CN114588077A - 液体抗微生物组合物 - Google Patents

液体抗微生物组合物 Download PDF

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CN114588077A
CN114588077A CN202210183721.5A CN202210183721A CN114588077A CN 114588077 A CN114588077 A CN 114588077A CN 202210183721 A CN202210183721 A CN 202210183721A CN 114588077 A CN114588077 A CN 114588077A
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dendritic polymer
cationic
disrupting
generation
branched polymer
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A·N·费洛斯
M·J·哈里南
D·密斯特里
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Gama Healthcare Ltd
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Abstract

提供了一种液体抗微生物组合物，用于消毒人或动物的皮肤，具体是需要消毒药物耐受生物体时。该组合物包含破坏细胞膜的阳离子杀微生物剂和能够抑制所述细胞膜的外排泵机制的阳离子枝化聚合物。破坏细胞膜的阳离子杀微生物剂优选是氯己啶、聚合双胍、奥替尼啶二盐酸盐和季铵化合物中的任一种或其组合。提供的枝化聚合物能够结合和破坏微生物的细胞膜，抑制或破坏细胞的外排泵机制，从而防止微生物株对越来越普遍的破坏细胞膜的阳离子杀微生物剂产生耐受性，尤其是当杀微生物剂包含氯己啶时。枝化聚合物优选是0代至3代的枝化聚合物，包含聚(丙烯亚胺)官能化的季铵、聚赖氨酸、具有基于糖的表面基团的枝状聚合物和聚酰胺胺(PAMAM)枝状聚合物中的任一种或其组合。组合物优选是可以由擦拭巾吸附的水性或水醇溶液、分散体或乳液形式。

Description

液体抗微生物组合物
技术领域
本发明涉及液体抗微生物组合物，具体涉及可能需要消毒药物耐受性生物体的在人或动物的皮肤消毒中使用的组合物。
背景技术
破开皮肤屏障和允许微生物进入而可能导致感染的手术之前需要消毒皮肤。这些微生物可以是来自环境或设备的外部污染物，或者可以是正常的共生皮肤菌落，虽然在正常的外部场合中是无害的，但是可能导致体内严重感染。还有益的是提供清洁和消毒不能沐浴或淋浴的医院患者的皮肤的方法。
出于这些目的在皮肤上已经使用了许多试剂。过去，使用氯化钙和其他氯供体化学试剂，但是这些物质攻击性高而损害皮肤。近来，使用诸如碘附、聚维酮碘、醇凝胶、水性氯己啶和含醇氯己啶制剂等试剂。单独的醇，不论是乙醇还是丙-2-醇，是有效的皮肤消毒剂，但是效果持续时间短。目前，含醇氯己啶是广泛使用的试剂选择，因为其组合了氯己啶的阳离子残留物和长效抗微生物活性以及醇的活性。70％醇与2-4％氯己啶的组合显示高度有效，在全球被广泛使用，尤其针对小的手术位点消毒和与中央线和静脉导管插管相关的消毒要求。
氯己啶和其他阳离子消毒剂也在基于水的皮肤护理制剂中被广泛使用，例如患者床浴擦拭巾、以液体或擦拭巾呈现的术前皮肤消毒产品、以及抗菌香波帽和制剂等产品中。它们优异的抗菌活性谱结合优良的残留活性和相对安全性是这些产品获得成功的主要原因。
