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CN1263463C - 含有过氧化物源和阳离子型聚合物防腐剂的改进的眼科和隐型眼镜用溶液 - Google Patents

含有过氧化物源和阳离子型聚合物防腐剂的改进的眼科和隐型眼镜用溶液 Download PDF

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CN1263463C
CN1263463C CNB018218148A CN01821814A CN1263463C CN 1263463 C CN1263463 C CN 1263463C CN B018218148 A CNB018218148 A CN B018218148A CN 01821814 A CN01821814 A CN 01821814A CN 1263463 C CN1263463 C CN 1263463C
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弗朗西斯·泽维尔·史密斯
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Abstract

一种眼科用溶液，含有重量比为0.01-0.0001%过氧化物产生剂和0.1-500ppm阳离子型聚合物防腐剂。

Description

含有过氧化物源和阳离子型聚合物防腐剂的 改进的眼科和隐型眼镜用溶液
本申请要求于2000年11月8日提交的美国临时专利申请No.60/246,689、No.60/246,707、No.60/246,708和No.60/246,709的权益。
技术领域
本发明涉及到用于保护眼睛、将活性药物释入眼睛、处理直接与眼角膜组织接触的眼科器具的眼科用溶液。眼科用溶液用于定期维护和调节眼睛，并用于维护眼睛用的器具如隐形眼镜。由于这些溶液和眼角膜组织紧密接触，经常出现一些问题或担忧。例如，直接与角膜接触的溶液，其组织适应性是很重要的，不能产生伤害和刺激。这种组织适应性对于处理与角膜组织接触的器具如隐形眼镜等用的溶液而言也是很重要的。进一步讲，长期与眼角膜接触会导致异物在角膜组织上的积累，溶液长期与这些装置接触也最终会引起有害反应。
防腐剂的效果，是根据溶液减少细菌活力或真菌数量而定的。一般来讲，在溶液的防腐效能和眼角膜组织适应性以及“舒适性”之间希望有折衷方案。进一步地，本发明涉及的溶液防腐体系的外延更宽，不仅对细菌有效，还能抗真菌感染。
美国专利US 4,758,595(Ogunbiyi等)报道，将特定浓度的聚亚己基双胍(PHMB)及其水溶性盐加入含有一种特殊的缓冲试剂和一种表面活性剂的溶液中，能够达到基本的消毒效果，同时对眼睛和镜片无伤害。
国际专利公报WO 91/01763报道，含很低浓度过氧化物的溶液，如0.01-0.5％最好是0.05-0.2％的溶液，即使不在中性时也有消毒作用。应用本发明能极大地增强在如此低浓度过氧化物的杀菌效果。
本发明涉及到改进的眼科用溶液，其优点是增强了防腐和抗微生物的效能。特别是溶液中含有低浓度的聚亚己基双胍(PHM)和一种过氧化物源，比起目前工艺水平的眼科用溶液，能增强防腐和抗菌效果。
发明内容
本发明涉及到眼科用溶液，与目前工艺水平的产品相比，作用范围更宽，有效浓度更低。特别要指出的是，研究发现：含有重量比为0.01-0.0001％过氧化物产生剂和0.1-500ppm阳离子型聚合物防腐剂的眼科用溶液具有有效的防腐能力，与目前工艺水平的防腐溶液相比，性能更佳。
本发明还涉及到在其使用时利用这种溶液的制品。例如，用于储藏供销售的隐形眼镜的小瓶，其内装有该溶液。
本发明涉及到眼科用溶液，与目前工艺水平的产品相比，作用范围更宽，有效浓度更低。特别要指出的是，研究发现：含有重量比为0.01-0.0001％过氧化物产生剂和0.1-500ppm阳离子型聚合物防腐剂的眼科用溶液具有改进的有效防腐能力，与目前工艺水平的防腐溶液相比，性能更佳。
过氧化物源包括双氧水、过硫酸钠、十水过硼酸钠、过氧化钠、过氧化脲、过氧乙酸和一种有机过氧化物。
阳离子型聚合物防腐剂包括聚双胍类物质如聚亚己基双胍(PHMB)及其复合物。这些阳离子型聚合物双胍类物质及其水溶性盐，具有如下分子结构
式中Z是一个有机双价桥基团，在整个聚合物中可以相同，也可以不同；n的平均数不少于3，最好是5-20；X1和X2是
-NH2和
