CN1197946C - 带有水合屏障材料的颗粒 - Google Patents
带有水合屏障材料的颗粒 Download PDFInfo
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- CN1197946C CN1197946C CNB988124483A CN98812448A CN1197946C CN 1197946 C CN1197946 C CN 1197946C CN B988124483 A CNB988124483 A CN B988124483A CN 98812448 A CN98812448 A CN 98812448A CN 1197946 C CN1197946 C CN 1197946C
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Classifications
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Abstract
描述了一种具有高稳定性和低尘污的颗粒。这种颗粒包括具有中度或高度水活度的水合屏障材料。还描述了这种颗粒的制造方法。
Description
发明背景
近来，酶的使用，尤其是微生物来源的酶的使用已经越来越普遍。酶被用于一些工业，包括例如淀粉工业、乳制品工业以及洗涤剂工业。众所周知洗涤剂工业中，酶尤其是蛋白水解酶的使用已经引起对洗涤剂工厂工人在工业卫生方面的关注，特别是因为与可使用酶的粉尘有关的健康危险。
自从洗涤剂行业引入酶以来，工业上已经提供了许多有关酶成粒化和包被的发展。请看例如下列有关酶成粒化的专利。
美国专利4,106,991描述了一种酶颗粒的改进配方，包括在进行成粒化的组合物之中包含占全部组合物干重2～40％w/w的精细分开的纤维素纤维。此外，该专利描述了蜡质物质可用于包被这种细粒的粒子。
美国专利4,689,297描述了含有粒子的酶，该粒子包含一个最大尺寸为150～2000微米的水可分散的粒子芯料，重量占芯料粒子重量10～35％的包围芯料粒子的均一酶层，以及一层均一包绕酶层的水溶性或水可分散的大分子成膜包被剂，其中酶和包被剂加起来占芯料粒子重量的25～55％。本专利描述的芯料材料包括粘土、封闭在包被了一层糊精的玉米淀粉层中的糖结晶、聚结的马铃薯淀粉、粒盐、聚结的柠檬酸三钠、皿结晶的氯化钠小薄片、皂土颗粒或小球、含有皂土、高岭土和岩藻土或者柠檬酸纳晶体的颗粒。成膜材料可以是脂肪酸酯、烷氧基化醇、聚乙烯醇或乙氧基化烷基苯酚。
美国专利4,740,469描述了一种酶颗粒状组合物，它基本由占重量1～35％的酶和平均长度100～500微米、长细比为0.05～0.7旦的占重量0.5～30％的合成纤维材料组成，剩余为膨胀剂或填充剂。该颗粒状组合物还可包含熔化的蜡质材料，例如聚乙二醇，最佳为色料如二氧化钛。
美国专利5,254,283描述了一种包被了非水溶性扭曲型(warp size)聚合物连续层的微粒材料。美国专利5324649描述了一种含芯料、酶层以及外包被层的含酶颗粒。该酶层以及任选地该芯料和外包被层含有乙烯聚合物。
WO91/09941描述了一种含酶制剂，由此制剂中酶晶体至少存在50％的酶活性。该制剂可以是浆料或细粒。
WO97/12958公开了一种微颗粒酶组合物。该颗粒通过流化床聚结而制成，从而使颗粒带有无数包被了酶的载体或晶种粒子，并由粘合剂结合在一起的。
然而，即使借助工业上提供的这些发展(如上述)，对于有额外优点的低尘酶颗粒仍有持续的需求。酶颗粒化工业中所要的额外优点是低残留颗粒制剂(此处低残留定义为不易在衣服或其它材料上留下明显的不溶性残留物)和稳定性得到改进的制剂。同时获得所有这些想要的特性是一个极大的挑战，因为例如许多象纤维性纤维素和扭曲型聚合物这样的延缓释放或低尘剂会留下不溶性残留物。
因此，本发明的一个目的即提供具有更高稳定性的低尘污、低残留、高度可溶的酶颗粒。本发明的另一目的是提供可得到这种改良颗粒制剂的工艺。