然而，虽然在健康护理中是高度有效和有益的产品，近来健康护理团体注意到对氯己啶的耐受性提高以及一些对氯己啶耐受的菌株越来越多。这是一个严重的问题。虽然与应用于皮肤的2-4％水平相比在浓度方面注意到耐受性水平增加较小；因为涉及延长的残留活性的整个作用机制以及非常低残留浓度在皮肤上的持续存在，这种低水平增加假定氯己啶的重要性。如果细菌耐受性增加，则氯己啶的残留活性效果将受到严重损害。关于针对氯己啶的增加的皮肤过敏反应，甚至是氯己啶导致的过敏性病例已经获得关注。
生物体通过突变和选择外排泵机制具有更大的有效性的那些的方式导致氯己啶和其他阳离子杀生物剂的耐受性增加。外排泵是诸如qacA和cepA的基因编码的蛋白质，嵌入在细菌细胞质膜中。其功能是识别穿透细胞壁并到达周质或细胞质的有毒、潜在的有害的试剂。然后，外排泵在该试剂到达其目标之前将它们挤出和排出至外部环境。因此，外排泵是将有害化合物从细菌细胞内转运至外部环境的转运蛋白。这可通过利用来自三磷酸腺苷(ATP)或质子动力势(pmf)的能量来实现。所谓的ABC转运蛋白直接利用ATP而RND 型外排泵利用水合氢离子pH梯度。外排泵表达和提高可以是因为染色体突变或质粒获取。外排泵机制的过度表达导致破坏细胞膜的抗微生物试剂的耐受性增加，可导致多药耐药性(MDR)菌株。
通过外排泵机制的研究理解其功能，并且随后可以抑制这些功能的方式。已鉴定了四种主要的外排泵抑制机制。它们阐述如下。
1.降低细菌细胞与在外排泵中发挥辅因子作用的诸如Ca2+等离子的接触。
2.抑制由质子动力势(pmf)提供的能量。
3.抑制提供用于维持pmf所需的水合氢离子的酶。
4.与外排泵接触的侵入性有害试剂竞争，例如通过非特异性阻断或细菌外膜涂层。
在提供局部抗菌治疗的临床应用中，并非所有这些外排泵抑制途径都同等可行。
除了氯己啶，已知其他阳离子杀微生物剂也是膜活性，它们击穿和/或穿透微生物细胞膜。它们的例子是聚合双胍如聚六亚甲基双胍(PHMB)、聚六亚甲基双胍盐酸盐，奥替尼啶二盐酸盐和季铵化合物。虽然这些阳离子杀微生物剂中的一些还没有显示形成外排泵机制的耐受性，认为抑制相对于这些杀微生物剂的流出泵机制也是有益的。
因此，本发明的目的是提供一种在人或动物的皮肤消毒中使用的液体抗微生物组合物，维持破坏细胞膜的阳离子杀微生物剂治疗皮肤的抗微生物益处，同时消除或减轻微生物通过外排泵途径形成针对其的耐受性增加。
发明内容
根据本发明，提供了一种在人或动物的皮肤消毒中使用的液体抗微生物组合物，包含破坏细胞膜的阳离子杀微生物剂和能够抑制所述细胞膜的外排泵机制的阳离子枝状聚合物。
申请人已发现，阳离子枝状聚合物能够结合和破裂细菌膜从而抑制或破坏流出泵机制。组合物中加入枝状聚合物也可提高组合物的抗病毒性质。这种枝状聚合物无需是本身足以符合调控规定的杀微生物剂，但因为它们抑制微生物细胞膜的流出泵机制的能力，它们显著降低微生物对与其一起的组合物中使用的破坏细胞膜的阳离子杀微生物剂形成提高的耐受性的能力。
还优选地，破坏细胞膜的阳离子杀微生物剂包含氯己啶、聚合双胍、奥替尼啶二盐酸盐和季铵化合物中的任一种或其组合。
优选地，破坏细胞膜的阳离子杀微生物剂是葡萄糖酸盐或乙酸盐形式的氯己啶。有益地，氯己啶在组合物中的浓度为0.25％至6.00％w/v。该浓度是适合在人和动物的皮肤上使用的局部消毒中应用的浓度。
枝状聚合物是围绕核心典型地对称的重复支化分子。通过控制核心基团、支化以及表面上的官能团的性质和数量，可以合成具有各种物理化学性质的枝状聚合物。存在许多对于本发明而言有价值的变化。
