CN1762381A - 含半乳甘露聚糖聚合物和硼酸盐的眼用组合物 - Google Patents
含半乳甘露聚糖聚合物和硼酸盐的眼用组合物 Download PDFInfo
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- CN1762381A CN1762381A CNA200510113689XA CN200510113689A CN1762381A CN 1762381 A CN1762381 A CN 1762381A CN A200510113689X A CNA200510113689X A CN A200510113689XA CN 200510113689 A CN200510113689 A CN 200510113689A CN 1762381 A CN1762381 A CN 1762381A
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- galactomannan
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Abstract
本发明涉及含胶凝化量的半乳甘露聚糖多糖与硼酸盐结合的眼用组合物。该组合物一经滴入眼内就会胶凝化或部分胶凝化。本发明还公开了眼用组合物用于眼局部给药的方法。
Description
本申请是申请日为1998年7月17日、发明名称为“含半乳甘露聚糖聚合物和硼酸盐的眼用组合物”的中国专利申请98807690.X的分案申请。
发明背景
本发明涉及使用辅料的眼局部给药用组合物，本发明尤其涉及包含半乳甘露聚糖聚合物和硼酸盐相结合的药用组合物以及将药用活性剂向患者进行可控给药的方法，其中该药用组合物以液态滴入眼内时会增稠而形成凝胶。这种由液态向凝胶的转变主要是由于pH值和离子浓度的改变而引起的。
已有眼局部给药用组合物的形态包括液剂、软膏剂、凝胶剂和植放剂。向眼内滴加的含药用活性物质的液态组合物，虽具有易于给药的优点，但由于在给药时部分药液常会因眨眼而被挤出来，或者因注入鼻道而被排出，因而滴加剂量不一定总是准确的。软膏或凝胶在眼内停留时间要比液体长一些，因此可达到较准确的给药量，但常会影响患者的视线。眼植放剂(包括可生物腐蚀的和非生物腐蚀的)也是可商购到的，但不是经常采用的给药方式。然而，眼植放剂的制备工艺较复杂，而且也会让使用者感到不舒服。有关非生物腐蚀的眼植放剂的另一问题是使用后还必须将其取出来。
美国专利4136173(Pramoda等人)和4136177(Lin等人)公开了包含黄原胶和刺槐豆胶的能以液态给药并在滴入眼内时形成凝胶的治疗用组合物。这些公开内容介绍了液态向凝胶态转变与pH值改变相关的机理。对pH值敏感的凝胶(如卡波姆胶、黄原胶、gellan以及上述专利公开的凝胶)必须在它们的酸基团的pKa值或低于pKa值(通常在pH值约2-5)条件下进行配制。然而，在低pH值下配制的组合物会对眼睛有刺激作用。美国专利4861760(Mazuel等人)公开了含有gellan胶的眼用组合物，该组合物在给药时呈非凝胶状态的液态，但当滴入眼内时，由于离子浓度的改变而会变成凝胶状。这些系统并没有使用小的交联分子，而是由于离子所处环境改变引起本身交联而具有凝胶特征的。美国专利5082579、5144590和5160643公开了以多糖与硼酸盐交联形成的凝胶作为油井压裂液的内容。这些专利介绍了硼酸盐和多糖在工业油井钻井方面的用途。
现今使用的眼用胶凝化液态系统存在若干缺点。例如，天然聚合物如黄原胶因来源不同和/或加工过程中生产控制条件的限制会产生许多不确定因素的缺点。这些不确定因素会使该化合物的性能(如可变的凝胶化特征)发生明显的不希望有的变化。热胶凝化系统如聚环氧乙烷/聚环氧丙烷嵌段共聚物(“PEO/PPO”)为了形成凝胶而要失水，因此会形成不透明的凝胶。聚乙烯醇(“PVA”)-硼酸盐结合的胶凝化系统需要在低pH值下配制，因此当滴入眼内时会对眼睛产生刺激作用。其它的胶凝化系统存在粘度、再水化以及与高压灭菌有关的浊点不稳定的问题。
