CN1232665A - 抗微生物组合物 - Google Patents

抗微生物组合物 Download PDF

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CN1232665A
CN1232665A CN99100879A CN99100879A CN1232665A CN 1232665 A CN1232665 A CN 1232665A CN 99100879 A CN99100879 A CN 99100879A CN 99100879 A CN99100879 A CN 99100879A CN 1232665 A CN1232665 A CN 1232665A
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H·B·贾姆帕尼
J·L·纽曼
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Johnson and Johnson Medical SAS
Ethicon Inc
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Abstract

本发明公开了一种作用迅速的含醇抗微生物组合物和采用该组合物进行表面消毒的方法,例如手的表面消毒。

Description

抗微生物组合物
本申请涉及到我的美国专利申请，一项申请的序列号为08/XXX,XXX、名称是以醇为基质的化妆品外观的抗微生物组合物，另一项序列号为08/YYY,YYY，名称是低粘洗剂、凝胶和膏，所有一起附上，这些文献指定给本发明的受让人并引入本文作为参考以便完全阐明。
本发明涉及到局部作用于一种基质例如手的抗微生物组合物。
含醇的抗微生物组合物应用于保健工业已经许多年了。最近，醇和葡萄糖酸洗必太组合物由于长期持久的效力和对微生物迅速杀灭力而被应用。然而，近来对抗生素药物有抵抗力和对大量其它的抗生素有多耐药性的微生物的出现，限制了含抗生素局部产品的使用。依据安全性和抗这些已有生物的性能，医疗工作者正在寻找适合他们需要的多功能产品。为医院环境提供一种方便剂型的抗微生物组合物是非常需要的。
一种解决该问题的尝试是使用多样的抗微生物组合物，如美国专利5,403,864公开的。该专利公开了一种含抗微生物化合物、三氯生和氯二甲酚的醇溶液。
除医院和保健环境之外，还有必要考虑到消费者中有关抗微生物组合物的意识日益增强，以及对适用于家庭的安全、温和和有效的组合物的渴望。优选的是，这些抗微生物组合物将解决这些问题，同时保持非干性状态，或者优选能提供减小抗微生物组合物刺激水平的水分。
因此，不断需要有效的，并同时对使用者无刺激的抗微生物组合物。
本发明的一个实施方案提供了一种抗微生物组合物，包含a)一种选自由大于30体积％的醇和有效剂量的三氯生组成的组的抗微生物剂；和b)一种有效剂量的苯氧乙醇、一种有效剂量的苯扎氯铵或者苄索氯铵和一种有效剂量的PHOSPOLIPIDCDM。
在本发明的第二个实施方案中，提供了一种含有效剂量三氯生、GERMALLPLUS和GERMABENⅡ的抗微生物组合物。此外，该抗微生物组合物也可选择性地包含一种有效剂量的PHOSPOLIPIDPTC。
在本发明的另外一个实施方案中，该抗微生物剂组合物也显示了对金黄色葡萄球菌(MRSA)的惊人的杀菌活性。本发明也显示了对粘质沙雷氏杆菌ATCC14756极佳的杀菌活性，该菌对基于三氯生的制剂显示微弱的敏感性。
按组合物的体积计算，本发明的醇含量大于约30体积百分比，一般是大约55至大约90体积百分比，优选60至大约85体积百分比，最优选60至大约70体积百分比。本发明中适用的醇包括乙醇、异丙醇、正丙醇和它们的混合物。本发明中乙醇可以单独使用，或者在另一个实施方案中规定本发明的醇含量为乙醇大约40至大约70体积％，异丙醇大约5至大约25体积％和正丙醇大约5至大约25体积％。
三氯生的用量为大约0.1至大约0.5，优选大约0.2至大约0.4重量百分比。
本发明包含一种混合物，该混合包括一种有效剂量的抗微生物苯氧乙醇、PHOSPHOLIPID CDM、苯扎氯铵和优选的GERMALL PLUS及GERMABENⅡ。苯氧乙醇用量为大约0.25至大约5.0重量百分比，优选大约0.3至大约0.7，最优选地是约0.05重量百分比。PHOSPHOLIPID CDM用量为大约0.01至大约1.0，优选大约0.03至大约0.7，最优选0.5重量百分比。苄索氯铵或者优选苯扎氯铵用量为大约0.02至大约1.0，优选大约0.08至大约0.5，最优选大约0.1至大约0.2重量百分比。
已经发现其它的抗微生物组合物在提高本发明的效力方面有显著作用。这些组合物包括三氯生、PHOSPHOLIPIDPTC、GERMALLPLUS和GERMABENⅡ。
在本发明中单独规定的GERMALLPLUS和GERMABENⅡ的用量各自在大约0.05至大约0.5重量百分比之间变化，优选的是0.1重量百分比。本发明中，发现同时使用GERMALLPLUS和GERMABENⅡ非常有效。一起使用时这两种物质的比例大约是重量比0.1∶1至1∶0.1，最优选的是重量比1∶1。
除上述的抗微生物组合物之外，在本发明中可以采用的其它的抗微生物剂包含尼生素、双胍啶、葡萄糖酸洗必太、二葡萄糖酸洗必太、醋酸洗必太、盐酸洗必太、tricloban、羟甲基甘氨酸钠、辛酰胶原酸(octanoyl collagenic acid)、十六烷基氯化吡啶鎓、苯酚、碘、对氯间二甲苯酚(PCMX)、聚合季铵化合物，它们的混合物等。抗微生物剂一般加入量大约为0.1至4.0重量百分比。
本发明采用的其它的优选组分包含PHOSPOLIPID PTC，用量大约为0.01至大约1.0，优选大约0.02至大约0.08，最优选的是大约0.05重量百分比。以1∶1的比例使用澳大利亚茶树油和柠檬香草油，其含量大约为0.5至10.0，优选大约1.0至大约7.0，最优选大约5.0重量百分比。
本发明一个较优选的实施方案规定大于40重量％的醇、一种有效剂量的苯氧乙醇、一种有效剂量的苯扎氯铵、一种有效剂量的GERMALL PLUS、一种有效剂量的GERMABEN-Ⅱ和一种有效剂量PHOSPOLIPIDCDM。此外，该抗微生物组合物还可以选择性地含有一种有效剂量的PHOSPOLIPID PTC。
