CN1486187A - 眼科用溶液中加入l-组氨酸 - Google Patents

眼科用溶液中加入l-组氨酸 Download PDF

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CN1486187A
CN1486187A CNA018218164A CN01821816A CN1486187A CN 1486187 A CN1486187 A CN 1486187A CN A018218164 A CNA018218164 A CN A018218164A CN 01821816 A CN01821816 A CN 01821816A CN 1486187 A CN1486187 A CN 1486187A
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histidine
hydrogen peroxide
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��ά�����ᡤʷ��˹
弗朗西斯·泽维尔·史密斯
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Abstract

本发明涉及一种眼科用水溶液，该溶液含有重量比为0.01－1.0％的L－组氨酸、0.01－0.0001％双氧水、0.1－500ppm某种阳离子型聚合物防腐剂，该防腐剂特别在抗真菌方面具有优良的抗菌活性。该溶液可用于多种用途，包括清洁隐形眼镜、漂洗眼睛中的镜片、贮藏镜片、用于眼睛释药的溶液。

Description

眼科用溶液中加入L-组氨酸
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
本发明涉及到用来维护眼睛、贮藏隐形眼镜或调节眼科医疗器具的眼科用溶液。众所周知，这类溶液在市场上有大量产品销售。有几种类型的溶液用于特殊用途。例如，隐形眼镜消毒溶液、隐形眼镜清洁溶液、隐形眼睛表面护理溶液、镜片漂洗溶液和眼睛润湿溶液等。
背景技术
由于这些镜片都是出于某种特殊用途而制造的，每种相应溶液也是为其消除眼睛感染源而制备的。解决这一感染问题的方法有许多，包括将溶液进行灭菌和将溶液装进容器中以避免污染；溶液中加入足够浓度的特殊防腐剂以避免微生物繁殖；同时可使用光辐射和加入氧化剂的办法。在采用化学试剂时，人们倾向于在溶液中加入一种防腐剂。研究发现，比起目前工艺水平加入单一防腐试剂的溶液，采用两种或更多种试剂复合物的溶液明显具有更强的防腐性能，尤其是采用一种阳离子型聚合物防腐剂、双氧水和L-组氨酸的复配试剂时，能增强溶液抗真菌污染的防腐效果。
这种明显效果在进一步采用某些(但非全部)隐形眼镜保护溶液制剂时可体现出来。特别要指出的是，溶液中应避免加入那些能够降低防腐剂功效的张力剂。
据美国专利US 4,029,817描述，亲水性的塑料材料可用于制造软质隐形眼镜。Seiderman的美国专利US 3,503,393和Wichterle的专利US2,976,576记述了在有水反应介质中制备聚羟基乙基异丁酸酐的亲水性聚合物的方法，这个聚合物具有较少交联度聚合水凝胶结构，是有弹性、柔软、透明的水凝胶。别的软性隐形眼镜由硅酮或其它合适材料制成。
在眼科方面，亲水性镜片尤其有用，这是因为它们有吸水性并膨胀成具有良好机械性能的软性物质，透明性好，同时在眼中取出后在目镜溶液和贮藏溶液中平衡时能保持其形状和大小。
但是，软质隐形眼镜的一个问题是它们的灭菌和清洁问题。亲水性软质隐形眼镜允许吸收大量水的特点，也允许吸收不然可用来清洁和灭菌的防腐剂，之后还会释入眼睛。而且，释放速度比吸收速度慢得多，因而防腐剂在镜片中能累积。这就会导致隐形眼镜的损害和污染，或者对敏感组织如结膜产生危害。
如R.E.，Phares在美国专利US 3,689,673中陈述的，亲水性软质隐形眼镜的灭菌，可以将其浸入一种含0.001-0.01％洗必泰的水溶液中并维持足够长的时间来达到。
其它美国专利涉及到不同的方法。美国专利US 3,591,329介绍的方法使用了浸有活性金属银的一种阳离子交换树脂；US 3,755,561的方法使用了一种含有聚乙烯基吡咯烷酮、一种聚烃基乙二醇和乙基汞硫代水杨酸钠的水溶液；US 3,873,696公开一种使用氯化钠与过一硫酸钾组合的溶液；US 3,876,768中使用了与次氯酸盐相似的氯化磷酸三钠；US 3,888,782中使用了洗必泰和聚乙烯基吡咯烷酮；US 3,911,107中使用了一种含有碘、聚乙烯醇和硼酸的碘仿溶液；US 3,912,450使用了含有一种表面活性剂的戊二醛乙醇溶液，并配有超声波仪。