美国专利4255415(Sukhbir等人)已经公开了与硼酸盐交联的聚乙烯醇。这些组合物是预形成凝胶，因而是难以分散的。WIPO公开WO94/10976(Goldenberg等人)公开了一种经过液态/凝胶转变的低pH值PVA-硼酸盐给药系统。但是，该系统只有有限的胶凝作用，并只有在随所用PVA的分子量而定的某些PVA浓度下才能发生胶凝作用的缺点。此外，由于交联位置是没有限制的，在添加碱时引起严重的局部胶凝作用已经制约了其生产，因此，为了克服这一缺点，在该组合物中已添加了聚乙烯吡咯烷酮。本发明的新颖胶凝化系统没有上述局限性。
本发明概述
本发明涉及包含半乳甘露聚糖聚合物和硼酸盐化合物的向眼内给药时能控制给药剂量的眼局部给药用组合物。本发明基于一种包含半乳甘露聚糖多糖和硼酸盐交联剂的、当pH值和离子浓度增高时会形成凝胶的新胶凝化系统。在本发明的新系统中，硼酸双二醇酯与多糖的糖部分中顺式二醇基团相交联。该组合物是以液态或部分胶凝化液态(下文称为“液态”)给药的，当组合物滴入眼内时会增稠而形成凝胶。或者，该组合物可不含药用活性物质，以便在治疗如干燥性眼疾时用作眼润滑或补充泪液。
本发明的半乳甘露聚糖-硼酸盐胶凝化系统较其它胶凝化系统有若干优点。其中之一是，本发明组合物是透明的溶液，而且生成的凝胶也是清沏透明的。虽然其它胶凝化系统在给药时可变成不透明或混浊的凝胶，但本发明清沏透明的凝胶可使被治疗的眼睛有更清晰的视线。本发明组合物可在微酸性至中性pH值下进行配制，而且只需要较小的pH值变化(即约0.5至1.0pH值单位)就可激活胶凝作用。这一性质可使因接触酸性而引起对眼的刺激作用的可能性降至最低，而在使用其它需要pH值改变约2.4-约4.4pH值单位(即在pH值约3-5下进行配制)的对pH值敏感的系统时是会对眼产生刺激作用的。半乳甘露聚糖聚合物也是热稳定的，甚至在高压灭菌条件下也不会出现浊点。因此，对于本发明含半乳甘露聚糖聚合物的组合物来说，不存在象PVA和卡波姆聚合物系统那样会因按比例放大成批生产时发生粘度和再水化的问题。
半乳甘露聚糖多糖是非离子型的，而且在酸性至中性pH值下与硼酸盐相结合基本上也是非离子型的。因此，该聚合物系统完全是与阴离子型、中性和阳离子型药物相容的。此外，该聚合物的存在不会损害防腐剂的防腐效果。一般来说，氯苄烷铵或其它阳离子防腐剂与阴离子聚合物(如gellan和鹿角菜胶)是相容的，因此，这些系统中可允许有过量的防腐剂。提高防腐剂浓度也会增加该组合物的刺激性和毒性。
本发明的半乳甘露聚糖-硼酸盐胶凝化系统还具有其它优点：半乳甘露聚糖聚合物分子量较低，因此容易制备和按比例放大生产；半乳甘露聚糖聚合物也是容易买到的，并已用于食品和个人保健品中，因而可认为这种聚合物是安全的。此外，本发明的半乳甘露聚糖-硼酸盐胶凝化组合物的胶凝化特征的可控性或可操作性与先有技术体系相比是较简单的。其它的单聚合物系统，如离聚物(如gellan胶和鹿角菜胶)及热凝胶(如poloxamine和泊洛沙姆)的胶凝化性质通常是与聚合物的分子量和聚合物中官能基团的数目有关的。因此，为了改变那些先有技术系统的凝胶点或胶凝度，就需要改性基体聚合物-强化胶凝活性(laborintensive activity)。与此不同的是，对本发明来说，为了将组合物调整至符合指定的要求，只要调整本发明组合物中硼酸盐与半乳甘露聚糖之比，就可得到具有各种不同胶凝化特征的组合物(见图1和2)。此外，如图3所示，本发明的半乳甘露聚糖(如瓜耳胶)具有极好的胶凝化稠度和再现性，尽管半乳甘露聚糖的来源和类型是不同的。
本发明组合物还有其它优点：本发明的半乳甘露聚糖聚合物和硼酸盐交联剂组合物呈液态，因此是易分散的。如美国专利4861760(Mazuel等人)公开的某些凝胶化系统(如gellan胶)是有触变性的，因而可能需要对它们进行震荡以增加流动性和使其易于分散。本发明组合物中所含的半乳甘露聚糖浓度(约0.2-0.5％)较某些需要浓度高的热胶凝化系统(如PEO/PPO嵌段共聚物)低。低浓度胶凝化聚合物与高浓度系统相比毒性低、易于防止微生物污染。