在另一个优选的实施例中，该抗微生物混合物含超过大约40重量百分比的醇、一种有效剂量的苯氧乙醇、一种有效剂量的苯扎氯铵、一种有效剂量的三氯生、一种有效剂量的GERMALL PLUS、一种有效剂量的GERMABEN-Ⅱ和一种有效剂量PHOSPOLIPIDCDM。
在本发明另一优选实施例中，该抗微生物混合物含超过大约40重量百分比的醇、一种有效剂量的苯氧乙醇、一种有效剂量的苯扎氯按、一种效剂量的苄索氯铵、一种有效剂量的三氯生、一种有效剂量的GERMALL PLUS、一种有效剂量的GERMABEN-Ⅱ和一种有效剂量PHOSPOLIPID CDM。
在本发明另一较优选的实施方案中，该抗微生物混合物为超过大约40重量百分比的一种醇例如乙醇、异丙醇和正丙醇的混合物，一种两种挥发油(essential oils)例如澳大利亚茶树油和柠檬香草油的混合物，一种有效剂量的苯氧乙醇、一种有效剂量的苯扎氯按、一种有效剂量的三氯生、一种有效剂量的GERMALL PLUS、一种有效剂量的GERMABEN-Ⅱ和一种有效剂量PHOSPOLIPID CDM。此外，该抗菌组合物还可以选择性地含有一种有效剂量的维他命E亚油酸。
随着时间的推移，本发明的抗微生物组合物发现具有瞬间和持久的活性。本发明的组合物也与一些抗微生物组合物有效地比较，这些组合物包含高浓度的葡萄糖酸洗必太或者市售产品如购自ZENECA制药厂的HIBISTAT和HIBICLENS，这些通常用于外科擦洗和消毒、手消毒和外科手术前患者的处理。
葡萄糖酸洗必太制剂清洗1至7次之间显示出活性上很大的增长，这在本领域中是公知的。这种活性的增强确认是由其极性结构和与皮肤的附着力引起的。在清洗10次并且以合适的活性抑制剂中和之后，第10次清洗时葡萄糖酸洗必太的活性明显下降(近似30-50％)，测试是依据个人保健洗手标准(HealthCare personel hand wash protocol)完成的。令人惊讶地，本发明的组合物能提供比这些其它众所周知的抗微生物剂更持久的抗微生物活性。
本发明的另一项优点是由抗微生物制品产生的残留活性。在初始使用时，并且在长时期内，本发明对广谱生物，能产生有效的保护作用，这些生物包含革兰氏阳性菌、革兰氏阴性菌、酵母菌和真菌。我们已经发现它不象其它的抗微生物组合物，这些组合物在杀微生物方面最初有效，但是在大约一小时后迅速丧失了它们的效力。令人惊奇地，在持续时间内本发明能有效地预防细菌出现，例如超过两小时的时间，优选大约3或者4小时或者更多。
在该制剂中，包含其它的组分以便增强该抗微生物组合物的效力的制剂是优选的。该制剂中包含的是挥发油，它们用于提高该抗微生物组合物作用速率以及残留活性。适合的挥发油包含澳大利亚茶树油、柠檬油、麝香草油、熏衣草油和丁香油以及它们的混合物。挥发油用于增加本发明的润肤性、保湿性、柔软性和渗透性。以总组合物的重量为基准，一般添加的这些油含量是大约1至大约10重量百分比，最优选地在大约5重量百分比。
本发明也采用与一种不饱和的多官能团剂如蔗糖的聚烯丙醚交联的丙烯酸作增稠剂。这些丙烯酸官能团化聚合物，通常称之为卡波姆，公开在美国专利Nos.2,798,053和3,133,865，它们引入本文作为参考。
选择适当的卡波姆能供给抗微生物制剂以期望的粘度值。为了具有预期的触觉，该制剂的粘度值必须超过大约5,000厘泊。优选的是，该制剂在25℃条件下具有大约9,000至大约22,000厘泊的粘度，最优选的是，该制剂在25℃条件下具有大约11,000至大约20,000厘泊的粘度。
采用一种增稠剂，该增稠剂是一种含有与一种蔗糖的不饱和聚烯丙醚交联的丙烯酸聚合物的添加剂。采用足够量的这种聚合物以得到具有期望粘度范围的凝胶组合物。
许多这些聚合物，在本领域中被称作卡波姆，分别由B.F.Goodrich,(Cleveland,Ohio)销售如CARBOPOL934、940和941；和由R.I.T.A(Crystal lake,IL)销售如ACRITAMER934,940和941。一般使用大约0.2至大约2.0重量百分比的卡波姆化合物，按总抗微生物组合物的重量计算，优选使用的量为大约0.4至大约0.7重量百分比。
在几种优选的中更优选的一种卡波姆聚合物是R.I.T.A.ACRITAMER505E，一种与季戊四醇醚交联的聚乙烯基羧基聚合物。优选ACRITAMER505E作一种胶凝剂或者粘度增强剂，因为在本发明中它能提供一种透明或者半透明的凝胶。
最优选的卡波姆是ULTREZ10(购自BF Goodrich)，一种改性共聚物，具有的主要部分是单烯烃的(monoolefinically)3至6个碳原子的不饱和羧酸单体或者其酸酐，次要部分是长链丙烯酸酯或甲基丙烯酸酯单体。该聚合物主要是丙烯酸和少量长链丙烯酸酯单体。美国专利No.5,004,598描述了这种聚合物，整体上引入本文作为参考。
本发明中另一处特别优选的组分组是粘性改良剂，例如硅酮醋、硬脂氧三甲基硅烷(stearoxy trimethyl silane)、环甲基硅油、乳酸十六烷基酯、乳酸烷基酯(一般长度为C12-C15)。在本发明中使用润湿剂，例如甘油、水、脂类、蜡等，也是很有用的。其它的溶剂也可以采用，例如丙二醇，以便制备一种更稳定的制剂。
其它可添加到该组合物中的组分包含香料、润肤剂、pH调节剂、粘度改良剂如丙烯酸聚合物、树胶、汉生胶等；transdermal增效剂、表面活性剂、染料、着色剂等。这些组分在本领域中是公知的，并且公开在美国专利No.5,403,864和5,403,587中。该制剂剩余物是由水组成，优选去离子水。水一般占抗微生物组合物重量的10至大约40重量％。
下列制剂具有非常有效的抗微生物性能。
1．乙醇(40-70％)，异丙醇(20-25％)，正丙醇(5-10％)
2．二异丁基苯氧基乙氧基乙基二甲基苄基氯化铵(0.05-0.5％)，通常称为苄索氯铵
3．通常称为三氯生的2,4,4’-三氯-2-羟基二苯醚(0.2-0.5％)
4．N,N-双(羟基甲基)脲(0.08-0.5％)、对羟基苯甲酸甲酯(0.009-0.5％)、对羟基苯甲酸丙酯(0.0025-0.5％)、1,2-丙二醇(0.050-0.056％)