发明概述
本发明的一个实施方案是包括蛋白质芯料和具有中度或高度水活度的水合屏障材料的一种颗粒。该水合屏障材料可以存在于一层或多层之中和/或包括在蛋白质芯料中。
本发明的另一个实施方案是包括酶芯料和具有中度或高度水活度的水合屏障材料的一种颗粒。该水合屏障材料可以存在于一层或多层中和/或包括在酶芯料中。
另一实施方案是制造上述颗粒的方法。
发明详述
本发明提供了具有改进的稳定性的低尘污颗粒。该颗粒包括蛋白质芯料和具有中度或高度水活度的水合屏障材料。
“蛋白质芯料”或“酶芯料”可以如在美国专利申请08/995,457中所述为均质的，也可以如在美国专利第5,324,649号所述为分层的。
本发明范畴之内的蛋白质包括药用重要的蛋白质，例如激素或者其它治疗用蛋白质以及工业上重要的蛋白质例如酶。
任何一种酶可单独用于本发明或者几种酶联合用于本发明。优选的酶包括那些能水解如污迹这样的底物的酶。已知这些酶为水解酶，包括但并不限于蛋白酶(细菌的、真菌的、酸性的、中性的或碱性的)、淀粉酶(α或β)、脂酶、纤维素酶及其混合物。特别优选的酶是枯草杆菌蛋白酶和纤维素酶。最优选的酶是此处引入作为参考的例如美国专利4,760,025、欧洲专利130 756 B1和欧洲专利申请WO91/06637中所描述的枯草杆菌蛋白酶，以及例如从Genencor International购买的Multifect L250TM和PuradaxTM纤维素酶。可用于本发明的其它酶包括氧化酶、转移酶、脱水酶、还原酶、半纤维素酶和异构酶。
值得注意，这种屏障材料可以一层或多层包被于蛋白质芯料表面，或者制成蛋白质芯料的一部分用来隔离或阻止水和失活的物质转运进入蛋白质。当这种屏障材料作为蛋白质芯料的一部分时，它可以分散于整个芯料或作为芯料中的一层。
具有中度或高度水活度的适宜的水合屏障材料可包括无机酸或有机酸的盐、糖类、多糖类、脂类、蛋白质或合成的聚合物，优选盐类。
术语“水活度”，以aw为符号，指的是在一个大气压下物质的固相或液相在平衡状态时的相对湿度分数，即在相同温度下，水蒸气分压和纯水上水蒸气分压的比值。当水在所有相之间的分配达到平衡即被定义为平衡。术语“相对湿度”通常用来描述在大气压下或者气相与固相达到平衡时的水分，并以百分数表示，在一个封闭的***内纯水的相对湿度为100％。因此，对于任一水活度值，都有一个相应的由％RH＝100*aw给出的相对湿度。
水活度通过本领域内已知的方法很容易测得，一般将材料样品置于水活度计的可控温小室内，例如购自Rotronic Instrument公司(Huntington，NY)的D2100型水活度器，并且按照显示器上所指示的使测量达到平衡。
“水合”屏障材料含有游离或结合水，或者两者都含有。发生水合的水可以在包被过程之中或之后加入。水合的程度将是材料自身以及所采用的温度、湿度和干燥条件的函数。
“中度或高度”水活度包括至少0.25的水活度，优选大于0.30的水活度，最优选大于0.35的水活度。此处提到的水活度是指包被了屏障材料但没有包被其他包被层的颗粒本身的水活度。其他包被层可能会掩盖作为不同层的屏障材料之水活度的准确测定。
不受理论局限，预计水活度大于0.25的材料在相对湿度大于25％的贮存条件下，吸收水分的驱动力将降低。大多数气候的相对湿度大于25％。许多洗涤剂的水活度在0.3和0.4之间的范围内。如果颗粒的水活度实际上高于周围洗涤剂或贮存气候的水活度，则颗粒吸收水分的驱动力会丧失，并且实际上颗粒还可能将水分释放到周围环境中。即便如果颗粒的水活度低于洗涤剂或相应的相对湿度，屏障层中存在的水会成为屏蔽从而限制水的量，并且因此使颗粒吸收的物质失活，影响蛋白质芯料。
如果是水合盐，水合材料是带有结晶结合水的结晶水合盐。应以如下方式选择和应用水合物，即得到的已包被的颗粒将有大于0.25的水活度，或者颗粒在接触试验中为干燥的前提下水活度尽可能高。以上述方式应用水合盐或者其他任何合适的水合屏障材料，可以预计这将消除颗粒进一步摄入水分的任何驱动力。重要的后果是，消除了转运可能对酶活性有害的例如过硼酸盐或过氧化阴离子这样的底物的驱动力。没有水作为媒介物，这些底物不大可能穿透酶芯料。经验数据证明，用稳定的水合盐包被酶芯料，大大地增强颗粒中酶的活性。
