CN1155367C - 微粒吸入制剂 - Google Patents
微粒吸入制剂 Download PDFInfo
- Publication number
- CN1155367C CN1155367C CNB988133849A CN98813384A CN1155367C CN 1155367 C CN1155367 C CN 1155367C CN B988133849 A CNB988133849 A CN B988133849A CN 98813384 A CN98813384 A CN 98813384A CN 1155367 C CN1155367 C CN 1155367C
- Authority
- CN
- China
- Prior art keywords
- weight
- surfactant
- aerosol preparations
- propellant
- phospholipid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 239000000443 aerosol Substances 0.000 claims abstract description 33
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 claims abstract description 17
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims abstract description 16
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- 210000002345 respiratory system Anatomy 0.000 claims description 6
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- 150000002632 lipids Chemical class 0.000 abstract description 2
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- 229910052739 hydrogen Inorganic materials 0.000 description 2
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
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- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
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Abstract
含有稳定的药物微粒的气溶胶制剂，微粒的平均大小为0.1-10微米，包覆着成膜的两亲性类脂，并分散于1，1，1，2-四氟乙烷(HFA134a)或1，1，1，2，3，3，3-七氟丙烷(HFA 227)喷射剂中。
Description
本发明涉及用类脂膜包覆并悬浮在氢氟烷烃喷射剂中的药物微粒气溶胶制剂。
发明背景
加压的计量给药吸入器(MDI)内的药物释放目前采用氯氟烃作为喷射剂。由于氯氟烃将被逐步淘汰(潜在地耗减臭氧层)，使用氯氟烃的上市产品必须用氢氟烷烃(HFA)喷射剂，例如杜邦化学公司(Nilmington，Delaware，USA)销售的1，1，1，2-四氟乙烷(HFA134a)和1，1，1，2，3，3，3-七氟丙烷(HFA 227)，重新配制。所提议的代用喷射剂的溶剂性质与氯氟烃很不相同。在物理化学性质(例如极性、蒸汽压和密度)方面的差异为研制使用氢氟烷烃作为喷射剂经肺部给药的加压计量给药吸入器中的药物产品提出了新的任务[Byron等人，呼吸器官药物释放(Resp.Drug.Deliv.)4(1994)]。
许多专利文献提到吸入制剂中的这些物理化学性质的差异。美国专利5,492,688涉及MDI制剂，该制剂使用90％重量以上的HFA 134a作为唯一的喷射剂，少于5％重量的微粒化药物颗粒和不到5％重量的极性表面活性剂，该表面活性剂选自聚乙二醇300、二乙二醇单乙醚、聚氧乙烯20失水山梨醇单油酸酯、丙氧基化的聚乙二醇和聚氧乙烯4十二烷基醚。