枝状聚合物也可分为几代，是指其合成过程中进行的重复支化循环的次数。每个连续的代导致大致是前一代的分子量两倍的枝状聚合物。分类为0 代至2代枝状聚合物(G0-G2)的较低代的枝状聚合物是没有可辨识的内部区域的柔性分子，而中等大小的3代(G-3)和4代(G-4)的枝状聚合物通常具有与枝状聚合物的外壳分离的内部空间。非常大的7代(G-7)和更大的枝状聚合物更像固体颗粒，由于其外壳结构而具有非常致密的表面。较高的代的枝状聚合物在表面上也具有更多暴露的官能团，使得它们能够定制化适合给定应用。
在本发明中，0代至3代枝状聚合物，更优选0代至2代枝状聚合物是优选的，因为它们形成平面、所谓的“海星”状构象并且已发现它们在破裂流出泵机制或微生物中比4代及以上的枝状聚合物更有效。
枝状聚合物可以是聚(丙烯亚胺)官能化的季铵、聚赖氨酸、具有基于糖 (例如甘露糖或麦芽糖)的表面基团的枝状聚合物。本发明中有价值的其他类型的枝状聚合物包括聚(酰胺-胺)或PAMAM枝状聚合物，尤其是具有表面氨基基团的那些。聚(酰胺-胺)或PAMAM枝状聚合物的核心是二胺，通常是乙二胺，与丙烯酸甲酯、然后是另一乙二胺反应，得到0代(G-0)PAMAM。连续反应产生更高的代。
大分子的枝状聚合物通常产生相对于分子大小低粘度的溶液，优选组合物包含0.01％w/v至2％w/v的枝状聚合物。当组合物包含2％至4％氯己啶溶液时该范围尤其有益。
优选地，组合物是水性或水醇溶液、分散体或乳液，例如采用异丙醇。
组合物也可包含表面活性剂以提供清洁和润湿性质，具有杀微生物性质的溶剂如醇，在硬水中使用可能存在问题的螯合剂。润肤剂和皮肤调理化学物质也可加入组合物中，例如醋酸生育酚。防腐剂如苯扎氯铵和/或柠檬酸也可以以合适的量加入。
组合物中优选包含0.05％w/v至5.00％w/v的表面活性剂。合适的表面活性剂是那些表征为环氧乙烷和环氧丙烷的二嵌段或三嵌段共聚物的那些，例如聚(环氧乙烷)-b-(环氧丙烷)-b-(环氧乙烷)，即PEO-PPO-PEO嵌段共聚物，末端为羟基。它们例如由BASF公司生产，以商品名普流罗尼
Figure RE-GDA0003638135400000051
销售。该公司销售的合适的表面活性剂是普流罗尼
Figure RE-GDA0003638135400000052
P85。这些嵌段共聚物表面活性剂可以作为单一分子量产品单独使用，例如选自诸如泊洛沙姆的共聚物，或者作为两种或更多种这样的表面活性剂的组合使用。其他合适的表面活性剂是聚乙二醇(PEG)，例如PEG 40。这些单独或组合的表面活性剂又可以与其他类型的表面活性剂组合，例如葡萄糖苷、多聚葡萄糖苷、直链醇乙氧基化物等。尤其优选非离子表面活性剂。
此外，优选显著比例的表面活性剂的亲水-亲脂平衡(HLB)值为10-17。这些表面活性剂是水溶性的，HLB值在12以上的那些用作水包油乳化剂。如果组合物是水性溶液以及配制成包含精油或精油组分作为表面活性剂(例如聚乙二醇)的话这是有益的，用于将精油在整个溶液中分配。
润湿剂如聚山梨酯20和非离子发泡表面活性剂如辛酰基/癸基葡糖苷也可添加到组合物中。
在水性或水醇溶液的组合物制剂中，表面活性剂形成的胶束不是希望的，这会降低组合物作为流出泵抑制剂的功效。因此，优选表面活性剂的浓度在其临界胶束浓度以下。有益地，表面活性剂的浓度在其临界胶束浓度以下至少10％。
此外，天然和合成聚阳离子可在本发明的组合物中发挥有用的作用。合成的聚阳离子的例子例如聚(烯丙胺)盐酸盐、聚六亚甲基双胍盐酸盐、聚(二烯丙基甲基氯化铵)、聚(乙烯亚胺)和聚乙烯吡咯烷酮。天然聚阳离子的例子是聚-L-鸟氨酸、聚-L-精氨酸、鱼精蛋和壳聚糖。
螯合剂例如依替膦酸(1-羟基乙烷1,1-二膦酸(HEDP))、乙二胺、二或四乙酸盐、膦酸盐、氮川乙酸盐(nitriloacetate)或其他也可加入组合物中，作为可能的精油或选择的精油组分。优选地，螯合剂的用量为组合物的 0.05％w/v至1.00％w/v。