US 3,888,782特别地介绍了一种水溶液，实质上是一种用于塑胶质亲水性软质隐形眼镜清洗和灭菌的等渗透压溶液，含有洗必泰和聚乙烯基吡咯烷酮等活性成分。据说该溶液对软质隐形眼镜配戴者的眼睛无毒害，当加入一定量的水溶性聚羟基乙基异丁酸酯时，可以避免隐形眼镜表面不透明物的沉淀积累。
US 4,029,817介绍了一种用于软质隐形眼镜灭菌的产品，这是一种无菌的水溶液，实质上是含一种活性成分为季铵盐化合物的等渗透压溶液。
美国专利US 4,758,595介绍了一种具有抗微生物或真菌活性的防腐溶液，是加入一定量双胍或其水溶性盐的缓冲溶液，但没有意识到需要给出宽谱范围的防腐效果。
US 4,361,548介绍的隐形眼镜灭菌和/或防腐溶液，含有重量比0.00001-0.1％氯化二甲基二烯丙基铵单聚物(分子量从10,000到1,000,000)，或选地加入重量比高达0.5％乙二胺四醋酸或其它防腐增强剂及缓冲试剂，但也没有提到一种多成分的防腐剂。
US 4,354,952报道了一种隐行眼镜用的灭菌和/或防腐溶液，溶液中含有重量比0.0035-0.04％的两性离子表面活性剂，组合有0.0005-0.01％的洗必泰、0.002-0.025％的非离子表面活性剂，可选地加入重量比低于0.5％的乙基汞硫代水扬酸钠或其它防腐增强剂和缓冲试剂等。虽然公开了一种含多种防腐剂的溶液体系，但并没有提及该体系具有多于累积的优点。
US 5,741,817概要地提及了氨基酸的使用，但该发明只涉及到甘氨酸与特定抗菌防腐剂的复配使用，而不是本发明的采用的特殊试剂。
U.S.Pat.No.6,022,732指出，以双氧水为有效成分的镜片消毒溶液是通过过氧化氢的还原体现其功效的。尤其是该专利介绍了用于分解含水液体介质如隐形眼镜消毒液中过氧化氢的组方及其使用方法。在一具体例子中，组方中含有一种有效分解过氧化氢的成分，当其释入含双氧水的液体水溶介质中时，能够分解或引起分解在含双氧水的液体水溶介质中的过氧化氢。该组方还含有一阻止剂成份，主要用来阻止过氧化氢分解的成份在该成份最初与该含双氧水的液体水溶介质接触后的一段时间内的释放。这一阻止剂成分包括从一组水溶性纤维素、纤维素衍生物或其混合物中选取的材料，分子量不低于20,000。该组方相对于一类似组方在其和该类似组方作用于相同的含双氧水的液体水溶介质以分解或引起其中的过氧化氢的分解时，可减少泡沫形成，其中，该类似组方具有一种阻止剂成分，包括分子量为10,000的类似材料。
类似地，US 5,660,862介绍了一个隐形眼镜消毒用的组方溶液，包括大体上是等渗透压的水溶液体介质，含双氧水有效成分以对与该水溶液体介质接触的隐形眼睛消毒，以及一定量溶于该水溶液体介质的过氧化氢还原剂，以增强该水溶液体介质的抗菌活性。组方中最好还进一步含有过渡金属离子，在有效浓度下能增强水溶液介质的抗微生物活性，且实质上是不含过氧化物酶的。
美国专利US 5,854,303介绍了一种聚合物材料，它与一种多价阳离子型螯合剂联用能抑制眼科病原体，尤其是原生动物的生长繁殖，可用于生产眼睛保护产品如隐形眼镜和用于容纳眼睛保护溶液和隐形眼镜的容器。
US 4,863,900介绍了一种减少病毒感染传染性的组方产品，它包含有一个典型适用的和药物允许的载体，其抗病毒有效成分是一种有24到500个氨基酸残基的多肽，该多肽含至少24个L-组氨酸残基。该专利中未曾提到L-组氨酸可用来与其它抗菌试剂合用以提高其效果。
US 5,741,817指出，甘氨酸能提高防腐剂的抗菌活性，可以用于眼科溶液并可用于替代乙二胺四醋酸(EDTA)，而US 5,494,937报道的溶液中含有甘氨酸和硼酸酯聚醇混合物、一种或数种阴离子或非离子表面活性剂、低分子量的氨基酸(如甘氨酸)。该体系中不含EDTA，而是含有抗菌性的表面活性剂。该专利特别提到了甘氨酸。
US 5,925,317进一步报道了向中性碘中加入组氨酸的两步方法，用以避免镜片污染。该专利指出“不知道人们以前已建议将组氨酸用于隐形眼镜维护产品，尽管Schutle，L.等在论文中讨论了过量碘对组氨酸的氧化作用”(The Substitution Reaction of Histidine and  Some Other ImidazoleDerivatives With Iodine.Tetrahedron，Suppl.7，pp.295-306(1965))。使用咪唑类化合物如组氨酸的一个缺点是形成的氧化产物会降解成褐色的分解产物。
US 6,008,195则将L-组氨酸用作聚合物抗菌剂的有效成份的侧链基团。
发明内容