优选盐类包括七水合硫酸镁、七水合硫酸锌、五水合硫酸铜、七水合磷酸氢二钠、六水合硝酸镁、十水合硼酸钠、二水合柠檬酸钠以及四水合乙酸镁。
本发明的颗粒还可包含一层或多层包被层。例如，这样的包被层可能为一层或多层中间包被层，或者这样的包被层可能为一层或多层外包被层，或者两者相结合。颗粒组合物中的包被层依据颗粒的最终用途可以承担许多功能的任意一种。例如，包被层可以使蛋白质能耐受漂白引起的氧化，包被层使颗粒一经导入水性介质就能导致期望的溶解速率，或者能提供阻隔周围环境湿气的屏障，从而增强酶的贮存稳定性并减少微生物在颗粒中生长的可能性。
合适的包被层包括聚乙烯醇(PVA)、聚乙烯吡咯烷酮(PVP)、纤维素衍生物例如甲基纤维素、羟丙基甲基纤维素、羟基纤维素、乙基纤维素、羧甲基纤维素、羟丙基纤维素、聚乙二醇、聚环氧乙烷、聚脱乙酰壳多糖、***树胶、黄原胶、角叉藻聚糖、胶乳聚合物以及肠溶衣。此外，包被剂可以同其他相同或不同种类的活性剂一起使用。
用于掺入颗粒包被层的合适的PVA包括经部分水解的、经完全水解的以及经中级水解的有从低到高粘度的PVA。优选地，外包被层包含有低粘度的经部分水解的PVA。其他可能使用的乙烯聚合物包括聚乙酸乙烯酯和聚乙烯吡咯烷酮。有用的共聚物包括，例如PVA-异丁烯酸基甲酯和PVP-PVA共聚物。
本发明的包被层还可包含一种或多种如下物质：增塑剂、膨胀剂、润滑剂、色料以及任选的附加酶。本发明的包被层内有用的合适的增塑剂包括，例如多元醇，如糖类、糖醇，或者聚乙二醇(PEG)、尿素、二醇、丙二醇或其他已知的增塑剂如柠檬酸三乙基酯、邻苯二甲酸三丁基酯或邻苯二甲酸二甲基酯或水。本发明的包被层内有用的合适的色料包括但不限于，精细分离的增白剂，例如二氧化钛或碳酸钙，或有色色料，或染料，或其组合。优选的色料为经溶解残留较低的色料。合适的膨胀剂包括糖类例如蔗糖或淀粉水解产物，例如麦芽糖糊精和玉米糖浆固体，粘土例如高岭土和皂土、以及滑石。合适的润滑剂包括非离子表面活性剂例如Neodol、牛脂醇、脂肪酸、脂肪酸盐例如硬脂酸镁以及脂肪酸酯。
本发明的外包被层优选地包含包被颗粒重量的大约1-25％之间。
本发明的颗粒中可以加入添加剂成分。添加剂成分可包括：金属盐；加溶剂；激活剂；抗氧化剂；染料；抑制剂；粘合剂；香料；酶保护剂/清除剂例如硫酸铵、柠檬酸铵、尿素、盐酸胍、碳酸胍、氨基磺酸胍、硫脲二氧化物、单乙醇胺、二乙醇胺、三乙醇胺、例如甘氨酸、谷氨酸钠等等的氨基酸、例如牛血清白蛋白、酪蛋白等等的蛋白质；表面活性剂包括阴离子表面活性剂、两性表面活性、非离子表面活性剂、阳离子表面活性剂以及长链脂肪酸盐；助洗剂；碱性或无机电解质；漂白剂；上蓝剂和荧光染料和增白剂；以及粘结抑制剂。
此处描述的颗粒可通过酶成粒化领域的技术人员已知的方法制备，包括皿包被法、流化床包被法、流化床聚结法、造粒法、圆盘成粒法、喷雾干燥法、挤出法、离心挤出法、成球法、转鼓成粒法、高剪切聚结法，或者这些技术的组合。
下列实例具有代表性，但不意味着仅限于此。本领域的技术人员基于此处所教授的内容能够选择其他蛋白质、蛋白质芯料、酶、酶芯料、晶种粒子、方法和包被剂。
实施例
实施例1. 包被了硫酸镁的蛋白酶颗粒的稳定性
A.在Deseret 60流化床包被器中加入54.1千克蔗糖/淀粉非pareil晶种使之流态化。在下列条件下将75.8千克的含有62.9克/千克枯草杆菌蛋白酶的蛋白酶超滤浓缩物喷射在这些芯料上。(范围指的是在指定斜升(ramp)时程中的初值和终值。)
斜升时间： 80分钟
流体进料速率 0.6-1.0升/分钟
雾化压力 75磅/平方英寸
入口空气温度 85-92摄氏度
出口空气温度 50摄氏度
流体化空气速率 18立方米/分钟
将22.2千克七水合硫酸镁加入22.2千克的水中制得硫酸镁溶液，并且在下列条件下将其喷射在包被了酶的芯料上，从而使最终颗粒的20％为七水合硫酸镁，小心控制使得流化床温度接近但稍微低于50摄氏度：