Figure C0182181400051
一组水溶性聚双胍类物质的平均分子量至少在1,000以上，最好是平均分子量1,000-50,000。这些游离碱所形成的合适的水溶性盐类物质包括但不限于盐酸盐、硼酸盐、醋酸盐、葡糖酸盐、硫酸盐、酒石酸盐和柠檬酸盐等。
如上所示的双胍类物质及制备方法在文献中有描述。例如，美国专利US 3,428,576记述了由一个二胺及其盐和一个双氰亚胺的二胺盐制备出聚双胍的方法。
大多数情况下，优先使用商品化的亚己基双胍聚合物，例如Zeneca(Wilmington.Del.)公司的商标为Cosmocil TM CQ的盐酸盐。这些聚合物及水溶性盐是指聚亚己基双胍(PHMB)或聚氨基丙基二胍(PAPB)。这里使用的这类聚亚己基双胍，意味着包含有一个或多个双胍基团，具有下面分子式：
式中Z、X1和X2如上所述，n为1-500。
取决于双胍类物质的制备方式，在上述分子式内占主导的化合物可以有不同的X1和X2基团，也可是相同基团。其它分子结构的化合物较少。这些化合物是已知的并在美国专利US 4,758,595和英国专利1,432,345中都有记述，这里将两个专利合并介绍。最好，水溶性盐是其n平均值在2-15，最好是3-12的化合物。
在一个具体实例中，一个聚合双胍与一个二聚双胍化合物复合使用。聚合双胍类化合物在与二聚双胍如1，1’-六亚甲基-二(5-[2-乙基己基]双胍)复合使用时，即使在浓度低到0.00001％(0.1ppm)时也有效果。研究也发现，当这些聚合双胍类物质与1，1’-六亚甲基-二(5-[2-乙基己基]双胍)或类似物复合使用时，抗菌活性更强，抗菌谱更广。
可以用别的非双胍类杀菌剂作为溶液的防腐剂，但它也可以具有强化另一种杀菌剂的杀菌效果、增加杀菌活性范围的功能。该物质具有杀菌剂的杀菌效果值，与溶液有相容性并且不会沉淀析出。其使用浓度范围为重量比0.00001-0.5％，最好是0.0001-0.1％。合适的杀菌补充剂包括但不限于季铵盐类化合物或聚合物、乙基汞水杨酸钠或苯基汞化卤、山梨酸、烷基三乙醇胺及它们的混合物。季铵盐化合物具有代表性的例子是与卤代洁尔灭的复合产物，比如正烷基二甲苯基苯基铵盐盐酸盐的平衡混合物。其它的例子包括眼科用的聚季铵盐如聚[(二甲基亚氨基)-1，4-二氯代-2-丁烯]、二氯代[(4-三(2-羟基乙基)铵)-2-丁烯基-[三(2-羟基乙基)铵](化合物登记号75345-27-6)，这些化合物大都从ONYX公司购买的聚季铵盐1(r)，也包括美国专利US 6,153,568记述的化合物。
与本配方中使用的杀菌剂形成盐的酸根来源于无机酸或有机酸。大多数情况下这些酸要保证形成的盐溶于水并且能提供阴离子，以利于人们使用，比如是药物允许的阴离子。这些酸包括盐酸、氢溴酸、磷酸、硫酸、醋酸、D-葡萄糖酸、2-吡咯烷-5-羧酸、甲磺酸、碳酸、乳酸和谷氨酸。
本发明溶液配方中也包括过氧化物源，比如双氧水等化合物，能够有效地提供一定量的过氧化氢，它门包括十水过硼酸钠、过氧化钠、过氧化脲、过氧乙酸和一种有机过氧化物等。
本发明溶液的pH值应当维持在5.0-8.0的范围，6.0-8.0比较好，最好是6.5-7.8。溶液中可以加入合适的缓冲试剂，比如硼酸、硼酸钠、柠檬酸钾，柠檬酸、碳酸氢钠、BIS-Tris Propane、TRIS及多种混合磷酸盐缓冲试剂(包括磷酸氢二钠、磷酸二氢钠和磷酸二氢钾的混合物)或它们的混合物。硼酸缓冲试剂用于增强PAPB的杀菌效果。一般来讲，缓冲试剂的加入量按重量比应在0.05-2.5％的范围内，最好是0.1-1.5％。
本发明的溶液中还可进一步包含有其它添加剂，这些添加剂包括但不限于缓冲试剂、张力剂、缓和剂、润湿剂、防腐剂、螯合剂、表面活性剂和酶等。
本发明中使用的眼科允许的螯合剂包括氨基酸类化合物或其形成的水溶盐，它们有乙二胺四醋酸(EDTA)、次氮基三醋酸、二乙基三乙胺五醋酸、羟乙基乙二胺三醋酸、1，2-二氨基环己基四醋酸、乙二醇双乙胺醚-N，N’-四乙酸(EGTA)、氨基二醋酸和羟乙基氨基二醋酸。这些酸可以以其水溶性盐，尤其是碱金属盐的形式使用。特别要指出的是，乙二胺四醋酸的二钠、三钠和四钠盐作为螯合剂效果较好，最好是EDTA二钠。
其它螯合剂如柠檬酸、多聚磷酸盐也可以在本发明中使用。本发明中使用的柠檬酸盐包括柠檬酸及其单、双和三碱金属盐。使用的多聚磷酸盐包括焦磷酸盐、三聚磷酸盐、四聚磷酸盐、三聚偏磷酸盐、四聚偏磷酸盐以及更高聚合度的磷酸盐。这些磷酸盐都以中性或酸性碱金属盐形式加入，比如钠盐、钾盐和铵盐。