5．氯化可可磷脂酰二铵(Coco Phosphotidyl PG-Dimonium chloride)(0.05-0.5％)
6．DL-和L-氧氟沙星(0.01-0.5％)
7．澳大利亚茶树油(1.0-5.0％)
8．柠檬草油(1.0-5.0％)
9．麝香草油(1.0-5.0％)
10．熏衣草油(1.0-5.0％)
11．丁香油(1.0-5.0％)
将有效剂量的组合物局部施用到某基质或者部位，例如手、粉刺部位，或导管注射部位等处时，本发明的抗微生物组合物对抑制微生物很有效。施用的有效量取决于环境因素，如作用时间长短、抗微生物组合物和基质的接触量，以及温度和蒸发率。本领域的普通技术人员能很容易地确定抑制微生物所必需的有效浓度。通常应用大约为0.5至大约10毫升，优选大约1.0至大约8毫升，最优选大约2.5至大约5毫升的抗微生物组合物。发现该剂量的抗微生物组合物是有效的，它可导致微生物总数的Log10减少量为2或更高。
本发明也可采用本领域公知技术制备成乳剂，参见美国专利5,308,890。可用一种阴离子、阳离子或非离子表面活性剂或者分散剂，或者其相容的混合物(例如一种阳离子或一种非离子表面活性剂的混合物)将活性组分、赋形剂等进行乳化，例如以组分的重量为基准，应用大约0.05重量％至大约5重量％的表面活性剂或分散剂进行乳化。适合的阳离子分散剂包含十二烷基氯化吡啶鎓、十六烷基二甲基醋酸胺(cetyldimethyl amine acetate)和烷基二甲基苄基氯化铵，这里的烷基具有8至18个碳原子。适合的阴离子分散剂包括例如碱性脂肪醇硫酸酯，如十二烷基硫酸钠等；磺酸芳基烷基酯(arylalkyl sulfonates)等；碱性烷基磺基丁二酸盐，如辛基磺基丁二酸钠等；和碱性芳基烷基聚乙氧基乙醇硫酸酯或磺酸酯，如具有1至5个氧乙烯基单元的辛基苯氧基聚乙氧基乙基硫酸钠等。适合的非离子分散剂包含，例如，具有7至18个碳原子的烷基和大约6至60氧乙烯基单元的烷基苯氧基聚乙氧基乙醇，例如，庚基苯氧基聚乙氧基乙醇；长链羧酸的乙烯氧化衍生物，例如月桂酸、十四烷酸、棕榈酸、油酸等；或者是例如在妥尔油中发现的那些含大约6至60氧乙烯基单元的酸的混合物；长链醇的乙烯氧化缩合物，例如含大约6至60氧乙烯基单元的辛基、癸基、十二烷基，或十八烷基醇；长链或支链胺的乙烯氧化缩合物，例如含大约6至60氧乙烯基单元的十二烷胺、十六烷胺和十八烷胺；和与一种或多种疏水丙烯氧化段结合的乙烯氧化段嵌段共聚物。高分子量的聚合物例如羟基乙基纤维素、甲基纤维素、聚丙烯酸、聚乙烯醇等均可用作乳化稳定剂和保护胶体。
下列的实施例用于说明本发明，但并不将本发明限制在下面的组合物中。除非相反地注明，本申请中出现的所有百分比均为重量百分比。
本申请中采用下列组合物：AMP 95是比例约为90∶5∶5的2-氨基-2-甲基-1-丙醇、2-(甲氨基)-2-甲基-1-丙醇和水的混合物，可自Angus化学公司购得。ACRITAMER505E是一种与季戊四醇的醚交联的聚乙烯羧基聚合物，R.I.T.A.可自伊利诺斯州Crystal Lake获得。ESS 9090IC是一种香料，可自Givudan-Roure公司获得。CERAPHYL 28主要是乳酸十六烷基酯，一种购自ISP VanDyk有限公司的蜡状固体。CERAPHYL41是C12-C15醇乳酸酯的混合物，购自ISP Van Dyk有限公司。DOW CORNING580蜡是硬脂氧三甲氧基硅烷和硬脂醇的混合物。GERMABENⅡ是一种含吡唑烷基脲(diazolidinyl urea)(约30％)；对羟基苯甲酸甲酯(约11％)；对羟基苯甲酸丙酯(约3％)；和丙二醇(约56％)的混合物，购自Sutton化学厂。GERMALLPLUS是一种吡唑烷基脲(diazolidinyl urea)(约99％)和3-碘代-丙炔基丁基氨基甲酸酯的混合物，购自Sutton化学厂。LEXOREZ 100是一种饱和交联羟基官能团；聚酯，包含甘油、二甘醇、己二酸酯交联聚合物，室温下是一种粘性的、疏水的液体并且在许多脂类和润肤剂中是可分散的。PHOSPOLIPIDCDM是氯化可可磷脂酰二铵[cocophosphatidyl(PG)-Dimonium chloride]，一种购自Mona工业有限公司的同合成物、磷脂。PHOSPOLIPIDPTC是cocamidopropyl phosphatidyl PG-dimonium chloride，购自Mona工厂。SILSOFTPEDM苯乙基二甲基硅油，购自Witco Corporation Osi Specialties,Inc.三氯生2,4,4’-三氯-2-羟基二苯醚。ULTREZ10聚羧乙烯聚合物，购自BE Goodrich,Cleveland Ohio，并且公开在美国专利5,004,598中，该专利的内容整体上引入本文作为参考。实施例1：配制和试验下列制剂制剂，结果如下所示：制剂1：乙醇75.8；ULTREZ 10 0.6；甘油1.5；LEXOREZ 100 0.25；CERAPHYL-41 0.5；CERAPHYL-28 0.5；三氯生0.3；AMP-95 pH6.4；ESS9090IC 0.06；环甲基硅油(245)1.5；二甲基硅油(225)0.5；Dow Corning580蜡0.20；SILSOFTPEDM 1.0；去离子水17.6；PHOSPOLIPID CDM 0.2。制剂2：乙醇50.0；异丙醇20；ULTREZ10 0.6；甘油1.5；LEXOREZ1000.25；CERAPHYL-41 0.5；CERAPHYL-28 0.5；三氯生0.3；AMP-95pH6.4；ESS 9090IC 0.06；环甲基硅油(245)1.0；二甲基硅油(225)0.5；Dow Coming 580蜡0.25；SILSOFT PEDM 1.0；去离子水23.5；PHOSPOLIPID CDM 0.2。制剂3：乙醇43.3；异丙醇25；正丙醇5.0；ULTREZ10 0.6；甘油1.5；LEXOREZ 100 0.25；CERAPHYL-41 0.5；CERAPHYL-28 0.5；三氯生0.3；AMP pH6.4；ESS 9090IC 0.06；环甲基硅油(245)2.0；二甲基硅油(225)0.5；DowComing580蜡0.1；SILSOFTPEDM 1.0；去离子水19.0；PHOSPOLIPIDCDM 0.2；苯氧乙醇0.2。