本发明涉及到一种眼科用水溶液，该溶液含有重量比为0.01-1.0％L-组氨酸、0.01-0.0001％双氧水、0.1-500ppm某种阳离子型聚合物防腐剂，该防腐剂特别在抗真菌方面具有优良的抗菌活性。该溶液可用于多种用途，包括清洁隐形眼镜、漂洗眼睛中的镜片、贮藏镜片、用于眼睛释药的溶液。
本发明溶液中还进一步加入表面活性剂，该表面活性剂可从那些已知工业品中选取，最好是一种羟基乙氧基蓖麻油。
本发明溶液可用于眼睛释药制剂，即将药剂加入溶液中，形成眼药水，再滴入眼中。也可以通过隐形眼镜与溶液接触，达到清洁、维护和贮藏隐形眼镜的目的。
本发明的一个目的是提供一种可用的溶液，它比目前工艺水平的产品有更强的杀菌性能。
本发明的另一个目的是提供一种眼科用溶液，比目前工艺水平的产品有更宽范围的抗菌谱。
本发明涉及到一种眼科用水溶液，溶液中含有重量比为0.01-1.0％的L-组氨酸、0.01-0.001％双氧水、0.1-500ppm阳离子型聚合物防腐剂，该防腐剂具有良好的防腐效能，尤其在抗真菌方面。该溶液可用于多种用途，包括清洁隐形眼镜、漂洗眼睛中镜片、贮藏镜片、眼睛释药制剂。本发明溶液中还可进一步加入表面活性剂，该表面活性剂可从那些已知工业品中选取，最好是羟基乙氧基蓖麻油。
组氨酸是一种基本氨基酸，是众所周知的化学品，可从大量的工业品制备。组氨酸可用于眼药膏等，且浓度很高，可参见美国专利US 5,811,446。
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
和
一组好的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有(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，具有下面所示的分子式：
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，反应的优势产物在上式中可以有不同的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No.1,432,345中都有记述，这里将两个专利合并介绍。最好，水溶性盐是那些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。
也可以用别的非双胍类杀菌剂作为溶液的防腐剂，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，或比如正烷基二甲苯基苯基铵盐盐酸盐的平衡混合物。其它的例子包括用于眼科应用的聚季铵盐如聚[(二甲基亚氨基)-1，4-二氯化-2-丁烯]、二氯化[(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)，或那些美国专利US 6,153,568记述的化合物。
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，它们包括十水过硼酸钠、过氧化钠、过氧化脲、过氧乙酸、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，这些添加剂有但不限于缓冲试剂、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和仪器是相适应的。
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0.01-0.35％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，其中前者中至少重量比40％以上成分是聚烃氧基乙烯。研究发现，表面活性剂含量在约重量比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.公司(Wyandotle，Mich.)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.公司(Parsippany，N.J.07054)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.公司(Wyandotte，Mich.)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。
