CN1893956A - 多西环素金属络合物固体剂型 - Google Patents
多西环素金属络合物固体剂型 Download PDFInfo
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- CN1893956A CN1893956A CNA2004800214594A CN200480021459A CN1893956A CN 1893956 A CN1893956 A CN 1893956A CN A2004800214594 A CNA2004800214594 A CN A2004800214594A CN 200480021459 A CN200480021459 A CN 200480021459A CN 1893956 A CN1893956 A CN 1893956A
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- Prior art keywords
- doxycycline
- metal complex
- solid dosage
- dosage forms
- aqueous solution
- Prior art date
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Abstract
本发明涉及多西环素金属络合物固体剂型。本发明还包括制备多西环素金属络合物固体剂型的方法。该方法包括步骤：(i)提供多西环素或者其生理学可接受盐的水溶液；(ii)将上述水溶液与金属盐混合；(iii)再与碱混合，以增加所述水溶液的pH，从而形成多西环素金属络合物的混悬液；(iv)干燥所述混悬液，从而形成多西环素金属络合物的干颗粒。
Description
发明背景
发明领域
[0001]本发明涉及多西环素金属络合物。更具体地，本发明涉及多西环素金属络合物固体剂型。
相关背景技术
[0002]多西环素(6-脱氧-5-羟四环素一水合物)是一种广谱抑菌化合物，它能有效地抗革兰氏阳性菌、革兰氏阴性菌、需氧菌和厌氧菌，以及螺旋菌、支原体、立克次体、衣原体和某些原生动物。其通过抑制细菌或者原生动物中蛋白合成起作用，能有效地杀死它们。通常在治疗由这些有机体引起的细菌感染中使用它，所述感染例如尿道感染、上呼吸道感染、痤疮、淋病、衣原体、炭疽、莱姆病等。
[0003]当人们服用多西环素时，建议应当避免补铁剂、多种维生素、补钙剂、抗酸剂或者缓泻药。这些物质通过降低多西环素的体内吸收而副面地降低其功效。
[0004]Villax的英国专利No.1,360,998公开了从粗反应混合物中分离α-6-多西环素的方法。该专利还公开了四环素的钙盐适于口服制剂，例如混悬剂。然而，已知多西环素的钙盐在碱性pH环境中特别不稳定。而且，Villax公开的方法使用有机溶剂，即甲醇。通常当有机溶剂被用于制备药用活性成分时，通常不期望它们出现在包含药用活性成分的固体剂型的制备过程中。显然，由于残存有溶剂，Villax公开的用于分离多西环素的制备方法不能用于制备适于人类给药的固体剂型。
[0005]多西环素是味道非常苦的药物。目前，仅可获得多西环素金属盐如多西环素钙的混悬剂。多西环素钙络合物混悬剂的优点在于其具有可接受的味道。但是发现许多人服用液体剂型是不方便的。由于没有实际可供的选择，即选择多西环素金属络合物固体剂型，他们必须忍受上述不便。
[0006]多西环素的另一来源是多西环素的海克酸盐。然而，它可引起并发症，例如食道溃疡。对多西环素的固体剂型而言，将不会有这样的问题。如果能够获得，多西环素钙络合物咀嚼片将不会引起食道溃疡，因为该药物不溶，因此，其将穿过食道环境而不会损害它。
[0007]然而，制备多西环素金属络合物固体剂型是非常困难的。例如，不知如何在水混悬液中过滤多西环素金属络合物，例如多西环素钙络合物。现有技术的方法不能从水溶液中获得相当纯的多西环素金属络合物。
发明简述
[0008]本发明涉及适于给药的多西环素金属络合物固体剂型。
[0009]本发明包括一种药物组合物的固体剂型，所述药物组合物包括：(i)多西环素金属络合物和(ii)一种或者多种可药用赋形剂。