制剂4：乙醇75.8；ULTREZ 10 0.6；甘油1.5；LEXOREZ 100 0.25；CERAPHYL-41 0.5；CERAPHYL-28 0.5；三氯生0.3；AMP-95 pH6.4；ESS 9090IC 0.06；环甲基硅油(245)1.0；二甲基硅油(225)0.5；Dow Coming 580蜡0.25；SILSOFT PEDM 1.0；去离子水17.5；PHOSPOLIPIDCDM 0.2；GERMABEN-Ⅱ0.05；防腐剂0.15。制剂5：乙醇75.8；ULTREZ 10 0.6；甘油1.5；LEXOREZ 100 0.25；CERAPHYL-41 0.5；CERAPHYL-28 0.5；苄索氯铵0.2；AMP-95 pH6.4；ESS 9090IC 0.06；环甲基硅油(245)1.0；二甲基硅油(225)0.5；Dow Coming 580蜡0.25；SILSOFT PEDM 1.0；去离子水17.1；PHOSPOLIPID CDM 0.2。制剂6：乙醇50；异丙醇20；ULTREZ 10 0.6；甘油1.5；LEXOREZ 1000.25；CERAPHYL-41 0.5；CERAPHYL-28 0.5；2,4,4-三氯-2-羟基二苯醚0.3；AMP-95 pH6.4；ESS9090IC 0.06；环甲基硅油(245)1；二甲基硅油(225)0.5；Dow Coming 580蜡0.25；SILSOFTPEDM 1.0；去离子水23.0；PHOSPOLIPID CDM 0.2；GERMABEN-Ⅱ0.2；乙二胺四乙酸钠(EDTA)0.1。制剂7：乙醇75.8；ULTREZ 10 0.6；甘油1.5；CERAPHYL-41 0.5；CERAPHYL-28 0.5；AMP-95 pH 6.4；ESS 9090IC 0.06；环甲基硅油(Dow Coming245液体)1.5；二甲基硅油(Dow Coming 225液体)0.5；Dow Coming580蜡0.1；SILSOFTPEDM 1.0；2,4,4’-三氯-2-羟基二苯醚0.3；DL-氧氟沙星0.05；去离子水17.4。制剂8：乙醇75.8；ULTREZ 10 0.6；甘油1.5；LEXOREZ 100 0.25；CERAPHYL-41 0.5；CERAPHYL-28 0.5；AMP-95 pH6.4；ESS9090IC0.06；环甲基硅油(245)1.5；二甲基硅油(DC 225号)0.5；DowComing580蜡0.1；SILSOFTPEDM 1.0；DL-氧氟沙星0.25；去离子水17.4。制剂9：乙醇75.8；甘油1；2,4,4’-三氯-2-羟基二苯醚0.3；ESS 9090IC0.06；三乙醇胺，(pH调节剂)，二甲基硅油(225号)1.0；澳大利亚茶树油1.5；去离子水19.4；ACRITAMER505E0.45；PEG-75羊毛脂0.5；熏衣草油1.5。制剂10：乙醇75.8；甘油1；2,4,4’-三氯-2-羟基二苯醚0.3；ESS 9090IC0.06；三乙醇胺(pH调节剂)，二甲基硅油(225号)1；去离子水19.4；ACRITAMER505E 0.45；PEG-75羊毛脂0.5；熏衣草油1.5。制剂11：乙醇75.8；甘油1；2,4,4’-三氯-2-羟基二苯醚0.3；ESS9090IC0.06；三乙醇胺(pH调节剂)，二甲基硅油(225号)1；去离子水19.4；ACRITAMER505E 0.45；PEG-75羊毛脂0.5；柠檬草油1.0。制剂12：乙醇75.8；甘油1；2,4,4’-三氯-2-羟基二苯醚0.3；ESS 9090IC0.06；三乙醇胺(pH调节剂)，二甲基硅油(225号)1；去离子水19.4；ACRITAMER505E 0.45；PEG-75羊毛脂0.5；麝香草油1.0。制剂13：乙醇75.8；甘油1；2,4,4’-三氯-2-羟基二苯醚0.3；ESS 9090IC0.06；三乙醇胺(pH调节剂)，二甲基硅油(225号)1；去离子水19.4；ACRITAMER505E 0.45；PEG-75羊毛脂0.5；丁香油1.0。
评价这些抗微生物制剂的体外临床功效，并将这些组合物的试验结果总结于表1、2和3中。
采用一种猪皮试验模型作为一项评价或者筛选许多抗微生物组合物样品的草案。由于根据皮肤的构成和性状猪皮类似于人的皮肤，猪皮适于模拟临床上由人完成的洗手操作。试验概括于猪皮作为评价局部抗微生物活性的试验基质，J.Clin.微生物学，九月号，1986,334-348页，然后制作试验模型。
猪皮试验包括：a)猪皮的制备；b)抗微生物的分析；c)与对照物计数。
将猪皮清洗、去毛然后冷冻。接着解冻并且切割成3×3cm的块。将皮安放在带有环氧树脂的支架上并且暴露皮侧。将这些皮置入包含一个过滤片的培特利式培养皿，该过滤片以1.0ml的水润湿以防止干燥。这些皮在冰箱中放置一个晚上。
在制备皮的同一天，一式两份将试验的微生物以标准方法接种到琼脂斜面和琼脂板上。通过从皮上随机切栓(plugs)(8mm的活体解剖栓(plug)，以检测猪皮块残留抗生素的存在，然后将栓的皮侧置入单独的接种有试验微生物的琼脂板内。第二天，检测琼脂板环绕猪皮的抑制区。抑制区表示残留抗生素并且皮肤未受损伤。
各种微生物的混悬液由头天晚上斜面培养物制得。通过以消毒棉拭轻轻地磨擦琼脂表面，将培养出来的细菌混悬入10ml的Butterfield缓冲剂。混和悬浮液以制备一种混合的近似109CFU/ml的细菌培养液。微生物滴度进一步稀释至得率近似107CFU/ml。两片猪皮接种0.05ml的稀释培养液。接种过的皮均与未接种的皮成对。接种过的皮和未接种的皮一起摩擦近似15秒，并且清除遮盖物在30℃保温大约15分钟，以使微生物在皮上干燥。在培养之后，将0.50ml的试验原料加入到每对皮块上。去掉培特利式培养皿的盖，在室温下培养。每组中的一个样本通过印在琼脂板上计数，而另外一相同的样本通过漂洗计数。
通过倒置安装支架并将皮压至标准法制备的含卵磷脂和多乙氧基醚的琼脂表面上，进行印刻。在规定的时间间隔进行印刻，然后在30℃左右保温大约24小时。
