由大于其它实施例的金红石晶体组成并且表现出较高的机械强度。
实施例V
将实施例I的产物在水中搅拌成淤浆而制成含有40%的固体的淤浆。将相当于5重量%的TiO2存在量的胶体形式的银加入到该淤浆中。将含有加入的胶体银的淤浆注射入带有250℃出口温度的喷雾干燥器中并且在滤袋上回收。在600℃下的烘炉中将在滤袋上回收的中间产物进一步煅烧3小时。扫描电子显微照片显示终产物由具有50μm平均直径的空心球组成,这些空心球由约2μm大小的结合的金红石晶体构成。孔径约为500nm。胶体银在所述结构的颗粒表面上形成约2nm厚的层。
实施例VI
在不同的温度和浓度条件与不同的化合物作为配体的条件下重复实施例V。将下列化合物用作配体:蛋白质;酶;聚合物;胶体金属;金属氧化物和盐;活性药物组分。考虑到配体的稳定性来调适温度。由于使用了有机化合物,所以温度一般限于约150℃。
实施例VII
使用蒸馏水将10ml小瓶的胶乳(Polysciences,2.5wt%的在10mL水中的0.5μm微球)稀释至总体积为40mL。用0.36g TyzorLA(Dupont)处理所得混合物。使用搅棒连续搅拌胶乳/Tyzor LA混合物。使用蠕动泵将约0.5mL/小时的酸计量加入该混合物。连续监测pH并且在一段时间内记录数值。将混合物的pH滴定至pH2。将胶乳浸涂在基质上并且通过在600℃下氧化除去有机胶乳。约0.5μm直径的空心陶瓷颗粒的变异值一般小于5.0%的平均直径。通过使用较小的微球,该方法可以产生具有相似均匀性的显著较小的颗粒(例如0.1μm、0.05μm和0.02μm)。
Claims (18)
1.组合物,包括陶瓷结构和药物,其中所述的陶瓷结构为近球形和空心的,且其中将所述的药物涂敷在所述陶瓷结构的空心部分内,并且其中平均结构直径在10nm-100μm。
2.权利要求1所述的组合物,其中所述的陶瓷结构包括氧化物,且其中该氧化物选自钛、锆、钪、铈、钇及其混合物。
3.权利要求2所述的组合物,其中所述的陶瓷结构包括二氧化钛或氧化锆。
4.权利要求3所述的组合物,其中所述的陶瓷结构包括二氧化钛。
5.权利要求1所述的组合物,其中所述的平均结构直径在10nm-1μm。
6.权利要求5所述的组合物,其中所述的结构直径在5μm-25μm。
7.权利要求1所述的组合物,其中所述的涂敷药物为阿片样物质激动剂。
8.权利要求7所述的组合物,其中所述的阿片样物质激动剂选自羟考酮、可待因、氢可酮、氢吗啡酮、左啡诺、哌替啶、美沙酮和吗啡。
9.权利要求8所述的组合物,其中所述的阿片样物质激动剂为羟考酮或吗啡。
10.利要求1所述的组合物,其中所述的陶瓷结构包括孔且其中孔径为1nm-5μm。
11.权利要求10所述的组合物,其中所述的陶瓷结构包括孔且其中孔径为5nm-3μm。
12.权利要求1所述的组合物,其中所述的空心陶瓷结构具有壁厚并且其中该厚度在10nm-5μm的范围。
13.权利要求12所述的组合物,其中所述的壁厚在50nm-3μm的范围。
14.权利要求1所述的组合物,其中所述的陶瓷结构表现出可测定的机械强度,且其中以颗粒的集合表示该机械强度,并且其中至少50%的颗粒在被施以5kg/cm2的力时可维持其总体完整性。
15.权利要求14所述的组合物,其中至少70%的颗粒可维持其总体完整性。
16.权利要求15所述的组合物,其中至少90%的颗粒可维持其总体完整性。
17.权利要求16所述的组合物,其中施加10.0kg/cm2的力。
18.权利要求17所述的组合物,其中施加15.0kg/cm2的力。
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2005
- 2005-07-13 CN CNA2005800266292A patent/CN101001610A/zh active Pending
- 2005-07-13 WO PCT/US2005/024858 patent/WO2006017336A2/en active Application Filing
- 2005-07-13 KR KR1020077003339A patent/KR20070042176A/ko not_active Application Discontinuation
- 2005-07-13 AU AU2005271781A patent/AU2005271781A1/en not_active Abandoned
- 2005-07-13 CA CA002573341A patent/CA2573341A1/en not_active Abandoned
- 2005-07-13 US US11/181,667 patent/US20060127486A1/en not_active Abandoned
- 2005-07-13 EP EP05790061A patent/EP1768651A4/en not_active Withdrawn
- 2005-07-13 JP JP2007521610A patent/JP2008506699A/ja active Pending
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JP2008506699A (ja) | 2008-03-06 |
EP1768651A4 (en) | 2008-09-10 |
WO2006017336A3 (en) | 2006-08-03 |
KR20070042176A (ko) | 2007-04-20 |
AU2005271781A1 (en) | 2006-02-16 |
US20060127486A1 (en) | 2006-06-15 |
CA2573341A1 (en) | 2006-02-16 |
EP1768651A2 (en) | 2007-04-04 |
WO2006017336A2 (en) | 2006-02-16 |
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