[0010]本发明还包括制备多西环素金属络合物固体剂型的方法。该方法包括步骤.(i)提供多西环素或者其生理学可接受盐的水溶液；(ii)将上述水溶液与金属盐混合；(iii)再与碱混合，以增加水溶液的pH，从而形成多西环素金属的混悬液；和(iv)干燥混悬液，形成多西环素金属络合物干颗粒。任选地，上述方法可包括混合一种或者多种可药用赋形剂的步骤。所述赋形剂可在干燥混悬液之前或者在形成多西环素金属络合物颗粒之后加入。而且，还可以对颗粒做进一步处理：将颗粒填充入胶囊或者压制成片。
[0011]在另一个实施方案中，制备多西环素金属络合物固体剂型的方法包括步骤：(i)提供多西环素或者其生理学可接受盐的水溶液；(ii)将上述水溶液与金属盐混合；(iii)再与碱混合，增加水溶液的pH，从而形成多西环素金属络合物的混悬液；(iv)将混悬液与一种或者多种可药用赋形剂混合以吸收水分，从而形成湿颗粒；和(v)干燥湿颗粒，形成多西环素金属络合物干颗粒。任选地，混合一种或者多种可药用赋形剂的步骤可在湿颗粒形成后进行。而且，还可以对干颗粒做进一步处理：将干颗粒填充入胶囊或者压制成片。
[0012]在另一个实施方案中，本发明涉及治疗细菌感染的方法，其包含在有效期内给予需要的宿主安全有效量的多西环素金属络合物固体剂型。
[0013]而且，本发明包括治疗由微生物和/或细菌引起的疾病的方法，包括在有效期内给予需要的宿主安全有效量的多西环素金属络合物固体剂型。
发明详述
[0014]为了本发明的目的，除非另有说明，给出的所有百分比表示重量百分比。
[0015]本发明的多西环素金属络合物和活性成分以“安全有效量”使用。可以理解其意思是指确实能改善受治疗的症状和/或病症的化合物或组合物的足够量，前提是该用量为可避免严重副作用的足够低量。被认为是安全和有效的化合物(例如多西环素金属络合物)的用量依多种因素而定。例如，应当考虑受治疗的病症和病症的严重性、年龄、体重、通常的健康情况、性别、日常饮食和受治疗的患者的体质、治疗的持续时间、当前治疗情况、使用的具体活性成分、使用的具体可药用赋形剂、给药时间、给药方式、排泄速率、药物联合及任何其它的相关因素。
[0016]术语″可药用赋形剂″可理解为意思是指本领域技术人员已知的任意生理学惰性的、药用非活性物质，其与选择使用的具体多西环素金属络合物的物理和化学特征是相容的。
[0017]本发明涉及给药予人类的适于药用的多西环素金属络合物固体剂型，即任意残存溶剂或者其它杂质以被认为是对人类消耗安全的水平存在。所述多西环素金属络合物可以是，例如多西环素钙络合物、多西环素镁络合物、多西环素钠络合物、或者多西环素锌络合物。多西环素金属络合物的一个优点是当将其给药于使用者/患者时，多西环素和矿物源是有益的。例如，多西环素钙络合物片剂可提供给使用者/患者多西环素源和钙源。
[0018]本发明与现有技术的教导相反，现有技术教导钙抑制四环素的吸收。然而，本发明人已经发现可从多西环素金属固体中吸收治疗量的多西环素，例如，如本发明教导的多西环素钙络合物的固体剂型。
[0019]理想地，多西环素已经经过完全络合。可理解为其意思是指至少约75％重量的多西环素是络合的。更优选地，至少约90％已经络合。然而，应当理解，可加入过量的多西环素或者金属盐以形成多西环素金属络合物。
[0020]假定在固体剂型中，多西环素金属络合物含有的金属和多西环素的摩尔比率为约0.5至约3。优选地，所述比率为约1.5至约2.5，更优选地，为约1∶2。
[0021]本发明还包括与可药用载体或者赋形剂和/或生物活性剂一起制成的药物组合物。该组合物包括(i)多西环素金属络合物和(ii)一种或者多种可药用赋形剂。
[0022]优选地，药物组合物可制成粉末、胶囊、片剂、包衣片、气雾剂、药丸、咀嚼片、锭剂、明胶填充胶囊等。
[0023]适宜的可药用赋形剂包括，但不限于聚合物、树脂、增塑剂、填充剂、润滑剂、粘合剂、崩解剂、成粒剂、溶剂、共溶剂、表面活性剂、防腐剂、甜味剂、矫味剂、缓冲系统、抗氧化剂、药物分级染料、颜料及其混合物。