本发明的溶液在贮藏、清洁、润湿、漂洗、浸泡和消毒时与渗透性刚性气体和亲水性隐形眼镜及其它眼科用装置仪器是相适应的。
本发明的一个典型的水溶液中可以添加某些组分，它们不影响上面所提到的活性成分的基本特征和新颖特点。例如张力剂、表面活性剂和增稠剂，它们有助于清洗隐形眼镜，或能润滑眼睛。合适的张力剂包括氯化钠，氯化钾，甘油或其它混合物。溶液的张力剂加入量可以按每公斤溶液大约240-310毫渗透分子(mOsm/kg)的量进行调节，用以保障溶液与视觉组织和亲水性隐形眼镜相适应。在一个具体例子中，溶液中含有0.01-0.5％重量比的氯化钠。
本发明的溶液中还可包含有表面活性剂，比如聚氧乙烯-聚氧丙烯非离子表面活性剂，例如可以从一组《CTFA国际化妆品成分词典》命名为Poloxamine或Poloxamer的商品中挑选。Poloxamine表面活性剂由聚烃氧基-聚烃氧基丙烯和乙烯基二胺加合而成，分子量由7,500到27,000，其中前者40％以上成分是聚烃氧基乙烯。研究发现，表面活性剂含量在重量比约0.01-15％的溶液在用于调节隐形眼镜时很有优点。这些表面活性剂可以从BASF Wyandotle Corp.(Wyandotle，Mich.)公司购买，其注册商标是“Tetronic”。Poloxamer是一个类似的表面活性剂系列，有聚氧乙烯、聚氧丙烯聚合物胶，可以从BASF Wyandotte Corp.(Parsippany，N.J.07054)公司购买，商标为“Pluronic”。
众所周知，表面活性剂的HLB值是评价一种非离子表面活性剂乳化性特征的重要因素。一般情况下，表面活性剂的HLB值越低，其亲油性越强；反之，HLB值越高，表面活性剂的亲水性就越强。BASF WyandotteCorp.(Wyandotte，Mich.)公司的各种Poloxamine和Poloxamer都给出了HLB值。本发明中使用的表面活性剂基于BASF公司报道的HLB值不低于18，最好是18-32。
已知是可用在润湿或反复润湿的溶液的相容性添加表面活性剂，也可以在本发明的溶液中使用。表面活性剂应能溶于镜片维护溶液并且不刺激眼睛组织。令人满意的非离子表面活性包括聚乙烯乙二醇脂肪酸酯如椰子油、聚山梨醇酯、聚氧乙烯或聚氧丙烯的长链烷基(C12-C18)醚。这类化合物包括聚山梨醇酯20(可以从ICI Americas Inc.，Wilmington，Del.19897公司购买，注册商标Tween20)、聚氧乙烯(23)月桂基醚(Brij35)、聚氧乙烯(40)硬脂酸酯(Myrj52)、聚氧乙烯(25)丙二醇硬脂酸酯(AtlasG2612)。其中Brij35、Myrj52、和AtlasG2612都是注册商标，它们都可以从ICI Americas Inc.，Wilmington，Del.19897公司购买。
其它各种表面活性剂都可以很方便地确定是否适用于本发明，方法如前所述。可以参照工具书McCutcheon’s Detergents and Emulsifiers.(NorthAmerican Edition，McCutcheon Divison，Mc Publishing Co.，Glen Rock，N.J.07452)和国际化妆品成分手册(CTFA International Cosmetic IngredientHandbook.Published by The Cosmetic，Toiletry and Fragrance Association，Washington，D.C.)。但是，比较好的表面活性剂是市售的BASF公司注册商标为Cremaphortm的表面活性剂，它们都是聚烃氧基乙氧基蓖麻油。
合适的增稠剂包括卵膦脂或纤维素衍生物，比如羟甲基纤维素、羟丙基纤维素和甲基纤维素。其加入量与上面提到的表面活性剂用量相似。
具体实施方式
例1
制备一份含有0.1％ Pluronic F127和2％甘油的水溶液，pH值调节到pH 7.65。将聚亚己基双胍(PHMB)加入到一半溶液中，并使其最终浓度为1ppm。另外制备一份含60ppm双氧水、0.1％ Pluronic F127和2.3％甘油的水溶液，pH值调节到pH 7.35。将PHMB加入到一半的溶液中，并使其最终浓度为1ppm。
检测这些溶液的抗金黄色葡萄球菌(S.aureus)和白色棒状杆菌(C.albicans)的活性。数据概括如下表：
  配方   S.aureus 4小时   C.albicans 4小时