世界专利WO 91/04011描述了一种自喷射的粉末气溶胶组合物，其中含有用单独一种非全氟化的表面活性分散剂包覆的。细分散和预微粒化的固体药物，悬浮在该分散剂基本上不溶的气溶胶喷射剂中。合适的分散剂包括各种油、失水山梨醇油酸酯、聚氧乙烯化失水山梨醇醚、卵磷脂和聚氧乙烯等。表面活性剂的用量要保持最低，以避免颗粒团聚和增大粒度。
世界专利申请96/19197涉及一种药物气溶胶制剂，其中含有(a)一种氢氟烷烃喷射剂；(b)一种可分散在喷射剂内的药学活性的多肽；和(c)一种表面活性剂，它是C8-C16脂肪酸或其盐、胆汁盐、磷脂或烷基糖类，该表面活性剂增强了多肽在下呼吸道内的系统吸收。同一发明人的世界专利申请96/19198涉及一种药物气溶胶制剂，其中含有一种HFA喷射剂，生理上有效量的供吸入的药物，和一种表面活性剂，该表面活性剂是C8-C16脂肪酸或其盐、胆汁盐、磷脂或烷基糖类。这两份专利都描述了活性物和表面活性剂在喷射剂中的物理混合物，但未涉及预先的包封步骤。
世界专利申请96/40089涉及用于气溶胶释放的药物组合物的一种药物气溶胶制剂，其中含有一种药物、一种卤化烷烃喷射剂和一种生物相容的C16以上的不饱和植物油。
世界专利申请90/11754涉及气溶胶制剂，其中含有一种以适合吸入给药形式存在的作为活性组分的吡咯抗真菌剂。
世界专利申请94/21228涉及一种医用气溶胶制剂，其中含有作为分散剂的二醇/二酸缩合物、喷射剂和治疗有效量的一种粒状药物。
世界专利申请96/06598涉及一种用于气溶胶释放的药物组合物，其中含有一种药物、一种非氯氟烃喷射剂和一种聚乙二醇化的甘油酯。
世界专利申请92/06675涉及一种气溶胶制剂，其中含有治疗有效量的倍氯美松17，21-双丙酸酯，氢氟烃1，1，1，2-四氟乙烷(HFA 134a)或1，1，1，2，3，3，3-七氟丙烷(HFA 227)喷射剂或其混合物，以及其量能使倍氯美松17，21双丙酸酯在喷射剂中加溶的乙醇。基本上所有的倍氯美松17，21-双丙酸酯都溶于制剂中，而且它基本上不含任何表面活性剂。
世界专利申请93/05765涉及一种加压的气溶胶组合物，其中含有一种液化的氢氟烷烃，一种可分散于其中的粉状药物，和一种溶于液化氢氟烷烃的聚合物。该聚合物包含作为重复结构单元的含酰胺单元或含羧酸酯单元。
美国专利4,174,295涉及一种用于气溶胶的喷射剂组合物，该组合物主要由占喷射剂组合物总重量5-60％的选自CH2F2和CF3-CH3的含氢氟烃和占喷射剂组合物总重量40-95％的含氢氯氟烃或含氢氟烃的混合物组成，所述的含氢氯氟烃或含氢氟烃分别选自CF3-CHCLF、CF3-CH2CL、CF3-CH2F、CCLF2-CF3或CHF2-CH3。
美国专利5,118,494涉及一种悬浮液气溶胶制剂，其中包括：含有选自1，1，1，2-四氟乙烷(HFA 134a)或1，1，1，2，3，3，3-七氟丙烷(HFA 227)或其混合物的一种氢氟烃的喷射剂；治疗有效量的粉状药物；和占制剂总重量约0.001-0.6％的、作为表面活性分散剂的一种全氟羧酸或其酯。此制剂中的药物在长期放置时基本上不结晶，容易再分散，而且在再分散时不会因很快絮凝而使药物剂量无法重复。
美国专利5,126,123涉及一种气溶胶吸入药物制剂，其中主要由悬浮在1，1，1，2-四氟乙烷中的一种生理有效量的微粒化吸入药物和一种1，1，1，2-四氟乙烷可溶的金氟表面活性剂组成。
美国专利5,182,097涉及一种用于通过吸入装置向患者释放药物的气溶胶制剂，其中含有的喷射剂只由1，1，1，2-四氟乙烷构成。该喷射剂构成气溶胶制剂的至少90％重量。制剂中还含有分散或溶解在喷射剂中的可吸入的药物，其粒径大小小于100μm。这种可吸入的药物在气溶胶制剂中的含量不超过5％(重量)。使用油酸作为表面活性剂以促进可吸入药物在喷射剂中的分散，油酸的量不超过气溶胶制剂的0.2％w/v。
美国专利5,202,110涉及用于计量给药吸入器的气溶胶制剂，其中含有一种药学上可接受的可吸入的喷射剂、作为分散或溶解在喷射中的可吸入药物使用的倍氯美松双丙酸酯的包合物或分子缔合物。倍氯美松双丙酸酯的包合物或分子缔合物是与1，1-二氯-2，2，2-三氟乙烷或1，1-二氯-1-氟乙烷或二甲醚形成的，该包合物或分子缔合物具有可以吸入的粒子大小。