本发明方法涉及本发明的含半乳甘露聚糖-硼酸盐组合物的局部给药方法。
本发明还涉及对半乳甘露聚糖进行高压蒸汽灭菌的消毒方法。
附图的简要说明
图1图示说明了在硼酸盐存在下，不同浓度瓜耳胶的胶凝化特征与pH值的关系。
图2图示说明了在瓜耳胶存在下，不同浓度硼酸盐的胶凝化特征与pH值的关系。
图3图示说明了三种不同类型/来源的瓜耳胶的凝胶化特征的均一性。
本发明的详细说明
本发明涉及包含一种或多种半乳甘露聚糖多糖和一种或多种硼酸盐化合物的眼用组合物。本发明还涉及利用这些组合物治疗各种眼疾(包括干燥性眼疾、青光眼、眼压过高、感染、过敏和炎症)的方法。
一般来说，可用于本发明中的半乳甘露聚糖源自瓜耳胶、刺槐豆胶和他拉胶。本文所用术语“半乳甘露聚糖”是指源自上述天然植物胶或类似的天然胶或者是以甘露糖或半乳糖部分或是以该两种基团为主要结构成分的合成胶的多糖。本发明的优选半乳甘露聚糖是由(1-4)-β-D吡喃甘露糖基单元与α-D-吡喃半乳糖基单元以(1-6)键合构成的直链聚糖。对于优选的半乳甘露聚糖来说，D-半乳糖与D-甘露糖之比是可以不同的，但通常是约1∶2-1∶4。D-半乳糖与D-甘露糖之比为约1∶2的半乳甘露聚糖是最优选的。此外，多糖的其它化学改性的变体也包括在“半乳甘露聚糖”的规定中，例如羟乙基、羟丙基及羧甲基羟丙基取代物也可成为本发明的半乳甘露聚糖。半乳甘露聚糖的非离子型变体如那些含烷氧基和烷基(C1-C6)基团的变体特别优选用于软凝胶中(如羟丙基取代物)。在非顺式羟基位上的取代物是最优选的。用于本发明的半乳甘露聚糖的非离子型取代物的实例是摩尔取代比约0.4的羟丙基瓜耳胶。阴离子型取代物也可用作本发明的半乳甘露聚糖，当需要制成硬凝胶(strongly responsive gels)时，阴离子型取代物是特别优选的。
可用于本发明组合物中的硼酸盐化合物是硼酸和其它药用盐(如硼酸钠(硼砂)和硼酸钾)。本文所用的术语“硼酸盐”是指所有药用硼酸盐。硼酸盐因其在生理pH值条件下有优良的缓冲容量和众所周知的安全性，而且与各种药物和防腐剂有相容性，因而是眼用配方中的常用赋形剂。硼酸盐还具有抑菌性和抑霉性特性，因而有助于组合物的防腐。
本发明组合物包含约0.1-5(重量/体积)％的一种或多种半乳甘露聚糖和约0.05-5(重量/体积)％的硼酸盐。优选的是，组合物含0.2-2.0(重量/体积)％半乳甘露聚糖和0.1-2.0(重量/体积)％硼酸盐化合物。最优选的是，该组合物含0.3-0.8(重量/体积)％半乳甘露聚糖和0.25-1.0(重量/体积)％硼酸盐化合物。具体的含量可随所要求的具体胶凝化性质而定，一般来说，硼酸盐或半乳甘露聚糖的浓度可配制成当组合物在胶凝激活时(即给药后)能达到适当的粘度。图1和图2分别图示了在指定pH值下，或调节半乳甘露聚糖浓度或调节硼酸盐浓度都可获得较硬或较软的凝胶。如果要求得到硬的胶凝化组合物，那么硼酸盐或半乳甘露聚糖的浓度可以高一些，如果要求得到较软的胶凝化组合物(如部分胶凝化组合物)，那么硼酸盐或半乳甘露聚糖的浓度可以低一些。其它因素(如组合物中的其它成分如盐、防腐剂、螯合剂等的性质和浓度)也可能影响本发明组合物的胶凝化特性。通常，本发明优选的未胶凝组合物(即还未经眼用激活形成凝胶的组合物)的粘度为约5-1000厘泊，本发明优选的胶凝组合物(即已经眼用激活形成凝胶的组合物)的粘度为约50-50000厘泊。
本发明的半乳甘露聚糖可源自多种原料，这类原料包括瓜耳胶、刺槐豆角以及他拉胶，下文将对它们进一步讨论。此外，半乳甘露聚糖还可通过常规合成路线或者通过对现有天然半乳甘露聚糖进行化学改性来获得。