斜升时间： 40分钟
流体进料速率 0.6-1.7升/分钟
雾化压力 45磅/平方英寸
入口空气温度 70-84摄氏度
出口空气温度 48-50摄氏度
流体化空气速率 18立方米/分钟
最后，聚合物包被溶液制备如下：将6.35千克Elvanol 5105聚乙烯醇、7.94千克二氧化钛和1.59千克Neodol 23-6.5T非离子表面活性剂溶于50.12千克水中，并且在下列条件下喷射在包被了盐类的酶芯料：
斜升时间： 10分钟，然后恒定为100分钟
流体进料速率 0.6升/分钟
雾化压力 75磅/平方英寸
入口空气温度 50摄氏度
出口空气温度 75-80摄氏度
流体化空气速率 18立方米/分钟
收集的颗粒每千克有大约40克的酶浓度。
B.加速的稳定性试验
许多配制于含漂白剂洗涤剂中的酶颗粒的稳定性通常是优良的，通常表现为在30至37℃以及70％至80％相对湿度下贮存6周以上，活性的丧失不超过10至20％。然而，为了有助于颗粒制剂的发展和筛选，期望拥有一种加速的方法以测定相对颗粒稳定性。加速的稳定性试验(AST)的条件要比酶颗粒或洗涤剂在现实的贮存或转运中所面临的条件苛刻得多。AST是一种“压力”试验，被设计用来区分制剂之间在数周或数月之后都不明显的差异。
在该试验中，受试洗涤剂基质从下列成分中制得：
72％ WFK-1洗涤剂基质 (WFK，Forschunginstitut fuer
Reinigungstechnologie e.V.，
Krefeld，德国)
25％ 一水合过硼酸钠 (Degussa公司，Allendale Park，New
Jersey)
3％ TAED漂白活化剂 (Warwick International，
(＝四乙酰基乙烯二胺) Mostyn，英国)
对于每一受试的酶样品，准备三个相同的试管，将1克受试基质和30毫克酶颗粒加入15毫升的锥形管内，并用手翻转盖塞的试管5-8次以混匀。用1/16英寸的钻头在试管塞上钻一个洞。立即对三个试管中的一个进行测定，其余的两个试管贮存在设定为50℃和70％相对湿度的潮湿小室内。贮存一天后测定两个被贮存试管中的一个；第二个试管在贮存3天后进行测定。贮存稳定性报告为第1天和第3天的剩余活性除以第0天的初始活性，以百分数表示。
酶活性的测定方法为：每个试管中加入30毫升含有20μl过氧化氢酶HP L5000(Genencor International，Rochester，NY)的pH5.5的0.25M MES缓冲液。之后，按照如下进行酶的测定：将10μl受试试管混合物和10μl sAARF蛋白酶底物加入980μl pH 8.6的0.1M Tris液中，然后在25℃孵育3分钟以上，测量410nm处的吸光度。吸光度对时间曲线的斜率乘以稀释因子和已知的指定蛋白酶消光系数，得到以mg/ml为浓度单位的酶活性。
上面在A中描述的过程重复三次以上，所存在的唯一的不同就是在这三个独立流程的每一个中分别将出口温度控制在40、60和70摄氏度设定点。应用了硫酸镁屏障包被之后，从所有的4批移出样品，并且在Rotronic水活度***中测定颗粒的水活度，报告见表1。根据上述加速的稳定性试验方法，在应用了最终聚合物包被之后，将两份颗粒置于WFK-1洗涤剂的配方之中，并在50℃和70％的相对湿度下贮存于带孔塞子的试管中共3天。1天和3天后从潮湿小室中取出试管并进行测定。剩余活性百分数报告于表1中。结果显示，出口温度为50摄氏度时包被硫酸镁的颗粒其稳定性明显高于出口温度为70摄氏度的颗粒，更加稳定的颗粒有大于0.35的水活度，而稳定性较低的颗粒则有低得多的水活度。
表1包被了硫酸镁的酶颗粒的稳定性
| 出口温度(℃) | MgSO4包被的蛋白酶芯料的Aw | 储存于漂白洗涤剂内的颗粒剩余活性百分数 | |||
| 0天 | 1天 | 3天 | |||
| 40506070 | 0.3740.4090.1400.165 | 100％100％ | 108％94％ | 97％63％ | |