[0024]可使用的聚合物包括，但不限于，羟丙基甲基纤维素(HPMC)自身和/或与羟丙基纤维素(HPC)、羧甲基纤维素、丙烯酸树脂例如Eudragit、甲基纤维素、乙基纤维素和聚乙烯吡咯烷酮或者其它市售的包衣膜制剂的联合。
[0025]适宜的增塑剂包括，但不限于，聚乙二醇、丙二醇、邻苯二甲酸二丁酯、蓖麻油、乙酰化单酸甘油脂、甘油醋酸酯及其混合物。
[0026]填充剂的实例包括，但不限于，乳糖、蔗糖、麦芽糊精、甘露醇、淀粉、微晶纤维素及其混合物。
[0027]可使用的润滑剂包括，但不限于，硬脂酸镁、硬脂酸、滑石及其混合物。
[0028]适宜的粘合剂包括，但不限于，甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、卡波普、聚维酮、阿拉伯树胶、瓜儿胶、黄原胶、西黄蓍胶、硅酸钙、硅酸铝镁、乙基纤维素、预胶化淀粉及其混合物。特别优选甲基纤维素、卡波普、黄原胶、瓜儿胶、聚维酮和羧甲基纤维素钠。
[0029]可使用的崩解剂包括，但不限于交联聚维酮、羧甲基淀粉钠、淀粉羟乙酸钠、羧甲基纤维素钠、褐藻酸、粘土、离子交换树脂及其混合物。
[0030]表面活性剂的实例包括，但不限于，聚氧乙烯山梨醇脂肪酸酯、聚氧乙烯单烷基酯、蔗糖单酯、羊毛脂和醚及其混合物。
[0031]适宜的防腐剂包括，但不限于苯酚、对羟基苯甲酸烷基酯、苯甲酸及其盐、硼酸及其盐、山梨酸及其盐、氯代丁醇、苯甲醇、硫柳汞、醋酸苯汞和硝酸苯汞、硝甲酚汞、氯化苯甲烃铵、氯化十六烷基嘧啶、尼泊金甲酯、尼泊金丙酯及其混合物。特别优选苯甲酸盐、氯化十六烷基嘧啶、尼泊金甲酯和尼泊金丙酯。
[0032]可使用的抗氧化剂包括，但不限于，生育酚及其衍生物、抗坏血酸、β-胡萝卜素、硒、亚硫酸氢钠、偏重亚硫酸钠、抗坏血酸棕榈酸酯及其混合物。
[0033]适宜的甜味剂包括，但不限于，蔗糖、葡萄糖、糖精、阿司帕坦及其混合物。特别优选蔗糖和糖精。
[0034]可使用的缓冲剂系统包括，但不限于，醋酸钾、碳化硼、磷酸、琥珀酸、苹果酸、酒石酸、柠檬酸、醋酸、苯甲酸、乳酸、甘油、葡糖酸、戊二酸、谷氨酸及其混合物。特别优选磷酸、酒石酸、柠檬酸和醋酸钾。
[0035]虽然也可以使用其它的溶剂，但是水为优选使用的溶剂。
[0036]适宜的共溶剂包括，但不限于，乙醇、甘油、丙二醇、聚乙二醇及其混合物。
[0037]本文描述的药物组合物包括约0.1重量百分比(wt.％)至约99.9wt％，优选约5.0wt.％至约50.0wt.％，最优选约10wt.％至约50wt％的多西环素金属络合物，和约0.1wt.％至约99.9wt.％，优选约5.0wt.％至约99.9wt％，最优选约50wt.％至约90wt.％的一种或者多种可药用赋形剂。
[0038]多西环素金属络合物固体剂型是使用新的制备方法制备的。该方法包括步骤(i)提供多西环素或者其生理学可接受盐的水溶液；(ii)将上述水溶液与金属络合物盐混合；(iii)再与碱混合，增加水溶液的pH，从而形成多西环素金属络合物的混悬液；和(iv)干燥混悬液，形成多西环素金属络合物的干颗粒。任选地，一种或者多种可药用赋形剂可在每一处理步骤之前、期间和之后混入。
[0039]多西环素或者其生理学可接受的盐可以是，例如多西环素海克酸盐、多西环素一水合物、多西环素角叉菜胶、多西环素磷酸盐或其混合物。将多西环素或者其生理学可接受的盐溶解于水溶液中。可使用任意适宜的方法将多西环素或者其盐溶解于水溶液中。通常，需要的所有这些都是一些混合的形式。优选地，水溶液包括至少约75wt.％的水。水溶液中也包括其它成分，例如乙醇。水溶液通常具有约1至约8的pH。
[0040]适宜的金属盐包括，但不限于，钙盐、钠盐、镁盐、锌盐及其混合物。特别优选的金属盐是氯化钙。加入金属盐时用或者不用混合，但是其通常被混入溶液。
[0041]将基于多西环素制剂的总重量计约1wt％至约50wt％的金属盐加入到水溶液中。优选地，金属盐为约1wt％至约25wt.％，更优选3wt％至约10wt.％。
[0042]将碱加入到水溶液中，并与其它的成份混合。所述碱以有效形成多西环素金属络合物的混悬液的量加入。通常，碱的加入使溶液的pH升至约2.5至约8的pH范围。适宜的碱包括，例如氢氧化钠、氢氧化钾、三乙醇胺、二乙醇胺、单乙醇胺、碳酸氢钠及其混合物。