瓜耳胶是Cyamopisis tetragonolobus(L.)Taub的磨碎胚乳，水溶性部分(85％)称为“guaran”(分子量为220000)，它是由(1-4)-β-D-吡喃甘露糖基单元与α-D-吡喃半乳糖基单元以(1-6)键合构成的直链聚糖。guaran中D-半乳糖与D-甘露糖之比为约1∶2。瓜耳胶已在亚洲栽培长达数个世纪并由于其增稠性能而主要用作食品和个人保键品中。它的增稠效果是淀粉的5-8倍。它的衍生物如那些含羟丙基或羟丙基三甲基氯化铵取代的衍生物已销售了十余年。瓜耳胶可从例如Rhone-Polulene(Cranbury，New Jersey)，Hercules，Inc.(Wilmington，Delaware)和TIC Gum，Inc，(Belcamp，Maryland)购得。
刺槐豆胶或角豆树胶是角豆树(Ceratonia Siliqua)种子的精制胚乳。这类植物胶中半乳糖与甘露糖之比为约1∶4。角豆树的栽培时间已很长了，在技术上是众所周知的。这类植物胶是可商购的。并可从TICGum，Inc.(Bekamp，Maryland)和Rhone-Polulene(Cranbury，NewJersey)购得。
他拉胶是从刺云实树(tara tree)的种子胶提取的，其中半乳糖与甘露糖之比为约1∶3。他拉胶在美国没有工业化生产，但可从美国以外的各种来源获得。
为了限制交联程度以得到较软的凝胶特性，可利用化学改性的半乳甘露聚糖如羟丙基瓜耳胶。不同取代度的化学改性半乳甘露聚糖可从Rhone-Polulene(Cranbury，New Jersey)商购。低摩尔(如低于0.6)取代的羟丙基瓜耳胶是特别优选的。
本发明组合物中也可添加其它成分，这类成分通常包括张力(tonicity)调节剂、螯合剂、药用活性物质、增溶剂、防腐剂、pH值调节剂以及载体。对于特定制备工艺来说，也可加入其它聚合物或单体如聚乙二醇和丙三醇。适用于本发明组合物的张力调节剂可包括盐类(如氯化钠、氯化钾以及氯化钙)，非离子型张力调节剂包括丙二醇和丙三醇，螯合剂可包括EDTA及其盐，增溶剂可包括CremophorEL和吐温80，其它载体可包括amberliteIRP-69，pH值调节剂可包括盐酸、三羟甲基氨基甲烷(Tris)、三乙醇胺和氢氧化钠以及适用的防腐剂可包括氯苄烷铵、聚季铵盐-1(polyquaternium-1)和聚亚己基双胍。上述实例只是说明性的，并不代表全部。适用于上述目的的成分的实例在眼用配方中是众所周知的也是本发明所预期的。
本发明的胶凝化系统与先有技术的胶凝化系统相结合也是本发明所预期的。这类系统可包括各种离聚物如黄原胶、gellan、鹿角菜胶和卡波姆以及热凝胶如乙基羟乙基纤维素。
一般来说，本发明组合物可用于将各种药用活性物质以滴入眼内方式给药，这类药物可包括(但不受此限制)：抗高血压药、抗青光眼药、神经保护药、抗过敏药、粘促分泌素(mucosecretagogue)、angiostatic、抗菌药、疼痛缓解药以及消炎药。
可用于本发明组合物中，并可经本发明方法给药的具有药用活性物质的实例包括(但不受此限制)：治青光眼药物(如倍他索洛尔、噻吗洛尔、毛果芸香碱、碳酸酐酶抑制剂和前列腺素(prostglamdins))，多巴胺能性拮抗剂，手术后抗高血压药(如对氨基可乐定(阿普尼定))，抗感染药(如环丙沙星和托普霉素)，非甾醇和甾醇类消炎药(如萘普生、双氯灭痛、舒洛芬、痛立消、四氢皮质甾醇和地塞米松)，蛋白质，生长因子(如表皮生长因子)以及抗过敏药。
任选的是，本发明组合物配方中可不包含药用活性物质，这类组合物可用来润滑眼睛或者为治疗如干燥性眼疾提供人造泪液。通常，人造泪液含有如上所述的张力调节剂、聚合物和防腐剂。如上所述，人造泪液中半乳甘露聚糖和硼酸盐的含量是可变的，但通常的用量分别为0.1-3.0(重量/体积)％和0.1-2.0(重量/体积)％。
通常，本发明组合物是分成两部分配制的，其一是经水化和灭菌的半乳甘露聚糖聚合物(第I部分)，其二是溶于水中和灭菌过滤的、要添加在组合物中的任何药用活性物质和/或其它成分(第II部分)。然后将第I部分与第II部分相混合，并调整所得混合物的pH值至规定值，一般为6.0-7.0。如果要添加的药用物质水溶性较低，则应在最后添加，在某些情况下，最好单独对药用物质进行灭菌处理，然后在无菌条件下将药用物质与其它成分合并在一起。