实施例2 包被了柠檬酸钠的蛋白酶颗粒的稳定性
A.在Vector 60包被器中，将25千克的蔗糖/淀粉非pareil晶种流体化，并且在下列条件将30千克浓度为65.9g/L总固体量18.3％的枯草杆菌蛋白酶浓缩物喷射在已经流体化的芯料上：
斜升时间： 55分钟
流体进料速率 0.5-0.9升/分钟
雾化压力 75磅/平方英寸
入口空气温度 60-95摄氏度
出口空气温度 50摄氏度
流体化空气速率 24立方米/分钟
13.2千克二水合柠檬酸三钠加入到19.7千克水中，制备柠檬酸三钠溶液。然后在下列条件下将其喷射到包被了酶的芯料上，使二水合柠檬酸三钠占最终颗粒的25％，小心控制使得流 化床温度接近50摄氏度：
斜升时间： 23分钟
流体进料速率 0.6-1.9升/分钟
雾化压力 75磅/平方英寸
入口空气温度 60-95摄氏度
出口空气温度 50摄氏度
流体化空气速率 24立方米/分钟
最后，聚合物包被溶液制备如下：2.94千克Methocel HPMC、0.98千克分子量600的聚乙二醇、2.06千克二氧化钛及0.59千克Neodol23-6.5T非离子表面活性剂溶解于55.88千克水中，然后在下列条件下将其喷射在盐包被的酶颗粒上：
斜升时间： 10分钟，然后恒定为80分钟
流体进料速率 0.5-0.7升/分钟
雾化压力 75磅/平方英寸
入口空气温度 75-80摄氏度
出口空气温度 60摄氏度
流体化空气速率 18立方米/分钟
获取的颗粒重49.5千克，酶浓度大约每千克40克。
B.上述过程在相同条件下重复，但是出口空气温度控制在70摄氏度。柠檬酸钠屏障包被被施加后，将两批样品移出，并且在Rotronic水活度***中测定颗粒的水活度，报告见表2。在施加了最终聚合物包被之后，将两份颗粒置于自动洗碟机洗涤剂基质之中，并在37℃下贮存于密封试管中共84天。14天、42天和84天后从潮湿小室中取出试管并进行测定。剩余的活性百分数报告于表2中。结果显示，出口温度为50摄氏度时包被柠檬酸钠的颗粒其稳定性明显高于出口温度为70摄氏度的颗粒，更加稳定的颗粒有大于0.25的水活度，而稳定性较低的颗粒则有低得多的水活度。
表2包被了柠檬酸钠的酶颗粒的稳定性
| 出口温度(℃) | 柠檬酸三钠包被的蛋白酶芯料的Aw | 储存于漂白洗涤剂内的颗粒剩余活性百分数 | |||
| 0天 | 14天 | 42天 | 84天 | ||
| 5570 | 0.2720.059 | 100％100％ | 90％86％ | 89％81％ | 87％75％ |
Claims (17)
1.一种包含蛋白质芯料和水合屏障材料的颗粒，其中水合屏障材料选自无机盐、有机酸盐，水合屏障材料包被于蛋白质芯料上，颗粒具有中度或高度水活度，其中中度或高度水活度为至少0.25。
2.权利要求1的颗粒，其中中度或高度水活度大于0.30。
3.权利要求1的颗粒，其中中度或高度水活度大于0.35。
4.权利要求1的颗粒，其中无机和有机酸盐选自七水合硫酸镁、七水合硫酸锌、七水合磷酸氢二钠、六水合硝酸镁、二水合柠檬酸钠和四水合乙酸镁。
5.权利要求1的颗粒，其中蛋白质为酶。
6.权利要求5的颗粒，其中酶选自水解酶、氧化酶、转移酶、脱水酶、还原酶、半纤维素酶和异构酶和其混合物。
7.权利要求5的颗粒，其中酶是枯草杆菌蛋白酶。
8.权利要求1的颗粒，其还含有一个或多个额外的包被层，其中一个或多个额外的包被层含有水合屏障包被上的外包被，所述外包被选自乙烯基聚合物、纤维素衍生物、聚乙二醇、聚环氧乙烷、聚脱乙酰壳多糖、***树胶、黄原胶、角叉藻胶、胶乳聚合物和肠溶衣。
9.权利要求8的颗粒，其中一个或多个额外的包被层含有抵抗漂白对蛋白质的氧化之包被。
10.权利要求8的颗粒，其中一个或多个额外的包被层含有一种或多种增塑剂、膨胀剂、润滑剂、颜料和酶。
11.根据权利要求1的颗粒，包含
酶芯料；
包被于酶芯料上的水合无机屏障盐，包被水合无机屏障盐后的酶芯料具有大于0.25的中度或高度水活度；