美国专利5,474,759涉及一种气溶胶制剂，它主要由有效量的药物、1，1，1，2，3，3，3-七氟丙烷(HFA 227)以及可有可无的一种赋形剂组成，该赋形剂是选自中等链长脂肪酸的丙二醇二酯或中等链长脂肪酸的甘油三酯。可加入或不加入表面活性剂和其它赋形剂。
世界专利申请96/32150涉及一种计量给药吸入器，其部分或全部内表面涂覆着一种或多种碳氟聚合物，与或不与一种或多种非碳氟聚合物组合，用于分散沙美特罗或其生理上可接受盐和碳氟化合物喷射剂，以及可有可无的一种或多种其它药理活性剂或者一种或多种赋形剂的吸入药物制剂。
世界专利申请96/32151涉及一种计量给药吸入器，其部分或全部内表面涂覆着一种或多种碳氟聚合物，与或不与一种或多种非碳氟聚合物组合，用于分散丙酸氟地松或其生理上可接受的溶剂化物和碳氟化合物喷射剂，以及可有可无的一种或多种其它药理活性剂或者一种或多种赋形剂的吸入药物制剂。
世界专利申请96/18384涉及一种药物气溶胶制剂，其中含有作为喷射剂的1，1，1，2-四氟乙烷(HFA 134a)，1，1，1，2，3，3，3-七氟丙烷(HFA 227)或其混合物，作为喷射助剂的1，1，2，2，3-五氟丙烷和粒状药物。
世界专利申请94/03153涉及一种药物气溶胶制剂，其中含有粒状倍氯美松双丙酸酯或其可接受的溶剂化物，以及碳氟化合物或含氢的氯氟烃喷射剂，该制剂基本上不含表面活性剂。
世界专利申请96/32099涉及一种计量给药吸入器，其部分或全部内表面涂覆着一种或多种碳氟聚合物，与或不与一种或多种非碳氟聚合物，用于分散舒喘灵或其生理上可接受的盐和氟碳喷射剂，以及可有可无的一种或多种其它药理活性剂或者一种或多种赋形剂的吸入药物制剂。
世界专利申请93/11745涉及一种药用气溶胶制剂，其中含有一种粒状药物、碳氟或含氢的氯氟烃喷射剂和高达喷射剂重量5％的一种极性助溶剂，该制剂基本上不含表面活性剂。
世界专利申请93/11743涉及一种药物气溶胶制剂，其中含有粒状药物沙美特罗、沙丁胺醇、丙酸氟地松、倍氯美松双丙酸酯或其生理上可接受的盐和溶剂化物，以及碳氟化合物或含氢的氯氟烃。该制剂基本上不含表面活性剂。
世界专利申请93/15741涉及倍氯美松双丙酸酯一水合物的药物气溶胶制剂，基本上所有一水合物的粒子大小都小于20微米，除了与一水合物相关的结晶水之外，制剂中至少有占制剂重量0.015％的水，制剂中还含有碳氟化合物或含氢的氯氟烃喷射剂。
世界专利申请93/11744涉及粒状药物和碳氟化合物或含氢的氯氟烃喷射剂的药物气溶胶制剂，该制剂基本上不含表面活性剂，而且此时药物不是沙美特罗、沙丁胺醇、丙酸氟地松、倍氯美松双丙酸酯或其生理上可接受的盐或溶剂化物。
本发明概述
根据本发明，现已出乎意料地发现，可以得到微粒在HFA 134a或HFA 227中特别稳定的悬浮液。这些微粒由涂覆着含磷脂膜的药物微粒构成。优选这些药物颗粒涂覆着磷脂和至少一种表面活性剂的混合物，该混合物形成了包封微粒外周的薄膜层。通过在磷脂或其它成膜的两亲类脂以及最好至少一种表面活性剂存在下进行超声或其它方法，包括高速剪切和/或撞击，将药物的平均粒子大小降至100nm至10μm，优选0.1-10μm。然后通过将悬浮液干燥，得到干的粉末。带涂层的颗粒干粉可方便地悬浮在喷射剂中。使用成膜组分以获得合适的密度和极性并减少药物颗粒聚结，从而形成在含氢氟烃喷射剂HFA 134a或HFA 227中充分分散和稳定的药物悬浮液。
本发明描述
在本发明的一个优选的方面，药物颗粒用磷脂和至少一种表面活性剂包覆，同时将粒子大小降至最终平均粒度为0.1-10微米。使用这些赋形剂是为了调节悬浮在喷射剂中的药物颗粒的密度、极性和表面张力。控制密度以减小分散的颗粒上浮分层或沉降倾向。制剂的密度优选为1.0-1.5g/ml，以便与HFA喷射剂的密度相匹配。另外，对颗粒的极性和表面张力的合适控制可减少药物颗粒的聚结，形成容易分散和稳定的药物悬浮液。
在膜涂层中，磷脂与表面活性剂的重量比为0.01-100，优选为0.02-50，更优选为0.04-25。使用的表面活性剂和助表面活性剂的类型和量依这些组分的相对溶解度和/或极性而定。因此制剂组合物要相对于每种药物逐一地最优化。包封法减少了为得到合格制剂所需的赋形剂的量。