  无防腐剂   0.05   -0.09
  PHMB   4.03   2.40
  双氧水   1.95   1.06
  PHMB+双氧水   ＞4.73   3.08
  市售产品1#   ＞4.73   0.54
  市售产品2#   ＞4.73   2.57
其中，市售产品1#的组方是：无菌的等渗透压的水溶液中含有氯化钠、聚氧乙烯-聚氧丙烯聚合物胶、磷酸氢二钠、磷酸二氢钠，且用0.025％的二水EDTA二钠和0.0001％的聚己酸酐防腐。
市售产品2#的组方是：无菌的等渗透压的溶液中含有HYDRANATE(羟基烷基卵膦脂)、硼酸、EDTA二钠、poloxamine、硼酸钠、氯化钠，用0.0001％ DYMED(聚氨基丙基双胍)防腐。
这个试验结果表明：聚亚己基双胍与双氧水复合使用，能增强溶液的抗金黄色葡萄球菌和白色棒状杆菌活性，其效果优于两种市售产品。
例2
                       PHMB-过氧化物
制备本组方溶液时，将L-组氨酸或Bis-Tris Propane溶于水，用1N盐酸将溶液的pH值调节至7.3。加入双氧水、Dequest 2010和聚亚己基双胍盐酸盐(PHMB)。用水稀释至特定体积。将白色棒状杆菌(C.albicansATCC 10231)接入每种溶液中，两小时后检测各种溶液的灭菌活性。灭菌活性是用起始培菌液的对数下降值来确定的。每种溶液的组方、浓度及抗菌活性总结如下表：
  对数下降值   防腐剂   缓冲试剂   双氧水  Dequest2010
  1.59   Bis-tris propane0.2％   无   无  0.006％
  2.05   Bis-tris propane0.2％   无   0.006％  0.006％
  1.25   L-组氨酸   无   无  0.006％
  0.2％
  1.85   L-组氨酸0.2％   无   0.006％   0.006％
结果表明：聚亚己基双胍与双氧水复合使用可以提高溶液的抗白色棒状杆菌活性。
例3
                        PHMB-
制备本组方溶液时，将L-组氨酸、Bis-Tris Propane或三羟甲基甲基甘氨酸(Tricine)溶于水，用1N盐酸将溶液的pH值调节至7.3。加入甘油、双氧水、Dequest2010和聚亚己基双胍盐酸盐(PHMB)。用水将溶液稀释至特定体积。将白色棒状杆菌(C.albicans ATCC 10231)接入每种溶液中，两小时后检测各种溶液的灭菌活性。灭菌活性是用起始培菌液的对数下降值来确定的。每种溶液的组方、浓度及抗菌活性总结如下表：
  对数下降值   防腐剂   缓冲试剂   甘油   双氧水  Dequest2010
  1.60   PHMB0.0001％   L-组氨酸0.2％   无   无  无
  2.38   PHMB0.0001％   L-组氨酸0.2％   无   0.006％  无
  1.27   PHMB0.0001％   L-组氨酸0.2％   无   无  0.006％
  2.25   PHMB0.0001％   L-组氨酸0.2％   无   0.006％  0.006％
  1.08   PHMB0.0001％   L-组氨酸0.2％   无   无   0.003％
  2.04   PHMB0.0001％   L-组氨酸0.2％   无   0.006％   0.003％
  1.57   PHMB0.0001％   L-组氨酸0.2％   0.50％   无   无
  2.15   PHMB0.0001％   L-组氨酸0.2％   0.50％   0.006％   无
  1.25   PHMB0.0001％   L-组氨酸0.2％   0.50％   无   0.006％
  2.04   PHMB0.0001％   L-组氨酸0.2％   0.50％   0.006％   0.006％
  1.08   PHMB0.0001％   L-组氨酸0.2％   0.50％   无   0.003％
  1.93   PHMB0.0001％   L-组氨酸0.2％   0.50％   0.006％   0.003％
  2.80   PHMB0.0001％   Bis-TrisPropane 0.2％   无   无   无
  3.69   PHMB0.0001％   Bis-TrisPropane 0.2％   无   0.006％   无