以及在水合无机屏障盐上的外包被，所述外包被选自乙烯基聚合物、纤维素衍生物、聚乙二醇、聚环氧乙烷、聚脱乙酰壳多糖、***树胶、黄原胶、角叉藻胶、胶乳聚合物和肠溶衣。
12.权利要求11的颗粒，其中酶芯料含有选自水解酶、氧化酶、转移酶、脱水酶、还原酶、半纤素酶、异构酶、其混合物。
13.权利要求11的颗粒，其中无机和有机酸盐选自七水合硫酸镁、七水合硫酸锌、七水合磷酸氢二钠、六水合硝酸镁、二水合柠檬酸钠和四水合乙酸镁。
14.权利要求11的颗粒，其中酶芯料含有用酶层包被的晶种粒子。
15.一种制备权利要求11的颗粒的方法，包括
提供酶芯料；和
于接近或略低于50℃下或者在出口温度为40℃-50℃下将水合无机屏障盐包被于酶芯料上；其中包被水合无机屏障盐后的酶芯料具有大于0.25的中度或高度水活度；和
在水合无机屏障盐上添加外包被，与在70℃下包被水合屏障材料的相似测试颗粒相比，所述颗粒显示保留较高的酶活性百分比，所述保留的酶活性在洗涤剂中贮存颗粒和测试颗粒至少14天后测定，其中，所述外包被选自乙烯基聚合物、纤维素衍生物、聚乙二醇、聚环氧乙烷、聚脱乙酰壳多糖、***树胶、黄原胶、角叉藻胶、胶乳聚合物和肠溶衣。
16.一种制备权利要求1的颗粒的方法，包括
提供蛋白质芯料；和
于接近或略低于50℃下或者在出口温度为40℃-50℃下将水合屏障材料包被于蛋白质芯料上；其中包被水合无机屏障盐后的蛋白质芯料具有至少0.25的中度或高度水活度，其中水合屏障材料选自无机盐、有机酸盐。
17.权利要求16的方法，还包括
在水合屏障材料上添加外包被，与在70℃下包被水合屏障材料的测试颗粒相比，所述颗粒显示保留较高的酶活性百分比，所述保留的酶活性在洗涤剂中贮存颗粒和测试颗粒至少14天后测定，其中，所述外包被选自乙烯基聚合物、纤维素衍生物、聚乙二醇、聚环氧乙烷、聚脱乙酰壳多糖、***树胶、黄原胶、角叉藻胶、胶乳聚合物和肠溶衣。
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- 1998-12-21 WO PCT/US1998/027214 patent/WO1999032595A1/en active IP Right Grant
- 1998-12-21 JP JP2000525517A patent/JP4367743B2/ja not_active Expired - Lifetime
- 1998-12-21 CA CA002313238A patent/CA2313238C/en not_active Expired - Lifetime
- 1998-12-21 ES ES98964195T patent/ES2276482T3/es not_active Expired - Lifetime
- 1998-12-21 BR BR9813768-9A patent/BR9813768A/pt not_active Application Discontinuation
- 1998-12-21 EP EP98964195A patent/EP1042443B1/en not_active Revoked
- 1998-12-21 DK DK98964195T patent/DK1042443T3/da active
- 1998-12-21 CZ CZ20002306A patent/CZ302123B6/cs not_active IP Right Cessation
- 1998-12-21 CN CNB988124483A patent/CN1197946C/zh not_active Expired - Lifetime
- 1998-12-21 NZ NZ505298A patent/NZ505298A/xx not_active IP Right Cessation
- 1998-12-21 KR KR1020007006768A patent/KR20010033321A/ko not_active Application Discontinuation