添加相容性表面活性剂可用于隐形眼镜润湿或反复润湿用的溶液，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剂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。这类化合物例如包括聚山梨醇酯20(可以从ICI Americas Inc.，Wilmington，Del.19897购买，注册商标Tween20)、聚氧乙烯(23)月桂基醚(Brjj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Cremaphor RH 40的表面活性剂，它们都是聚烃氧基乙氧基蓖麻油。
具体实施方式
实施例
下面这些实例，说明了发明者的意图范围，但还没有包括发明者所有的权益要求。这些实例只是表明本发明具有实用性，并不意味着对此有限止性的解释。
例1
                          组氨酸-过氧化物
制备本组方时，将L-组氨酸溶于水。溶液的pH值用1N盐酸调节至7.3。加入双氧水、Dequest 2010和聚亚己基双胍盐酸盐(PHM)。用水将溶液稀释至特定体积。在每种溶液中加入白色棒状杆菌(C.albicansATCC 10231)，两小时后检测各溶液的抗菌活性。溶液的抗菌活性是根据起始培菌液菌体的对数下降值而确定的。各溶液组成、浓度和抗菌活性总结如下表
对数下降值 防腐剂 缓冲试剂 过氧化氢  Dequest2010
 1.25  PHMB0.0001％ L-组氨酸0.2％ 无  0.006％
 1.85  PHMB0.0001％ L-组氨酸0.2％ 0.006％  0.006％
结果表明，组氨酸与双氧水复配使用可以增加溶液的抗菌(C.albicans)活性。
例2
                       组氨酸--过氧化物
制备本组方时，将L-组氨酸溶于水。溶液的pH值用1N盐酸调节至7.3。加入氯化钠、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。在每种溶液中加入白色棒状杆菌(C.albicansATCC 10231)，两小时后检测各溶液的抗菌活性。溶液的抗菌活性是根据起始培菌液菌体的对数下降值而确定的。各溶液组成、浓度和抗菌活性总结如下表：
 对数下降值 防腐剂 缓冲试剂 氯化钠 双氧水 Dequest2010
 0.50  PHMB0.0001％ L-组氨酸0.2％ 0.4％ 无 0.006％
 1.08  PHMB0.0001％ L-组氨酸0.2％ 0.4％ 0.006％ 0.006％
结果表明，组氨酸与双氧水复配使用可以增加溶液的抗菌(C.albicnas)活性。
例3
                      组氨酸-过氧化物
制备本组方时，将L-组氨酸溶于水。溶液的pH值用1N盐酸调节至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。在每种溶液中加入白色棒状杆菌(C.albicansATCC 10231)，两小时后检测各溶液的抗菌活性。溶液的抗菌活性是根据起始培菌液菌体的对数下降值而确定的。各溶液组成、浓度和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 Dequest2010
 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％
实验结果表明：每一组对比试验中，加入0.006％双氧水可以增加溶液的抗菌(C.albicans)活性。数据还表明，溶液抗菌活性的增加与Dequest 2010的加入无关。
例4
                           组氨酸-过氧化物
制备本组方时，将L-组氨酸溶于水。溶液的pH值用1N盐酸调节至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。在每种溶液中加入白色棒状杆菌(C.albicans ATCC10231)，两小时后检测各溶液的抗菌活性。溶液的抗菌活性是根据起始培菌液菌体的对数下降值而确定的。各溶液组成、浓度和抗菌活性总结如下表：
 对数下降值  防腐剂 缓冲试剂 双氧水 Dequest2010
 2.01  PHMB0.0001％ 组氨酸0.2％ 无 无
 2.42  PHMB0.0001％ 组氨酸0.2％ 0.006％ 0.003％
 0.73  市售产品1
 1.95  市售产品2
注：市售产品1的配方是：无菌等渗透压水溶液中含有氯化钠、聚氧乙烯-聚氧丙烯聚合胶、磷酸二氢钠、磷酸氢二钠、防腐剂为0.025％二水EDTA二钠和0.0001％的polyhexanide。
市售产品2的配方是：无菌等渗透压水溶液中含有HYDRANATE(羟基烷基膦酸脂)、硼酸、EDTA二钠、poloxamine、硼酸钠和氯化钠，防腐剂为0.0001％的DYMED(聚氨基丙基双胍)。