重要的是，包括磷脂在内的表面活性剂的总量优选多于药物量的0.1％，但少于200％。
发明详述
制备方法
超声法：超声法籍助空穴作用减小超分子药物和磷脂结构的大小。此方法产生小的空穴，它们在崩溃时以高速将物质推压在一起，产生粉碎和剪切作用。这同时使各组分破碎成亚微米级的碎片并包覆在微粒的疏水表面上。在本发明中，药物、磷脂、表面活性剂和任何附加组分与溶剂混合在一起后进行超声。超声处理是用装有0.5英寸探头的550型超声粉碎器(Fischer Scientific)在5-10℃的受控温度和设立功率3-5下进行5-60分钟，直到平均粒子大小达到0.1-5微米。为了更好地控制温度，采用自动化的开停机各10秒的循环操作进行超声。
然后通过冷冻干燥或喷雾干燥将产物转化成干燥形式，得到的粉末随后悬浮在HFA 134a或HFA 227中。
涉及用高压产生高速剪切和撞击的方法：将药物与其它合适的组分一起用本领域已知的高压均化法和/或微流态化进行均化。在微流态化法中，通过相反方向的液体微射流的撞击产生高剪切作用，同时在颗粒之间和在流化床壁处产生撞击。在高压均化法中，样品在高压和高剪切下流过狭窄的小孔，并受到壁面的撞击，快速减压至大气压力。然后产物经冷冻干燥或喷雾干燥转化成干燥形式，得到的粉末随后悬浮于HFA 134a或HFA 227中。超声和高速剪切及撞击法不限于水介质，它也可以在挥发性的有机介质内进行。
在空气中尺寸减小：药物晶体也可以通过在空气中高速撞击而减小尺寸，然后依次用磷脂和表面活性剂包覆。随后通过冷冻干燥或喷雾干燥将产物转化成干燥形式，形成的粉末悬浮在HFA 134a或HFA227中。
通过在飞行中结晶减小尺寸：可以将磷脂、表面活性剂、药物和任何附加成分在挥发性溶剂中的溶液喷雾，同时通过在飞行中蒸发来除去溶剂。将干燥的颗粒收集在光滑的表面上并悬浮于一种喷射剂中。
通过受控结晶法减小尺寸：例如用超临界流体结晶。
本发明组合物除活性物质外，还将包括至少一种磷脂和可有可无的至少一种表面活性剂。
合适的磷脂实例是：饱和或不饱和形式的二酰基磷脂酰胆碱；饱和或不饱和形式的二酰基磷脂酰甘油，二酰基磷脂酰乙醇胺，二酰基磷酯酰肌醇和二酰基磷脂酰丝氨酸及其相应的溶血磷脂。
合适的表面活性剂的实例有：
1.聚氧乙烯-失水山梨醇-脂肪酸酯；例如单和三月桂基、棕榈基、硬脂基和油基酯；如称作聚山梨酸酯、商品名称为“Tween”的一类产品。
2.聚氧乙烯脂肪酸脂，例如商品名称Myrj(如Myrj 52)的一类已知的聚氧乙烯硬脂酸酯产品。
3.聚氧乙烯蓖麻油衍生物，例如一类已知的作为Cremophors销售的产品。特别合适的是聚氧乙烯35蓖麻油(Cremophor EL)和聚氧乙烯40氢化蓖麻油(Cremophor RH40)。
4.维生素E或其衍生物，例如聚乙二醇1000D-α-生育酚丁二酸酯(维生素E TPGS)。
5.PEG甘油脂肪酸酯，例如PEG-8甘油辛酸/癸酸酯(商品名称Labrasol)、PEG-4甘油辛酸/癸酸酯(Labrafac Hydro WL 1219)、PEG-32甘油月桂酸酯(Gelucire 44/14)、PEG-6甘油单油酸酯(Labrafil M 1944 CS)、PEG-6甘油亚油酸酯(Labrafil M 2125CS)。
6.丙二醇单和双脂肪酸酯，例如丙二醇月桂酸脂、丙二醇辛酸/癸酸酯，以及商品名称transcutol的二乙二醇单乙醚。
7.失水山梨醇脂肪酸酯，例如已知的一类商品名称Span的产品(如Span 20)。
8.聚氧乙烯-聚氧丙烯共聚物，例如已知的一类称作pluronic或Poloxamer的商品，如Poloxamer 188 NF。
9.甘油三乙酸酯
10.甘油单脂和乙酰化的甘油单酯，例如甘油单油酸酯、甘油单硬脂酸酯和单及二乙酰化的甘油单酯。
11.胆汁盐
12.聚乙二醇(PEG)，例如PEG 300、PEG 400、PEG600、PEG1000、PEG 1500、PEG 3400、例如已知的商品名称为Carbowax、Lutrol E和Hodag EPG的一类产品。
13.取代的纤维素产品，例如羟丙基甲基纤维素、羧甲基纤维素钠和羟丙基纤维素。
14.丙烯酸聚合物，例如已知的一类称作Carbopol的商品。
合适的磷脂和表面活性剂不限于上述的这些，而是可以包括能增强制剂药学性能的任何化合物。