在每次时间间隔，将0.2ml letheen巯基乙酸盐中和肉汤液体培养基加至每对皮的表面。收集从使用两块皮所得的10ml洗液并计数存活的微生物。连续稀释等分(0.5ml)的洗涤肉汤液体培养基至用完4.5ml的letheen巯基乙酸盐中和肉汤液体培养基。琼脂板于30℃下保温大约48小时，然后计数。
结果如下所示：表1．具有混合培养物的猪皮试验结果制剂   接种对照(BL)Log10减少量
       (Log10)15分钟    60分钟  120分钟1            7.42    1.8      2.48    1.852            5.84    1.1      2.7     2.383            7.24    1.7      2.65    0.834            7.42    1.78     1.76    3.765            5.84    4.1      2.8     2.176            5.84    3.55     2.65    2.107            5.84    3.82     3.38    3.618            5.84    4.14     3.94    4.44HIBISTAT     5.84    3.0      3.3     0.62*混合培养物，每种培养物质代表：绿脓杆菌ATCC 15442，肺炎克雷伯杆菌ATCC 11296，藤黄微球菌ATCC 7468，粪肠球菌ATCC 29212
本领域的普通技术人员可意识到log10减少量的值越高，组合物的效力越高。log10减少量是原始细菌计数和每次处理后所得计数之差。
应用金黄色葡萄球菌ATCC 33592的猪皮试验结果检测同样的制剂。结果以分钟为单位，如下表2所示：表2制剂   接种对照  log10减少量
      (BL)   15分钟   60分钟  120分钟
    (Log10)1        7.55    2.28     2.06    1.982        4.99    1.37     1.88    0.033        7.55    2.45     3.04    2.544        7.55    4.2      2.22    1.85        4.99    1.74     1.96    2.196        4.99    0.15     2.23    2.187        4.99    2.58     2.83    3.148        4.99    2.84     2.65    2.86HIBISTAT 4.99    2.45     1.54    0.85
表2的结果表明采用异丙醇制剂能得到极佳的对金黄色葡萄球菌的杀菌活性。采用粘质沙雷氏杆菌ATCC 14756的猪皮试验标准测验同样的制剂。结果如下表3所示：表3
制剂  接种对照 log10减少量
    (BL)    15分钟      60分钟  120分钟
   (Log10)1       7.01    1.93       1.25    1.042       5.17    2.32       0.96    0.43       7.01    2.1        1.77    1.104       7.01    3.53       3.07    0.775       5.17    2.64       1.64    1.486       5.17    3.32       2.18    0.327       5.17    2.18       3.29    2.268       5.17    3.52       2.9     1.639       7.04    2.12       3.08    2.7810      7.04    4.52       3.51    2.9611      7.04    3.76       3.89    2.8912      7.04    3.23       3.36    3.3113      7.04    4.11       3.89    1.93HIBISTAT5.17    2.08       2.06    0.03
表3表明采用含挥发油的，特别是含柠檬草油、熏衣草油、百里香油、澳大利亚茶树油和丁香油的乙醇和异丙醇抗微生物制剂，能得到极佳的对粘质沙雷氏杆菌ATCC 14756的杀菌活性。实施例2
以上述实施例1所得结果为基准，配制四种制剂(A-D)，并且根据修正的个人保健洗手标准(Health Care Personnel Handwash protocol)，评价它们的体外效力。这四种制剂如下：制剂A：乙醇(重量的92.3％)75.8；ULTREZ10 0.6；甘油0.5；LEXOREZ100 0.25；CERAPHYL-41 0.5；CERAPHYL-28 0.5；三氯生(2,4,4-三氯-2-羟基二苯醚)0.3；苯氧乙醇0.3；苯扎氯铵(50％溶液)0.2；PHOSPHOLIPIDCDM 0.05；GERMALLPLUS+GERMABENⅡ(1∶1重量比)0.2；维他命E亚油酸盐0.05；AMPpH6.4；ESS 9090IC 0.06；去离子水20.4。制剂B：除未应用三氯生之外，制剂B基本类似于制剂A。乙醇75.8；ULTREZ10 0.6；甘油0.5；LEXOREZ100 0.25；CERAPHYL-41 0.5；CERAPHYL-28 0.5；苯氧乙醇0.3；苯扎氯铵(50％溶液)0.2；PHOSPHOLIPID CDM0.05；GERMALLPLUS+GERMABENⅡ(1∶1)0.2；维他命E亚油酸盐0.05；AMP pH6.4；ESS 9090IC 0.06；去离子水20.5。制剂C：乙醇75.8；ULTREZ 10 0.6；甘油1.5；LEXOREZ 100 0.25；CERAPHYL41 0.5；CERAPHYL28 0.5；2,4,4’-三氯-2-羟基二苯醚0.3；苯氧乙醇0.3；苄索氯铵0.1；苯扎氯铵(50％溶液)0.1；PHOSPHOLIPID CDM0.05；GERMALLPLUS+GERMABEN(1∶1)0.2；维他命E亚油酸盐0.05；AMPpH6.4；ESS 9090IC 0.06；环甲基硅油(245)2.5；二甲聚硅氧烷(225)0.5；DowComing580蜡0.1；SILSOFTPEDM 0.5；去离子水15.8。