半乳甘露聚糖的灭菌处理可通过高压蒸汽灭菌法来实施。因为聚糖聚合物在高压蒸汽灭菌条件下会解聚，因而最好以非水性的高压加热处理。具体方法是将多糖聚合物分散在适用的有机液体如低分子量聚乙二醇中，然后将所得的悬浮液进行高压加热以对该聚合物灭菌。经灭菌的聚合物在与其它成分混合前应先在无菌条件下进行水化。
下面实施例说明对本发明半乳甘露聚糖进行灭菌的一种新颖方法。
实施例1
预备：一个混合容器(20升不锈钢压力罐)、一个0.2微米灭菌过滤器、一个接受容器(20升坛子)、一个4.5微米净化过滤器、一个0.2微米灭菌过滤器、一个排气过滤器及灌装设备都经高压蒸汽灭菌。
在上方装有搅拌器的烧杯中，添加已称重的聚乙二醇400(200克)，在搅拌下将已称重的羟丙基(“HP”)瓜耳胶(100克)缓慢分散在聚乙二醇中，直到完全混合均匀。准确称量120.0克HP瓜耳胶/PEG-400分散体于置有磁力搅拌子的500毫升Schott瓶中，准备用高压蒸汽灭菌。在第二个500毫升Schott瓶中也准确称入120.0克与上相同的分散体，用作高压蒸汽灭菌循环的标准样。向两个瓶中添加1.3毫升纯净水(相当于在有效性研究时，向两瓶接种微生物悬浮液的体积量)。将两个Schott瓶置于磁力搅拌台上混合10分钟。采用125℃、80分钟的有效时间-温度循环对HP瓜耳胶/PEG-400分散体进行高压蒸汽灭菌。
包括在最终配方中的其它成分可用技术上已知的各种方法分别制备。制成的混合物经无菌过滤滤入混合容器中，HP瓜耳胶/PEG-400制剂也进行无菌过滤。
在无菌条件下，将HP瓜耳胶/PEG-400分散体转移到已预灭菌的混合容器中。用无菌纯净水冲洗瓶内残留物并加入混合容器中，然后再向容器中补充室温无菌纯净水使容器内分散体准确地达到容器理论容量的95％(19.0升或19.06千克)。以中速混合容器中的HP瓜耳胶/PEG淤浆至少2小时。以使其水合。然后将容器中的物料通过4.5微米预先灭菌的净化过滤器转移至预先灭菌的置有搅拌子的接受容器中。过滤时由于物料在过滤器外壳和滤芯上的粘附因而会有某些损失，(如果以压力罐为混合容器，则推荐的澄清过滤压力为约30磅/平方英寸)。检查pH值并根据需要可用1N Na0H或1N HCl调节pH至6.9-7.1(目标为7.0)。为此，每升物料大约需3-4毫升1N NaOH才达到所要求的pH值。最后向物料补充适量的无菌纯净水至规定的批重量并慢速混和至少30分钟。
下列实施例进一步说明本发明优选的眼用组合物：
实施例2
下面是含噻吗心安的眼局部给药用组合物的一个实施例。
| 化合物 | 含量％(w/v) |
| 马来酸噻吗心安 | 0.68* |
| 硼酸 | 0.5 |
| 瓜耳胶 | 0.5 |
| PEG-400 | 1.0 |
| 氯化钠 | 0.5 |
| 氯苄烷铵 | 0.01 |
| 氢氧化钠/盐酸 | 适量至pH6.5 |
| 纯净水 | 适量 |
*0.68％马来酸噻吗心安相当于0.5％噻吗心安
上例配方是由先制备的第I部分与第II部分混合配制的。首先将瓜耳胶分散在PEG-400中并经高压蒸汽灭菌后作为第I部分；将其它成分溶解在约90(体积)％的水中并经灭菌过滤滤入接受容器中作为第II部分，然后在无菌条件下将第I部分添加到第II部分中。其后在无菌条件下调整pH值并直至最终的重量(体积)。最后，在无菌条件下让混合液通过1.0微米净化过滤器以除去粒状物。
实施例3
下面是含噻吗心安的眼局部给药用组合物的另一个实施例。
| 化合物 | 含量％(w/v) |
| 马来酸噻吗心安 | 0.34* |
| 硼酸 | 0.5 |
| 瓜耳胶 | 0.25 |
| 丙三醇 | 1.0 |
| 氯苄烷铵 | 0.005 |
| 氢氧化钠/盐酸 | 适量至pH7.0 |
| 纯净水 | 适量 |