  2.20   PHMB0.0001％   Bis-TrisPropane 0.2％   无   无   0.006％
  3.18   PHMB0.0001％   Bis-TrisPropane 0.2％   无   0.006％   0.006％
2.18 PHMB0.0001％ Bis-TrisPropane 0.2％ 无 无   0.003％
  3.05   PHMB0.0001％   Bis-Tris   无   0.006   0.003％
  Propane 0.2％   ％
  2.78   PHMB0.0001％   Bis-TrisPropane 0.2％   0.50％   无   无
  3.32   PHMB0.0001％   Bis-TrisPropane 0.2％   0.50％   0.006％   无
  2.29   PHMB0.0001％   Bis-TrisPropane 0.2％   0.50％   无   0.006％
  3.29   PHMB0.0001％   Bis-TrisPropane 0.2％   0.50％   0.006％   0.006％
  2.13   PHMB0.0001％   Bis-TrisPropane 0.2％   0.50％   无   0.003％
  3.31   PHMB0.0001％   Bis-TrisPropane 0.2％   0.50％   0.006％   0.003％
  1.64   PHMB0.0001％   Tricine 0.2％   无   无   无
  2.05   PHMB0.0001％   Tricine 0.2％   无   0.006％   无
  1.16   PHMB0.0001％   Tricine 0.2％   无   无   0.006％
  1.76   PHMB0.0001％   Tricine 0.2％   无   0.006％   0.006％
  1.17   PHMB0.0001％   Tricine 0.2％   无   无   0.003％
  1.78   PHMB0.0001％   Tricine 0.2％   无   0.006％   0.003％
结果表明，每对组方溶液在加入0.006％双氧水时可以提高抗白色棒状杆菌活性。同时试验数据显示溶液抗菌活性的增加并不依赖于Dequest2010。
例4
                PHMB-过氧化物
制备本组方溶液时，将Tricine、柠檬酸、N-二(羟乙基)甘氨酸、L-组氨酸、甘氨酸、或赖氨酸溶于水中。用1N盐酸将溶液的pH值调节至7.3。加入双氧水、Dequest2010和聚亚己基双胍盐酸盐(PHMB)。用水将溶液稀释至特定体积。将白色棒状杆菌(C.albicans ATCC 10231)接入每种溶液中，两小时后检测各种溶液的灭菌活性。灭菌活性是用起始培菌液的对数下降值来确定的。每种溶液的组方、浓度及抗菌活性总结如下表：
  对数下降值   防腐剂   缓冲试剂   双氧水   Dequest2010
  1.90   PHMB0.0001％   Tricine 0.2％   无   无
  2.09   PHMB0.0001％   Tricine 0.2％   0.006％   0.003％
  0.25   PHMB0.0001％   柠檬酸0.2％   无   无
  0.70   PHMB0.0001％   柠檬酸0.2％   0.006％   0.003％
  2.01   PHMB0.0001％   N-二(羟乙基)甘氨酸0.2％   无   无
  2.47   PHMB0.0001％   N-二(羟乙基)甘氨酸0.2％   0.006％   0.003％
  2.01   PHMB0.0001％   组氨酸0.2％   无   无
  2.42   PHMB0.0001％   组氨酸0.2％   0.006％   0.003％
  1.94   PHMB0.0001％   甘氨酸0.2％   无   无
  2.89   PHMB0.0001％   甘氨酸0.2％   0.006％   0.003％
  2.69   PHMB0.0001％   赖氨酸0.2％   无   无
  2.84   PHMB0.0001％   赖氨酸0.2％   0.006％   0.003％