制剂D：乙醇43.2；异丙醇25；正丙醇5；ULTREZ 10 0.6；甘油1.5；LEXOREZ100 0.25；CERAPHYL-41 0.5；CERAPHYL-28 0.5；2,4,4’-三氯-2-羟基二苯醚0.3；苯氧乙醇0.3；苯扎氯铵(50％溶液)0.2；维他命E亚油酸盐0.025；AMP pH6.4；ESS9090IC 0.06；环甲基硅油(245)3.5；二甲聚硅氧烷(225)0.5；DowComing580蜡0.1；SILSOFTPEDM 0.5；柠檬草油2.5；澳大利亚茶树油2.5；去离子水12。将这些制剂与市售的以葡萄糖酸洗必太为基质的产品对照，如购自ICIAmericans的抗微生物剂HIBISTAT和HIBICLENS。表4．个人保健洗手标准(Health Care personnel handwash protocol)为基线的LOG10减少量制剂      基线    洗1     洗3     洗7     洗10A         8.23    3.55    3.08    3.67    3.03B         8.56    4.13    3.4     3.92    3.04C         8.36    3.75    3.15    3.06    3.18D         8.45    4.26    4.42    4.55    4.57HIBISTAT  8.23    3.25    3.94    5.31    2.86HIBICLENS 8.32    2.2     2.6     3.0     2.9
实施例1的四种制剂在洗1(log10减少量为2)和洗10(log10减少量为3)均符合FDA的要求。可以看到制剂A-D比市售的产品更有效。在10次人工洗涤上，乙醇和葡萄糖酸洗必太的联用显示出极佳的协同作用，但是在第10次洗涤时，采用中和剂抑制其活性后，log减少量比第7次洗涤的值下降了40至50％。令人惊奇地，本发明的全部四种制剂在效力上并没有重复这种下降。实施例3
采用上面实施例1和2描述的抗微生物制剂，并做小的改动后，制备另外的实验制剂，如乳剂。在四个时间间隔、两种浓度下，采用对8种典型微生物(革兰氏阳性菌、革兰氏阴性菌和真菌)的体外杀菌试验，由制备的8个样品评价四种制剂的效力。
本实施例中使用的制剂如下所示；制剂A’：水80.32、丙二醇4、肉豆蔻酸十四酸酯1.5、油酸1.25、硬脂酸1.25、甘油硬脂酸酯1.25、多乙氧基醚61 1.2、棕榈酸异丙酯1、二甲聚硅氧烷1、硬脂氧三甲基硅烷1、脱水山梨糖醇硬脂酸酯0.8、蜡醇0.5、硬脂醇0.5、人工蜂蜡0.5、苯甲醇0.3、卡波姆941 0.8、香料IFF 1906AD 0.2、乙二胺四乙酸二钠+NaOH 0.15+0.8、苯氧乙醇0.4、乳酸0.5、GERMABEN-Ⅱ0.25、泛酰醇0.2、乙酸生育酚0.05、维他命E亚油酸盐0.05、三氯生0.3。制剂B’：水80.32、丙二醇4、肉豆蔻酸十四酸酯1.5、油酸1.25、硬脂酸1.25、甘油硬脂酸酯1.25、多乙氧基醚61 1.2、棕榈酸异丙酯1、二甲聚硅氧烷1、硬脂氧三甲基硅烷1、脱水山梨糖醇硬脂酸酯0.8、蜡醇0.5、硬脂醇0.5、人工蜂蜡0.5、苯甲醇0.8、卡波姆941 1.0、香料IFF 1906AD 0.2、乙二胺四乙酸二钠+NaOH 0.15+0.75、苯氧乙醇0.4、乳酸0.5、羟基甲基甘氨酸钠(50％活性)0.3、GERMABEN-Ⅱ0.25、氯化苄甲乙氧铵0.2、乙酸生育酚0.05、维他命E亚油酸酯0.05、磷脂PTC+CDM(1∶1)1、三氯生0.3、GS-甘草0.1。制剂C’：水80.32、丙二醇4、肉豆蔻酸十四酸酯1.5、油酸1.25、硬脂酸1.25、甘油硬脂酸酯1.25、多乙氧基醚61 1.2、棕榈酸异丙酯1、二甲聚硅氧烷1、硬脂氧三甲基硅烷1、脱水山梨糖醇硬脂酸酯0.8、蜡醇0.5、硬脂醇0.5、人工蜂蜡0.5、苯甲醇0.3、卡波姆941 0.8、香料IFF 1906AD 0.2、乙二胺四乙酸二钠+NaOH 0.15+0.75、苯氧乙醇0.4、乳酸0.5、GERMALL Plus 0.3、GERMABEN-Ⅱ0.25、苯扎氯铵(50％)0.2、乙酸生育酚0.05、维他命E亚油酸酯0.05、磷脂PTC+CDM(1∶1)1、三氯生0.3。制剂D’：水80.32、丙二醇4、肉豆蔻酸十四酸酯1.5、油酸1.25、硬脂酸1.25、甘油硬脂酸脂1.25、多乙氧基醚61 1.2、棕榈酸异丙酯1、二甲聚硅氧烷1、硬脂氧三甲基硅烷1、脱水山梨糖醇硬脂酸酯0.8、蜡醇0.5、硬脂醇0.5、人工蜂蜡0.5、苯甲醇0.3、卡波姆941 0.8、香料IFF 1906AD 0.2、乙二胺四乙酸二钠+NaOH 0.15+0.75、苯氧乙醇0.4、乳酸0.5、辛酰胶原酸(octanoylcollagenic acid)0.3、GERMABEN-Ⅱ0.25、十六烷基氯化吡啶鎓0.2、乙酸生育酚0.05、维他命E亚油酸酯0.05、磷脂PTC+CDM(1∶1)1、三氯生0.3。表5．乳剂的体外杀菌活性微生物               ATCC  杀灭99.99％细菌所需时间*
                       A′    B′    C′    D′粪肠球菌(MDR)        51299 60     60     15     15金黄色葡萄球菌(MRSA) 33592 60     60     15     60sec.金黄色葡萄球菌        6538 60     60     15     15粘质沙雷氏杆菌       14756 ＞60   60     15     60sec.肺炎链球菌            6303 15     15     15     30sec.大肠杆菌             11229 15     15     30sec. 30sec.绿脓杆菌             15442 30sec. 30sec. 30sec. 30sec.白色念珠菌           10231 全部结果均超过60除另行注明外，所有时间单位均是分钟；sec.即秒。