如上所述，优选地包含精油或精油组分以及将其分散到整个组合物中的合适的溶剂。合适的溶剂包括乙醇和聚乙二醇，它们也可以以上文所述的表面活性剂的形式存在。精油或精油组分优选地是组合物的0.01％w/v至 1.00w/v％。
上文所述本发明的组合物最大程度地降低形成针对组合物中破坏细胞膜的阳离子杀微生物剂的抗微生物耐受性的风险。枝化聚合物与微生物的细胞膜相互作用，导致微量粘度降低。在哺乳动物中已注意到，这伴随着P-糖蛋白活性的抑制。已发现在结构类似于P-糖蛋白(P-gp)的ABC流出转运蛋白的细菌中发生类似的作用。强能量消耗、流出蛋白的抑制和后续的ATP消耗导致药物流出系统的关闭，从而增加杀微生物剂输入；实质上生物体对杀微生物剂增敏。
对转运机制的干扰可以通过膜ATP酶分析和细胞钙黄绿素分析来检测。孔蛋白表达也可以通过溴化乙锭或吖啶橙技术来检测，评价具体的制剂的功效及其对患者护理的各个方面的关联性。同样，抑制流出泵机制也将对生物膜产生和微生物群的群体感应产生有益影响。这将进一步改善本发明涵盖的制剂中杀微生物剂的功效。
其他化合物也可能适合加入本发明的具体制剂中。具体说，也可以抑制流出泵机制的化合物。这可以从各种化学基团获得，包括吩噻嗪神经活性药物、某些精油和精油组分如小檗碱、意大利蜡菊(helichrysum italicum)、香叶醇、蒎烯、α姜碱、萜、茶树油等以及一些复合表面活性剂。
为了证明使用枝状聚合物在抑制耐受微生物的流出泵机制中的有效性，检测氯己啶二葡萄糖酸盐针对选择的细菌的最小抑制浓度(MIC)，然后与包含阳离子枝状聚合物的氯己啶二葡萄糖酸盐制剂进行比较。该方法采用MIC测定的双重稀释(50％稀释)浊度法。检测采用
Figure RE-GDA0003638135400000071
C以及Thermo实验室分析有限公司(Thermo Labsystems,Inc.)的后续软件进行，分析孵育的分光光度计中的2x 100孔。与选择的细菌一起，在各种组合中加入或不加入各种阳离子枝状聚合物，在孔中制备氯己啶二葡萄糖酸盐的双重稀释液。微孔板在37℃孵育，在24小时的时间内以规则的时间间隔通过光密度测定最小抑制浓度。
选择用于检测的细菌是绿脓假单胞菌，因为其基因组包括所需的基因 (cepA)。采用该测试方案，因为其能够立即测定多种制剂。因此，该方法能够在采用相同条件处理时比较氯己啶二葡萄糖酸盐对照与包含阳离子枝状聚合物的制剂。
进行初始测试以确定单独的氯己啶二葡萄糖酸盐和阴性对照的MIC，消除制剂中其他化学成分的潜在干扰。单独的氯己啶二葡萄糖酸盐和排除阳离子枝状聚合物的含氯己啶二葡萄糖酸盐的制剂之间未观察到显著性差异。可见，采用氯己啶二葡萄糖酸盐、枝化聚合物和嵌段共聚物的组合获得最佳结果。然而，虽然测试证明枝化聚合物和枝化聚合物嵌段共聚物制剂的有效性，但是并非所有制剂同等有效。
附图说明
图1和2是单独的氯己啶二葡萄糖酸盐和与阳离子枝化聚合物组合时的 MIC结果。
具体实施方式
检测的四种制剂如下所示，两种是水性溶液，两种是水醇溶液。氯己啶二葡萄糖酸盐浓度双重稀释。在制剂中，仅嵌段共聚物和枝化聚合物不变，即它们没有被稀释。测试结果在附图中以图形方式显示，其中，图1和2是单独的氯己啶二葡萄糖酸盐和与阳离子枝化聚合物组合时的MIC结果。测试中采用的四种制剂如下。
1.0代(G-0)枝化聚合物
Figure RE-GDA0003638135400000082
2.0代(G-0)枝化聚合物
Figure RE-GDA0003638135400000081
3.第1代(G-1)枝化聚合物
Figure RE-GDA0003638135400000091
4.第1代(G-1)枝化聚合物
Figure RE-GDA0003638135400000092