结果显示，聚亚己基双胍—双氧水复合组方溶液的抗菌性能比较强。
例5
                      PHMB-过氧化物
制备本组方溶液时，将Bis-Tris Propane、L-组氨酸或三羟甲基甲基甘氨酸(Tricine)溶于水中。用1N盐酸将溶液的pH值调节至7.3。加入张力剂、双氧水、Dequest2010和聚亚己基双胍盐酸盐(PHMB)。用水将溶液稀释至特定体积。将白色棒状杆菌(C.albicans ATCC 10231)接入每种溶液中，两小时后检测各种溶液的灭菌活性。灭菌活性是用起始培菌液的对数下降值来确定的。每种溶液的组方、浓度及抗菌活性总结如下表：
  对数下降值   防腐剂   缓冲试剂   张力剂   润湿剂   双氧水   Dequest2010
  3.85   PHMB0.0001％   Bis-TrisPropane 0.2％   无  CremophorRH 40   无   无
  4.70   PHMB0.0001％   Bis-TrisPropane 0.2％   无  CremophorRH 40   0.006％   0.003％
  2.42   PHMB   L-组氨酸   无  Cremophor   无   无
  0.0001％   0.2％  RH 40
  3.34   PHMB0.0001％   L-组氨酸0.2％   无  CremophorRH 40   0.006％   0.003％
  2.17   PHMB0.0001％   Tricine   无  CremophorRH 40   无   无
  2.69   PHMB0.0001％   Tricine   无  CremophorRH 40   0.006％   0.003％
  3.70   PHMB0.0001％   Bis-TrisPropane 0.2％   甘油3％  CremophorRH 40   无   无
  4.40   PHMB0.0001％   Bis-TrisPropane 0.2％   甘油3％  CremophorRH 40   0.006％   0.003％
  2.19   PHMB0.0001％   L-组氨酸0.2％   甘油3％  CremophorRH 40   无   无
  2.94   PHMB0.0001％   L-组氨酸0.2％   甘油3％  CremophorRH 40   0.006％   0.003％
  2.19   PHMB0.0001％   Tricine   甘油3％  CremophorRH 40   无   无
  2.45   PHMB0.0001％   Tricine   甘油3％  CremophorRH 40   0.006％   0.003％
  2.19   PHMB0.0001％   L-组氨酸0.2％   丙二醇3％  CremophorRH 40   无   无
  2.95   PHMB0.0001％   L-组氨酸0.2％   丙二醇3％  CremophorRH 40   0.006％   0.003％
  4.40   PHMB0.0001％   Bis-TrisPropane 0.2％   山梨糖醇5％  CremophorRH 40   无   无
  4.70   PHMB0.0001％   Bis-TrisPropane 0.2％   山梨糖醇5％  CremophorRH 40   0.006％   0.003％
  3.36   PHMB0.0001％   L-组氨酸0.2％   山梨糖醇5％  CremophorRH 40   无   无
  3.92   PHMB0.0001％   L-组氨酸0.2％   山梨糖醇5％  CremophorRH 40   0.006％   0.003％
  2.54   PHMB0.0001％   L-组氨酸0.2％   肌醇5％  CremophorRH 40   无   无
  3.08   PHMB0.0001％   L-组氨酸0.2％   肌醇5％  CremophorRH 40   0.006％   0.003％
试验数据显示，加入0.006％的双氧水能提高聚亚己基双胍的抗菌功效。在溶液中含有Cremophor RH 40、组氨酸、Tricine、Bis-Tris Propane、甘油、丙二醇和山梨糖醇时，结论是一致的。

Claims (4)