根据本发明的组合物，除药物、磷脂和表面活性剂外，还可包括其它组分。例如，组合物中除上述组分外，还可包括一种或多种组分、添加剂或稀释剂，例如可药用的这些成分，或者无机物、防冻剂(如海藻糖和甘露醇)、防氧化剂和防腐剂。
本发明的气溶胶制剂可用于疾病的局部或全身治疗，并可以例如局部方式给药，或通过上和下呼吸道(包括经鼻)给药。
以下是本发明组合物的示例说明性而非限制性的实施例。
在以下实施例中，微粒制剂(30ml规模)是通过向合适溶剂中加入各组分后进行超声制得的。然后利用例如冷冻干燥法蒸发掉溶剂。
随后称量适当重量的干粉放入气溶胶瓶中，接着每瓶内加约40mlHFA 134a。然后用手摇动瓶子约1分钟，在水浴式超声器中超声15-30分，和/或在摇床上放置过夜。
成分 Wt％
实施例1
倍氯美松双丙酸酯 0.0657
DPPC1 0.0263
Myrj 52 0.0263
HFA 134a 99.882
实施例2
倍氯美松双丙酸酯 0.327
DPPC 0.177
DMPG2 0.0026
Poloxamer 188 NF 0.0654
HFA 134a 99.428
实施例3
倍氯美松双丙酸酯 0.0657
DPPC 0.0131
Poloxamer 188 NF 0.0066
PEG 300 0.0066
HFA 134a 99.908
实施例4
9-去氟肤轻松 0.3274
DPPC 0.0655
Poloxamer 188 NF 0.0524
PEG 1000 0.0131
HFA 134a 99.542
11，2-二棕榈酰磷脂酰胆碱
21，2-二肉豆蔻酰磷脂酰甘油
实施例5
醋酸曲安缩松 0.2622
DPPC 0.0524
Poloxamer 188 NF 0.0420
PEG 1000 0.0105
HFA 134a 99.633
实施例6
沙丁胺醇 0.1313
DPPC 0.0368
Myrj 52 0.0263
HFA 134a 99.806
Claims (14)
1.一种主要由稳定化的药物微粒组成的并具有密度为1.0-1.5g/ml的气溶胶制剂，该微粒的平均大小为0.1-10微米，用一种或多种成膜的磷脂和至少一种表面活性剂包覆着，并分散于1，1，1，2-四氟乙烷(HFA 134a)或1，1，1，2，3，3，3-七氟丙烷(HFA 227)喷射剂中，其中包覆的药物微粒的密度与喷射剂的密度基本上相同，而涂覆在药物微粒上的涂层量按药物的重量计为高于0.1％至小于200％。
2.权利要求1的气溶胶制剂，其中喷射剂占制剂重量的至少70％。
3.权利要求2的气溶胶制剂，其中喷射剂占制剂重量的至少90％。
4.权利要求2的气溶胶制剂，其中药物占制剂重量的5％以下。
5.权利要求1的气溶胶制剂，其中磷脂与表面活性剂的重量比在0.01-100的范围。
6.权利要求1或5的气溶胶制剂，其中磷脂与表面活性剂的重量比在0.02-50的范围。
7.权利要求1，5或6的任一项权利要求的气溶胶制剂，其中磷脂与表面活性剂的重量比在0.04-25的范围。
8.权利要求1的气溶胶制剂，其中磷脂在制剂中的含量少于20％重量。
9.权利要求1或8的气溶胶制剂，其中磷脂在制剂中的含量少于5％重量。
10.权利要求1的气溶胶制剂，其中表面活性剂在制剂中的含量少于20％重量。
11.权利要求1或10的气溶胶制剂，其中表面活性剂在制剂中的含量少于5％重量。
12.装有其密度为1.0-1.5g/ml的气溶胶制剂的计量给药吸入器，该制剂主要由其平均粒度为0.1-10微米的药物微粒组成，微粒上包覆着磷脂和至少一种表面活性剂的混合物，并分散在HFA 134a或HFA 227喷射剂中，其中带涂层的药物微晶体的密度与喷射剂的密度基本相同，药物微粒上的涂层的量多于药物重量的0.1％并少于200％。
13.用于向上呼吸道或下呼吸道释放的其密度为1.0-1.5g/ml的药物微粒，该微粒的平均大小为0.1-10微米，包覆着一种成膜的两亲性类脂和至少一种表面活性剂，并分散在可药用的载体中，其中涂覆在药物微颗粒上的磷脂量按药物重量计为多于0.1％并少于200％。
14.用于向上呼吸道或下呼吸道释放的其密度为1.0-1.5g/ml的干粉，它基本上由平均粒度为0.1-10微米的药物微粒构成，包覆着一种成膜的两亲性类脂和至少一种表面活性剂，其中涂覆在药物微颗粒上的两亲性类脂的量按药物的重量计为多于0.1％并少于200％。