[0043]加入的碱的用量依多种因素而定，包括水溶液的pH和混悬液配方。通常，加入基于多西环素制剂总重量的约1wt％至约5wt.％的碱。更优选地，加入约2wt％至约4wt.％的碱。
[0044]可使用多种技术干燥混悬剂。例如，在一个实施方案中，使用喷雾干燥器，将混悬剂喷雾到赋形剂上。过滤混悬剂除去水。其它方法包括倾析、蒸发、冷冻干燥、盘式干燥、流化床干燥等。
[0045]在另一个实施方案中，制备多西环素金属络合物固体剂型的方法包括步骤：(i)提供多西环素或者其生理学可接受盐的水溶液；(ii)将上述水溶液与金属盐混合；(iii)再与碱混合，增加水溶液的pH，从而形成多西环素金属络合物的混悬液；(iv)将混悬液与一种或者多种可药用赋形剂混合以吸收水分，从而形成湿颗粒；和(v)干燥湿颗粒，形成多西环素金属络合物的干颗粒。该实施方案的步骤(i)-(iii)与现有技术描述的从混悬剂形成固体剂型的方法类似。
[0046]然而，该实施方案使用赋形剂以促进形成湿颗粒。本发明人已经发现了赋形剂例如微晶纤维素，当其与混悬液混合时，赋形剂将吸收混悬液中的水分。获得含有约5wt％至约99wt.％的水的湿颗粒或者浆液。优选地，湿颗粒中的水分为约25wt％至约60wt.％。通过形成这样的湿颗粒，干燥过程可进行的更容易。
[0047]可在任一制备步骤中的任意过程中混入一种或者多种可药用赋形剂。而且，赋形剂可以以多于一步加入。
[0048]湿颗粒可通过盘式干燥、流化床干燥、倾析、蒸发、冷冻干燥及其联合或者本领域已知的其它方法干燥。
[0049]令人期望的是，将多西环素金属络合物颗粒干燥至基于多西环素金属络合物颗粒总重量计含水量为约1wt％至约15wt％。更优选地，水分应当少于约10wt.％。更优选地，为约1wt％至约6wt.％。
[0050]形成的多西环素金属络合物是含有颗粒和粉末的干粒形式。干颗粒可与赋形剂例如润滑剂例如硬脂酸镁混合。最终混合物可做进一步处理：填充入胶囊。
[0051]本发明还发现了在干燥步骤之后形成的多西环素金属络合物颗粒非常适于压片。实际上，适当选择配方，可在不使用另外的压片赋形剂条件下进行压片处理。与其它合成方法不同，本发明另一显著的优点是，本发明的方法不需要纯化步骤以除去不想要的杂质。这使得该方法更加有效，并有助于直接从多西环素金属络合物颗粒制片。然而，应当理解，可加入片剂赋形剂。如前所述，赋形剂即润滑剂可在干燥混悬剂或者湿颗粒之前或者之后加入。简单地加入赋形剂，并与其它成分混合。
[0052]在一个优选的实施方案中，片剂为咀嚼片。这将非常有利于那些患有食道溃疡的患者，因为多西环素金属络合物的咀嚼片在食道环境中是不溶的。因此，咀嚼片将以无害的方式穿过食道。
[0053]而且，本发明的固体剂型可含有另外的成份。例如，另外的成份可以包括天然的和人工的矫味剂、甜味剂、着色剂、包衣赋形剂、粘合剂、崩解剂、润滑剂等。
[0054]所述固体剂型通常以片剂、胶囊、粉末、颗粒、锭剂、气雾剂、药丸、咀嚼片等形式口服给药。可包括赋形剂以便于片剂形成，所述赋形剂例如粘合剂，例如糖浆、阿拉伯树胶、明胶、山梨醇、西黄耆胶或者聚乙烯吡咯烷酮；填充剂，例如乳糖、糖、玉米淀粉、磷酸钙、山梨醇或者甘氨醇；压片润滑剂，例如硬脂酸镁、滑石、聚乙二醇或者二氧化硅；崩解剂例如马铃薯淀粉、或者可接受的润湿剂例如十二烷基硫酸钠。而且，也可使用本领域已知的方法对片剂包衣。
[0055]本发明也包括治疗细菌感染的方法。该方法包括给予宿主例如人类或者动物安全有效量的多西环素金属络合物固体剂型的步骤。可用多西环素金属络合物治疗的细菌感染的实例包括尿道感染、上呼吸道感染、痤疮、淋病尿道炎、衣原体、梅毒、炭疽、莱姆病等。
[0056]多西环素金属络合物固体剂型可用于治疗由细菌和微生物引起的疾病。细菌和微生物的非限定性实例包括革兰氏阳性微生物、革兰氏阴性微生物、需氧菌、厌氧菌、螺旋菌、支原体、立克次体、衣原体、密螺旋体、李斯特菌属、炭疽杆菌、梭形梭菌、衣氏放线菌、梭状芽胞杆菌、尿素分解尿素原体、回归热(疏)螺旋体、杜克雷(氏)嗜血杆菌、鼠疫耶尔森(氏)菌、土拉热弗朗西丝(氏)菌、霍乱弧菌、布鲁氏菌、胎儿弯曲菌、杆菌状巴尔通(氏)体、肉芽肿鞘杆菌和原生动物。所述治疗需要在有效期内给予安全有效量的多西环素金属络合物的固体剂型。