上面的数据表明，制剂D′在杀灭上述革兰氏阳性菌和革兰氏阴性菌上具有优异的效力。
在无水基质中制备，即制成乳剂时，本发明的抗微生物组合物显示出类似的活性。尤其对金黄色葡萄球菌(MRSA)和粘质沙雷氏杆菌(ATCC 14756)，制剂D′显示出良好的效果。大多数含三氯生的抗微生物制剂对粘质沙雷氏杆菌(ATCC 14756)作用不大。本发明的抗微生物组合物，尤其是制剂D′，在局部皮肤护理产品象醇凝胶、膏、洗剂、消毒液、外科术前制剂、清洁剂、软膏、治疗剂和其它抗致病菌的用品上具有潜在的用途。实施例4
试验本发明组合物的刺激性和致敏性。配制下列制剂：制剂1去离子水28.7、乙醇62、ULTREZ10 0.45、甘油0.5、环甲基硅油1.25、Dow Corning580蜡0.025、SILSOFTPEDM 0.2、CERAPHYL-28 0.5、CERAPHYL-41 1.0、需要量的AMP95(pH调节剂)、1906ADMODI 0.1。制剂2去离子水27.7、乙醇62、ULTREZ 10 0.55、甘油0.5、环甲基硅油1.25、Dow Coming 580蜡0.025、SILSOFTPEDM 0.2、CERAPHYL-28 0.5、CERAPHYL-411.0、需要量的AMP95(pH调节剂)、1906 AD MODI 0.06、苯氧乙醇0.5、苯扎氯铵(50％活性)0.16、苄索氯铵0.08、PHOSPHOLIPID CDM0.05、GERMALLPlus 0.1、GERMABENⅡ0.1。
在研究之前，筛选受试者以确定他们符合包含/排斥标准。对每个受试者提供一个研究活动进度表。诱导期由九(9)次研究材料的连续施用构成，并对试验部位进行后续评价。在施用这些小块之前，用皮肤标记物，即龙胆紫标记试验部位。要求这些受试者在施用之后大约24小时去掉这些小块。每隔48小时这些受试者返回实验室以评价试验部位，并且重新施用完全相同的小块。在第九次评价后，给这些受试者10-14天的休息期。在休息期后，在研究的第六周开始激发期，将同样的小块施用到预先未受试验的部位。24小时后由受试者去掉小块，又过另外的24小时和48小时将试验部位分级。施用48和72小时之后进行分级。一个受试者在诱导过程必须有九次(9)施用和不少于八次(8)的后续读数，并且在激发期必须有一种(1)产品的施用和两次(2)读数，这样他才可被认为是完成试验者。在完成研究的101个受试者中，没有发现此制剂引起的过敏和刺激。实施例6
研究上面实施例5所应用的两种制剂，以确定它们的加湿性能。十五个受试者将这些制剂施用到小腿外侧干燥的皮肤上。采用SKICON皮肤表面液体比重计测量皮肤增加的水分。全部结果报告为SKICON测量基线的平均百分比改变。通过测量四个不同试验部位的加湿值并将所测得的加湿值的平均值与基线值比较，得出这里的百分比平均结果。
           30分钟     1小时    2小时制剂1          4.6％    16.7％    19.9％制剂2          5.5％    18.8％    23.3％未处理的对照组 16.5     35.3％    39.7％结果表明制剂1和2作用相似，与未处理的对照组相比，均优于对照组。这表明这些制剂是非干性的。这两种制剂奇特之处在于，没有发现这种含有高浓度乙醇的制剂产品具有明显的干燥作用。
为评价该抗微生物剂性能，采用各种微生物菌株试验下面制备的制剂产品：去离子水27.8；乙醇62.0(按体积计)；ULTREZ 10 0.55；甘油0.5；环甲基硅油(245)1.25；DowComing 580蜡0.025；SILSOFTPEDM0.2；CERAPHYL-28 0.5；CERAPHYL-41 1.0；苯氧乙醇0.5；苯扎氯铵(50％活性)0.2；PHOSPHOLIPID CDM 0.05；GERMABLLPLUS 0.1；GERMABENⅡ 0.1；1906-AD ModI 0.06和pH调节剂。
该制剂的抗微生物性能以99％(w/v)浓度评价，露置十五秒、三十秒和一分钟。采用0.1ml的等分的大约1.0×109CFU/ml的激发悬浮液制备样品，并添加至9.9ml的产品，充分混合达到99％(w/v)的浓度。用一已校准的分钟/秒计时器计时15秒、30秒和一分钟露置时间。
把0.1ml的激发悬浮液放入含有9.9ml Butterfield′s磷酸盐缓冲液的消毒试管中。这缓冲液用作对照物。以Butterfield′s磷酸盐缓冲液制备适当的十倍稀释液。在35℃保温大约1-2天后，采用手摇计数器对板上的菌落计数。平板菌落数的常用对数值与原始菌落数比较。需要说明的是下面所报告的数目10+7是指107。结果如下所示：
有机体蜡状芽孢杆菌枯草杆菌白色念珠菌粪肠道球菌大肠杆菌绿脓杆菌鼠伤寒沙门氏菌粘质沙雷氏杆菌 暴露时间15秒30秒60秒15秒30秒60秒15秒30秒60秒15秒30秒60秒15秒30秒60秒15秒30秒60秒15秒30秒60秒15秒30秒60秒     接种浓度LOG5.71185.71185.71185.43935.43935.43937.36647.36647.36647.18477.18477.18477.36087.36087.36087.08647.08647.08646.80286.80286.80287.3567.3567.356     接种浓度CFU/ml5.150×10+55.150×10+55.150×10+52.750×10+52.750×10+52.750×10+52.3250×10+72.3250×10+72.3250×10+71.530×10+71.530×10+71.530×10+72.2950×10+72.2950×10+72.2950×10+71.220×10+71.220×10+71.220×10+76.350×10+66.350×10+66.350×10+62.270×10+72.270×10+72.270×10+7     