1、一种眼科用溶液，含有重量比为0.01-0.0001％的双氧水和0.1-500ppm的聚亚己基双胍。
2、如权利要求1的溶液，其特征是，还含有重量比为0.05-2.5％的缓冲试剂，所述缓冲试剂选自：硼酸、硼酸钠、柠檬酸钾、柠檬酸、碳酸氢钠、Tris、磷酸二氢钠、磷酸氢二钠和磷酸二氢钾及它们的混合物。
3、如权利要求2的溶液，其特征是，还进一步含有一种表面活性剂。
4、一种隐形眼镜药水瓶，包括：一个药水瓶；一副隐形眼镜；足以浸没所述隐形眼镜的溶液，其中溶液含有重量比为0.01-0.0001％的双氧水和0.1-500ppm聚亚己基双胍。
CNB018218148A 2000-11-08 2001-11-08 含有过氧化物源和阳离子型聚合物防腐剂的改进的眼科和隐型眼镜用溶液 Expired - Fee Related CN1263463C (zh)

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WO2002040062A3 (en) 2002-09-06
JP2013122609A (ja) 2013-06-20
DE60135478D1 (de) 2008-10-02
AU2002225950B2 (en) 2006-08-10
CY1110596T1 (el) 2015-04-29
JP5923211B2 (ja) 2016-05-24
CA2428994A1 (en) 2002-08-15
JP2016040613A (ja) 2016-03-24
EP1992340A1 (en) 2008-11-19
CY1108438T1 (el) 2014-04-09
AU2002251685B8 (en) 2006-06-15
EP1339414A4 (en) 2006-03-15
US20060078626A1 (en) 2006-04-13
EP1339414B1 (en) 2010-01-06
PT1337262E (pt) 2008-10-24
AU2595002A (en) 2002-05-21
DK1339414T3 (da) 2010-04-19
ES2337446T3 (es) 2010-04-26
AU3954502A (en) 2002-05-27
JP2004526186A (ja) 2004-08-26
PT1339414E (pt) 2010-03-03
JP5258139B2 (ja) 2013-08-07
DK1337262T3 (da) 2008-12-15
WO2002038077A3 (en) 2002-07-25
ATE406167T1 (de) 2008-09-15
DK1331902T3 (da) 2008-12-08
CN1212847C (zh) 2005-08-03
CN1486187A (zh) 2004-03-31
AU2002251685B2 (en) 2005-10-27
CA2434961A1 (en) 2002-05-16
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JP5301498B2 (ja) 2013-09-25
DE60135572D1 (de) 2008-10-09
CA2434961C (en) 2010-05-25
CN1505520A (zh) 2004-06-16
ATE405265T1 (de) 2008-09-15
JP2010266867A (ja) 2010-11-25
EP1337262A2 (en) 2003-08-27
ATE454157T1 (de) 2010-01-15
JP2004512901A (ja) 2004-04-30
CN1212848C (zh) 2005-08-03
ES2578679T3 (es) 2016-07-29
ES2311555T3 (es) 2009-02-16
EP1331902A4 (en) 2006-02-08
DE60141039D1 (de) 2010-02-25
EP1992340B1 (en) 2016-05-11
JP5868338B2 (ja) 2016-02-24
CA2428994C (en) 2010-05-11
CA2428997A1 (en) 2002-05-23

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