实施例1
表1
| 成分 | ％w/w | 总量 |
| 多西环素海克酸酯 | 16.5 | 830g |
| 氯化钙 | 5.6 | 280g |
| 氢氧化钠 | 2.6 | 130g |
| 微晶纤维素 | 74.9 | 3760g |
| 硬脂酸镁 | 0.4 | 20g |
将16.5g的多西环素海克酸酯溶于水制成20-25％的多西环素海克酸酯溶液。也通过将5.6g的氯化钙溶于水制备50％的氯化钙溶液。根据在表1中指定的含量组合并混合多西环素海克酸酯溶液和氯化钙溶液。
然后将5N氢氧化钠加入到混合物中。这样增加混合物的pH至约5。优选地，增加pH至约6，更优选地，增加pH高于约6，但是低于约8。这样形成了多西环素钙金属混悬液。
然后将赋形剂微晶纤维素(74.9g)加入到混悬液中。微晶纤维素吸收和吸附混悬液中的水分，形成湿颗粒制剂。
使用流化床或者盘式干燥器干燥湿颗粒以降低水分至小于10％，优选至约1％至约6％，从而形成干颗粒。
将干粒碾磨通过14-目筛。
将0.4g的硬脂酸镁作为润滑剂加入，以形成最终的干粒。
此时，可加入着色剂。
现在，可将干粒填充入明胶胶囊，或者压制成片。
一旦制成明胶胶囊或者片剂，可在片剂上应用包衣膜。
实施例2
表2
| 成分 | ％w/w | 总量 |
| 多西环素海克酸酯 | 19.3 | 2480g |
| 氯化钙 | 6.5 | 840g |
| 氢氧化钠 | 3.0 | 380g |
| 微晶纤维素 | 71.0 | 9120g |
| 硬脂酸镁 | 0.2 | 30g |
除了依照上述表2中列出的改变每种成分重量百分比外，按照实施例1的制备方法制备。
[0057]虽然本发明根据其具体的实施例进行上述描述，显然，在不背离本文公开的发明内容的情况下，可进行大量的改变、变更和变化。因此，意味着在本发明的精神和附加的权利要求的广泛范围内，其包含所有这样的改变、变更和变化。本文引用的所有的发明申请、专利和其他出版物被全部引入作为参考。
Claims (23)
1.适于给药的多西环素金属络合物固体剂型。
2.权利要求1的固体剂型，其中所述的多西环素金属络合物为多西环素钙络合物。
3.权利要求1的固体剂型，其中所述的固体剂型选自粉末、颗粒剂、片剂、包衣片、明胶填充胶囊、药丸和咀嚼片。
4.药物组合物固体剂型，包括(i)多西环素金属络合物固体剂型；和(ii)一种或者多种可药用赋形剂。
5.根据权利要求4的组合物，其中所述的多西环素金属络合物为多西环素钙络合物。
6.权利要求4的组合物，其中所述的可药用赋形剂选自：聚合物、树脂、增塑剂、填充剂、润滑剂、粘合剂、崩解剂、成粒剂、溶剂、共溶剂、表面活性剂、防腐剂、甜味剂、矫味剂、缓冲系统、抗氧化剂、药物分级染料、颜料及其混合物。
7.权利要求4的组合物，其中所述的可药用赋形剂是微晶纤维素。
8.制备多西环素金属络合物固体剂型的方法，包括步骤
(i)提供多西环素或者其生理学可接受盐的水溶液；
(ii)将上述水溶液与金属盐混合；
(iii)再与碱混合，以增加水溶液的pH，从而形成多西环素金属络合物的混悬液；和
(iv)干燥混悬液，形成多西环素金属络合物的干颗粒。
9.权利要求8的方法，其中所述的多西环素金属络合物为多西环素钙络合物。
10.权利要求8的固体剂型，其中所述的多西环素或其生理学可接受的盐的水溶液是将多西环素或其生理学可接受的盐溶于水溶液，形成约1至约8的pH范围的溶液制备的。
11.权利要求8的方法，其中所述的金属盐选自钙盐、镁盐、钠盐、锌盐及其混合物。
12.权利要求8的方法，其中所述的金属盐为氯化钙。
13.权利要求8的方法，其中所述的碱为氢氧化钠。
14.权利要求8的方法，其中所述的颗粒含有小于约10wt.％的水分。
15.权利要求8的方法，其中所述的干燥步骤通过选自下述的方法进行：喷雾干燥、流化床干燥、盘式干燥、倾析、蒸发、冷冻干燥及其联合。
16.权利要求8的方法，还包括在所述干燥步骤之前混入一种或者多种可药用赋形剂。