*0.34％马来酸噻吗心安相当于0.25％噻吗心安
上列组合物可按与配制实施例2组合物相同的方法配制而成。
实施例4
下面是人造泪液的实施例。
| 化合物 | 含量％(w/v) |
| 硼酸羟丙基瓜耳胶丙二醇聚季铵盐-1氢氧化钠/盐酸纯净水 | 0.50.31.40.0005适量至pH6.8适量 |
上列组合物可按与配制实施例2组合物相同的的方法配制而成。
本发明有多种形态，不限于上述具体细节，在不违背本发明原理和不牺牲本发明优点的前提下，在附后的权利要求书范围内，对这些细节是可作各种变更的。
Claims (7)
1.一种适合用作眼用润滑剂或人造泪液组合物的无菌眼部药物组合物，该组合物包括0.1-3.0(重量/体积)％选自瓜耳胶及其衍生物的半乳甘露聚糖和0.1-2.0(重量/体积)％的硼酸盐化合物以及水。
2.权利要求1的组合物，其中硼酸盐化合物选自硼酸、硼酸钠、硼酸钾以及它们的混合物。
3.权利要求2的组合物，其中半乳甘露聚糖包括羟丙基瓜耳胶。
4.权利要求1的组合物，其中硼酸盐化合物包括硼酸。
5.权利要求1的组合物，其中半乳甘露聚糖包括羟丙基瓜耳胶，硼酸盐化合物包括硼酸。
6.权利要求1-5任一项的组合物，其中该组合物的pH值为微酸性至中性。
7.权利要求6的组合物，其中该组合物的pH值为6至7。
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| TWI486178B (zh) * | 2009-12-03 | 2015-06-01 | Alcon Res Ltd | 含有羧基乙烯基聚合物之奈米粒子懸浮液 |
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1998
- 1998-07-17 CN CNB98807690XA patent/CN1229110C/zh not_active Expired - Lifetime
- 1998-07-17 PT PT98936847T patent/PT999825E/pt unknown
- 1998-07-17 ES ES98936847T patent/ES2206965T3/es not_active Expired - Lifetime
- 1998-07-17 BR BRPI9811574-0A patent/BR9811574B1/pt not_active IP Right Cessation
- 1998-07-17 PT PT03014536T patent/PT1348427E/pt unknown
- 1998-07-17 AU AU85705/98A patent/AU737442B2/en not_active Expired
- 1998-07-17 DK DK98936847T patent/DK0999825T3/da active
- 1998-07-17 DE DE69839355T patent/DE69839355T2/de not_active Expired - Lifetime
- 1998-07-17 CA CA002296080A patent/CA2296080C/en not_active Expired - Lifetime
- 1998-07-17 US US09/423,762 patent/US6403609B1/en not_active Expired - Lifetime
- 1998-07-17 WO PCT/US1998/014596 patent/WO1999006023A1/en active IP Right Grant
- 1998-07-17 EP EP03014536A patent/EP1348427B1/en not_active Expired - Lifetime
- 1998-07-17 CN CNB2004100420023A patent/CN100408100C/zh not_active Expired - Lifetime