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| US09/016,265 | 1998-01-30 | ||
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| CN1283989A CN1283989A (zh) | 2001-02-14 |
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1998
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- 1998-12-30 EP EP98965051A patent/EP1051154A1/en not_active Ceased
- 1998-12-30 KR KR1020007008094A patent/KR20010040402A/ko not_active Application Discontinuation
- 1998-12-30 IL IL13747298A patent/IL137472A/xx not_active IP Right Cessation
- 1998-12-30 WO PCT/US1998/027922 patent/WO1999038493A1/en not_active Application Discontinuation
- 1998-12-30 AU AU20244/99A patent/AU756464B2/en not_active Ceased
- 1998-12-30 JP JP2000529227A patent/JP2002501885A/ja not_active Withdrawn
- 1998-12-30 CN CNB988133849A patent/CN1155367C/zh not_active Expired - Fee Related
- 1998-12-30 CA CA002319100A patent/CA2319100C/en not_active Expired - Fee Related
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2000
- 2000-07-13 SE SE0002643A patent/SE0002643L/xx not_active Application Discontinuation
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2010
- 2010-06-04 JP JP2010128713A patent/JP2010248206A/ja active Pending
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| IL137472A (en) | 2005-08-31 |
| CA2319100C (en) | 2008-05-27 |
| CN1283989A (zh) | 2001-02-14 |
| WO1999038493A1 (en) | 1999-08-05 |
| JP2010248206A (ja) | 2010-11-04 |
| US6086376A (en) | 2000-07-11 |
| IL137472A0 (en) | 2001-07-24 |
| AU756464B2 (en) | 2003-01-16 |
| SE0002643L (sv) | 2000-09-04 |
| KR20010040402A (ko) | 2001-05-15 |
| JP2002501885A (ja) | 2002-01-22 |
| SE0002643D0 (sv) | 2000-07-13 |
| AU2024499A (en) | 1999-08-16 |
| EP1051154A1 (en) | 2000-11-15 |
| CA2319100A1 (en) | 1999-08-05 |
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