- 1998-12-21 AU AU19373/99A patent/AU745104B2/en not_active Ceased
- 1998-12-21 US US09/581,717 patent/US6602841B1/en not_active Expired - Lifetime
- 1998-12-21 AT AT98964195T patent/ATE344313T1/de not_active IP Right Cessation
- 1998-12-21 PL PL98342655A patent/PL342655A1/xx unknown
-
2003
- 2003-07-30 US US10/630,217 patent/US20040029756A1/en not_active Abandoned
-
2008
- 2008-05-01 US US12/113,422 patent/US20080206830A1/en not_active Abandoned
-
2012
- 2012-01-30 US US13/361,860 patent/US20120214727A1/en not_active Abandoned
-
2013
- 2013-12-16 US US14/107,765 patent/US20140141971A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| CA2313238C (en) | 2009-05-12 |
| JP2001527024A (ja) | 2001-12-25 |
| JP4367743B2 (ja) | 2009-11-18 |
| CZ302123B6 (cs) | 2010-10-27 |
| CN1282367A (zh) | 2001-01-31 |
| DE69836348T2 (de) | 2007-05-16 |
| CA2313238A1 (en) | 1999-07-01 |
| KR20010033321A (ko) | 2001-04-25 |
| US6602841B1 (en) | 2003-08-05 |
| AU745104B2 (en) | 2002-03-14 |
| US20040029756A1 (en) | 2004-02-12 |
| ATE344313T1 (de) | 2006-11-15 |
| CZ20002306A3 (cs) | 2001-10-17 |
| BR9813768A (pt) | 2000-10-10 |
| EP1042443B1 (en) | 2006-11-02 |
| DK1042443T3 (da) | 2007-03-05 |
| AU1937399A (en) | 1999-07-12 |
| US20120214727A1 (en) | 2012-08-23 |
| ES2276482T3 (es) | 2007-06-16 |
| NZ505298A (en) | 2002-10-25 |
| PL342655A1 (en) | 2001-07-02 |
| US20080206830A1 (en) | 2008-08-28 |
| WO1999032595A1 (en) | 1999-07-01 |
| US20140141971A1 (en) | 2014-05-22 |
| EP1042443A1 (en) | 2000-10-11 |
| DE69836348D1 (de) | 2006-12-14 |
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| C14 | Grant of patent or utility model | ||
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