结果显示：组氨酸与双氧水复合使用能增强溶液的抗菌活性，其抗菌性能优于两种市售产品。
例5
                    组氨酸-过氧化物
制备本组方时，将L-组氨酸溶于水。溶液的pH值用1N盐酸调节至7.3。加入Cremophor RH 40、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。在每种溶液中加入白色棒状杆菌(C.albicans ATCC 10231)，两小时后检测各溶液的抗菌活性。溶液的抗菌活性是根据起始培菌液菌体的对数下降值而确定的。各溶液组成、浓度和抗菌活性总结如下表：
 对数下降值 防腐剂 缓冲试剂 添加剂 双氧水 Dequest2010
 2.51  PHMB0.0001％ L-组氨酸0.2％ CremophorRH40 无 无
 3.27  PHMB0.0001％ L-组氨酸0.2％ CremophorRH40 0.006％ 0.003％
结果显示：组氨酸与双氧水复合使用能增强溶液的抗菌活性。
例6
                     组氨酸-过氧化物
制备本组方时，将L-组氨酸溶于水。溶液的pH值用1N盐酸调节至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。在每种溶液中加入白色棒状杆菌(C.albicansATCC 10231)，两小时后检测各溶液的抗菌活性。溶液的抗菌活性是根据起始培菌液菌体的对数下降值而确定的。各溶液组成、浓度和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 Dequest2010
 2.42  PHMB0.0001％ L-组氨酸0.2％ 无 CremophorRH40 无 无
 3.34  PHMB0.0001％ L-组氨酸0.2％ 无 CremophorRH40 0.006％ 0.003％
 2.19  PHMB0.0001％ L-组氨酸0.2％ 甘油3％ CremophorRH40 无 无
 2.94  PHMB0.0001％ L-组氨酸0.2％ 甘油3％ CremophorRH40 0.006％ 0.003％
 2.19  PHMB0.0001％ L-组氨酸0.2％ 丙二醇3％ CremophorRH40 无 无
 2.95  PHMB0.0001％ L-组氨酸0.2％ 丙二醇3％ CremophorRH40 0.006％ 0.003％
 3.36  PHMB0.0001％ L-组氨酸0.2％ 山梨糖醇5％ CremophorRH40 无 无
 3.92  PHMB0.0001％ L-组氨酸0.2％ 山梨糖醇5％ CremophorRH40 0.006％ 0.003％
 0.68  市售产品1
 2.99  市售产品2
 2.98  市售产品3(Opti-Free Express)
注：市售产品1的配方是：无菌等渗透压的水溶液中含有氯化钠、聚氧乙烯-聚氧丙烯聚合胶、磷酸氢二钠、磷酸二氢钠，防腐剂为0.025％的二水EDTA二钠和0.0001％的polyhexanide。
市售产品2的配方是：无菌的等渗透压的水溶液中含有HYDRANATE(羟基烷基膦酸酯)、硼酸、EDTA二钠、poloxamine、硼酸钠和氯化钠，防腐剂是0.0001％的DYMED(聚氨基丙基双胍)。
实验数据显示：加入0.006％的双氧水与组氨酸复合使用能增强溶液的抗菌(C.albicans)活性；在溶液中含有Cremophor RH 40、甘油、丙二醇和山梨糖醇时结果是一致的。所有组方中加入双氧水和组氨酸的溶液的抗菌活性与市售产品相当或更优。

Claims (2)

1.一种眼科用溶液，包含有：
0.01-1.0％重量比的L-组氨酸；
0.0001％-0.01％重量比的双氧水；及
0.1-500ppm的阳离子型聚合物防腐剂。
2.一种给眼睛提供漂洗溶液的方法，由以下步骤组成：
将溶液与眼睛接触，该溶液包含：
0.01-1.0％重量比的L-组氨酸；
0.0001-0.01％重量比的双氧水；及
0.1-500ppm的阳离子型聚合物防腐剂。
CNB018218164A 2000-11-08 2001-11-08 含有l－组氨酸的眼科用溶液 Expired - Fee Related CN1212848C (zh)

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ATE406167T1 (de) 2008-09-15
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