除了上述测试制剂，根据本发明的抗微生物组合物的制剂的其他优选的实施例如下所述。
实施例1
氯己啶葡萄糖酸盐 2.00％w/v
PEO-PPO-PEO嵌段共聚物 1.00％w/v
聚丙烯亚胺(PPI)枝化聚合物 0.01％w/v
乙二胺四乙酸二钠
(二钠EDTA) 0.05％w/v
水 至100％
实施例2
氯己啶葡萄糖酸盐 2.00％w/v
聚丙烯亚胺(PPI)枝化聚合物 1.00％w/v
PEO-PPO二嵌段共聚物 0.05％w/v
HEDP 0.02％
乙醇 70％
水 至100％
实施例3
氯己啶葡萄糖酸盐 4.00％w/v
香叶醇 1.00％w/v
聚赖氨酸枝化聚合物 0.05％w/v
聚六亚甲基双胍盐酸盐 0.50％w/v
苯氧乙醇 0.20％w/v
PEG 40 0.50％w/v
水 至100％
实施例4
苯扎氯铵 1.00％w/v
氯化十六烷基吡啶鎓 0.50％w/v
阳离子枝化聚合物 1.00％w/v
辛酰基葡糖苷表面活性剂 0.05％w/v
PEO/PPO嵌段共聚物表面活性剂 0.50％w/v
水 至100％
实施例5
奥替尼啶二盐酸盐 2.00％w/v
PAMAM枝化聚合物 1.00％w/v
聚山梨酯20 0.50％w/v
甘油 1.00％w/v
芦荟 0.50％w/v
基于精油的芳香剂 0.10％w/v
EDTA二钠盐0.05％w/c
水 至100％
实施例6
氯己啶葡萄糖酸盐 2.5％w/v
异丙醇 70.0％w/v
聚丙烯亚胺枝化聚合物 1.5％w/v
苯氧乙醇 0.2％w/v
水 至100％
应理解，适合人皮肤应用的制剂可以还包含常规成分如润肤剂、芳香剂和皮肤调理剂，取决于除了消毒之外所需的性质。这些制剂适合用作手术洗消液、皮肤伤口的清洁剂、术前皮肤制剂、手部杀菌洗剂等。在所有情况下，破坏细胞膜的阳离子杀微生物剂优选的浓度为0.25％w/v至6.00％w/v。其他类似的应用包括兽医学和畜牧业中的那些，例如日常卫生产品，尤其是挤奶前的卫生制剂和乳头浸泡。
本发明的组合物可以与例如机织、编织或非机织材料的擦拭巾、海绵以及复合材料(例如，方便使用的香波帽)联用。合适的擦拭巾可以由聚烯烃、聚酯、粘胶、棉花、纤维素或其他纤维中的任一项或其混合物构成。海绵擦拭巾可以由聚氨酯构成。组合物可以由这些复合材料、擦拭巾或海绵吸附，然后包装成适合由浴盆、水桶、流包装填塞物或独立密封的包裹物或包囊分配。

Claims (10)

1.用于抑制细胞膜的外排泵机制的阳离子枝状聚合物。
2.根据权利要求1所述的枝状聚合物，其中所述枝状聚合物是第0代至第3代枝状聚合物中的任一种或其组合。
3.根据权利要求1或2所述的枝状聚合物，其中所述枝状聚合物属于第1代。
4.根据前述权利要求中任一项所述的枝状聚合物，其中枝状聚合物是季铵官能化的聚(丙烯亚胺)、聚赖氨酸、具有基于糖的表面基团的枝状聚合物和聚酰胺胺(PAMAM)枝状聚合物中的任一种或它们的组合。
5.根据前述权利要求中任一项所述的枝状聚合物，其中所述枝状聚合物是聚(丙烯亚胺)。
6.根据前述权利要求中任一项所述的枝状聚合物，其中所述枝状聚合物是聚酰胺胺(PAMAM)枝状聚合物。
7.根据前述权利要求中任一项所述的枝状聚合物，其中所述枝状聚合物是第1代聚酰胺胺(PAMAM)枝状聚合物。
8.包含根据权利要求1-7中任一项的枝状聚合物的抗微生物组合物。
9.根据权利要求1-7中任一项所述的阳离子枝状聚合物或根据权利要求8所述的抗微生物组合物，用于对人或动物的皮肤进行消毒。
10.根据权利要求1-7中任一项所述的枝状聚合物或根据权利要求8所述的抗微生物组合物，用于预防或治疗由微生物特别是耐药性生物引起的感染。
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