17.权利要求8的方法，还包括在形成所述颗粒之后混入一种或者多种可药用赋形剂。
18.权利要求8的方法，还包括压制所述颗粒，从而形成片剂的步骤。
19.权利要求8的方法，其中所述的多西环素或者生理学可接受的盐选自：多西环素海克酸酯、多西环素一水合物、多西环素角叉菜胶、多西环素磷酸酯及其混合物。
20.按照权利要求8的方法制备的多西环素金属络合物固体剂型。
21.制备多西环素金属络合物固体剂型的方法，包括步骤：
(i)提供多西环素或者其生理学可接受盐的水溶液；
(ii)将上述水溶液与金属盐混合；
(iii)再与碱混合，以增加所述水溶液的pH，从而形成多西环素金属络合物的混悬液；
(iv)将所述混悬液与一种或者多种可药用赋形剂混合以形成湿颗粒；和
(v)干燥所述湿颗粒。
22.治疗细菌感染的方法，包括步骤：在有效期内给予需要的宿主安全有效量的多西环素金属络合物固体剂型。
23.治疗由微生物和/或细菌引起的疾病的方法，包括步骤：在有效期内给予需要的宿主安全有效量的多西环素金属络合物固体剂型。
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-
2004
- 2004-07-22 CN CNA2004800214594A patent/CN1893956A/zh active Pending
- 2004-07-22 AU AU2004261143A patent/AU2004261143B2/en not_active Expired
- 2004-07-22 CA CA2533150A patent/CA2533150C/en not_active Expired - Lifetime
- 2004-07-22 CN CN2012102296595A patent/CN103040773A/zh active Pending
- 2004-07-22 WO PCT/US2004/023427 patent/WO2005011707A1/en active Application Filing
- 2004-07-22 NZ NZ544826A patent/NZ544826A/en not_active IP Right Cessation
- 2004-07-22 US US10/896,045 patent/US7485319B2/en active Active
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2006
- 2006-01-05 IL IL173005A patent/IL173005A0/en active IP Right Grant
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2008
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|---|---|
| US20110171299A1 (en) | 2011-07-14 |
| AU2004261143A1 (en) | 2005-02-10 |
| NZ544826A (en) | 2008-07-31 |
| AU2004261143B2 (en) | 2009-11-05 |
| CA2533150C (en) | 2013-03-12 |
| US8415331B2 (en) | 2013-04-09 |
| US20050019396A1 (en) | 2005-01-27 |
| IL173005A0 (en) | 2006-06-11 |
| CA2533150A1 (en) | 2005-02-10 |
| CN103040773A (zh) | 2013-04-17 |
| WO2005011707A1 (en) | 2005-02-10 |
| US7485319B2 (en) | 2009-02-03 |
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