- 1998-07-17 KR KR10-2000-7000863A patent/KR100507984B1/ko not_active IP Right Cessation
- 1998-07-17 DE DE69818675T patent/DE69818675T2/de not_active Expired - Lifetime
- 1998-07-17 AT AT98936847T patent/ATE250923T1/de active
- 1998-07-17 CN CN200510113689XA patent/CN1762381B/zh not_active Expired - Lifetime
- 1998-07-17 AT AT03014536T patent/ATE391492T1/de active
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- 1998-07-22 ZA ZA986533A patent/ZA986533B/xx unknown
- 1998-07-29 AR ARP980103738A patent/AR013272A1/es active IP Right Grant
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1999
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2000
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2002
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2003
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2004
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2006
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2007
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2008
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2013
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- 2013-11-04 CY CY2013040C patent/CY2013040I2/el unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI486178B (zh) * | 2009-12-03 | 2015-06-01 | Alcon Res Ltd | 含有羧基乙烯基聚合物之奈米粒子懸浮液 |
| US9662398B2 (en) | 2009-12-03 | 2017-05-30 | Alcon Research, Ltd. | Carboxylvinyl polymer-containing nanoparticle suspensions |
| CN102860949A (zh) * | 2012-08-31 | 2013-01-09 | 马应龙药业集团股份有限公司 | 眼部抗皱护肤品及其制备方法 |
| CN102860949B (zh) * | 2012-08-31 | 2014-07-02 | 马应龙药业集团股份有限公司 | 眼部抗皱护肤品及其制备方法 |
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