暴露后Avg.Pop.LOG1.00001.00001.00004.73644.69024.68571.00001.00001.00001.39791.00001.00001.00001.00001.00001.00001.00001.00001.00001.00001.00001.00001.00001.0000 暴露后Avq.pop.CFU/ml1.00×10+11.00×10+11.00×10+15.450×10+44.90×10+44.850×10+41.00×10+11.00×10+11.00×10+12.50×10+11.00×10+11.00×10+11.00×10+11.00×10+11.00×10+11.00×10+11.00×10+11.00×10+11.00×10+11.00×10+11.00×10+11.00×10+11.00×10+11.00×10+1  Log减少量4.71184.71184.71180.70290.74910.75366.36646.36646.36645.78686.18476.18476.36086.36086.36086.08646.08646.08645.80285.80285.80286.35606.35606.3560 减少量％99.9981％99.9981％99.9981％80.1818％82.1818％82.3636％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％99.9999％
该制剂显示出极佳的抗微生物活性，对全部列出的微生物减少量为99％。上面的微生物包含广泛的各种微生物，包括革兰氏阳性菌、革兰氏阴性菌和真菌。实施例8
除了试验品之外，指示受试者不要使用任何抗微生物和或杀菌剂用品。将大约11.5ml的消毒熔融大豆酪蛋白水解琼脂(molten soybean casein digest agar)填充至培特利式培养皿。接种之前固化该琼脂并将其放入35℃恒温箱中过夜。在胰酶解酪蛋白大豆肉汤液体培养基中培养试验细菌，并且将其稀释以得到每10微升大约200-300菌落形成单位(CFU)。用10微升的接种棒将10微升的最终稀释液传送至每个琼脂平板的表面上，并且用此棒在平板表面上涂布。在施用到受试者臂上之前，让该平板在培特利式培养皿中干燥15-30分钟。施用到受试者臂上之前，在臂上使用70％异丙醇大约10秒钟，以减少污染的可能性。技术人员将大约2.5ml的试验溶液用至受试者臂的掌侧表面。然后受试者从手腕至肘部涂匀该溶液直到试验品消失。
在施用和晾干后，用抗微生物溶液立即(处理后5分钟内)、处理后1小时、3小时、5小时或者8小时激发受试者。该抗微生物溶液是市售的62％(按体积)乙醇(标识为A)和上面实施例7中使用的制剂(标识为B)。结果如下：
处理：暴露时间 未处理过的试验点* 处理过的试验点*
    B-8小时     77     83
    118     125
    64     71
    103     115
    88     111
    107     97
    平均菌落     92.8     100
    B-5小时     124     125
    84     83
    135     89
    67     93
    87     21
    134     40
    平均菌落     105     76
    B-3小时     132     6
    87     0
    127     3
    107     10
    153     86
    113     48
    平均菌落     120     26
    B-1小时     79     63
    100     5
    68     81
    71     2
    127     10
    118     0
    平均菌落     94     27
    A-1小时     139     169
    130     136
    121     164
    137     167
    98     135
    99     117
    平均菌落     121     148
    B-5分钟     91     0
    142     1
    116     2
    86     0
    95     0
    91     0
    平均菌落     104     0.5
*菌落形成单位(CFU)上面的数据表明本发明在5分钟时杀灭微生物是非常有效的，并且3小时后在防止微生物的生长方面具有非常有效的残留活性。

Claims (10)

1．一种抗微生物组合物，包含：a)一种抗微生物剂，选自由大于30体积百分比的醇和有效剂量的三氯生组成的组；和b)有效剂量的苯氧乙醇、苯扎氯铵或苄索氯铵；和氯化可可磷脂酰二铵。
2．权利要求1的组合物，其中苯氧乙醇为大约0.25至大约5.0重量百分比；苯扎氯铵大约为0.02至大约1.0重量百分比；以及氯化可可磷脂酰二铵为大约0.01至1.0重量百分比。
3．权利要求1的组合物，其中a)部分的抗微生物化合物是三氯生。
4．权利要求1的组合物，该组合物还含有效剂量的吡唑烷基脲和3-碘代-丙炔基丁基氨基甲酸盐。
5．权利要求4的组合物，其中吡唑烷基脲和3-碘代-丙炔基丁基氨基甲酸盐为大约0.05至大约0.5重量百分比。
6．权利要求4的组合物，该组合物还含有效剂量的吡唑烷基脲；对羟基苯甲酸甲酯；对羟基苯甲酸丙酯；和丙二醇。
7．权利要求6的组合物，其中吡唑烷基脲；对羟基苯甲酸甲酯；对羟基苯甲酸丙酯；和丙二醇的量为大约0.05至大约0.5重量百分比。
8．一种抑制金黄色葡萄球菌(MRSA)的方法，包含对基质局部给一种抗微生物有效剂量的权利要求1的组合物。
9．一种抑制粘质沙雷氏菌ATCC 14756的方法，包含对基质局部给一种抗微生物有效剂量的权利要求1的组合物。
10．一种包含一种有效剂量的分散剂、醇、有效剂量的苯氧乙醇、苯扎氯铵和氯化可可磷脂酰二铵的乳剂。
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