CN101573031B - 抗微生物组合物 - Google Patents
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Abstract
抗微生物组合物,包括(a)由脂肪酸与酯化的碱性氨基酸缩合而成的阳离子表面活性剂,例如月桂酰精氨酸酯和(b)抗生素,例如β-内酰胺类抗生素、多肽类和喹诺酮类。上述组合物可以单独作为抗微生物制剂使用,或者与医疗用品或医疗装置联用。
Description
发明领域
本发明涉及新型抗微生物组合物及其制备方法和使用方法,所述抗微生物组合物包括:(a)由脂肪酸与酯化的碱性氨基酸(dibasicamino acid)缩合而成的阳离子表面活性剂和(b)抗生素。更具体地说,本发明涉及新型抗微生物组合物,包括月桂酰精氨酸酯(lauricarginate)(LAE)和选自β-内酰胺类抗生素,多肽类和喹诺酮类的抗生素。本发明还涉及利用上述新型抗微生物组合物的医疗装置。
发明背景
每年,在美国患者要经历大量的外科手术。现有数据显示每年完成的手术大约有2700万例。全部病例中约2%-3%会发生手术后感染或手术部位感染(“SSI”)。总计每年超过675,000例SSI。
每当在手术环境中使用医疗装置时,就会有感染的风险。感染的风险随着介入或植入式医疗装置(invasive or implantable medicaldevice)的使用而显著地增加,例如静脉内导管、动脉移植物、鞘内或大脑内的分流器和假体装置,当与人体组织和体液密切接触时,这些医疗装置为病原体创造了入侵的入口。SSI的发生往往与群集在医疗装置上的细菌有关。例如,在外科手术期间,来自周围环境的细菌可能进入手术部位并且附着于医疗装置上。细菌可以利用植入式医疗装置作为到达周围组织的通道。这样的细菌群集在医疗装置上可能导致患者感染、发病和死亡。
许多用于降低与介入或植入式医疗装置有关的感染风险的方法已经被开发出来,即在医疗装置中加入抗微生物剂。当使用这些装置时,它们预期地提供了有效水平的抗微生物剂。例如,医疗装置可以含有如β-内酰胺类抗生素、多肽类和喹诺酮类的抗生素。然而,由于抗生素稳定性低以及更值得注意的抗生素抗性细菌越来越多地出现,含有抗生素的医疗装置可以遭致功效损失。例如,尽管已知β-内酰胺类抗生素对金黄色葡萄球菌(S.aureus)——被认为是外科感染的最常见起因的细菌品种有效,但这类抗生素对于抗生素抗性细菌则无效,例如MRSA(耐甲氧苯青霉素金黄色葡萄球菌(Staphylococcus aureus))和MRSE(耐甲氧苯青霉素表皮葡萄球菌(Staphylococcus epidermidis))。
上述问题的一个解决方案是联用抗生素和非抗生素抗微生物剂破坏或抑制抗生素抗性细菌的生长。特别地,如果非抗生素抗微生物剂具有与抗生素剂不同的生物有效度模式和作用模式则是有利的。常常需要使用不同作用模式的抗微生物剂混合,来实现对不同生物体、尤其是针对抗生素抗性细菌的更广谱抗微生物活性。
US20050192547 A1描述在医疗装置中联用防腐剂与抗生素。特别地,此文献描述应用(i)二甲胺四环素、三氯生和铋盐;(ii)二甲胺四环素、氯己定化合物和铋盐;以及(iii)二甲胺四环素、苯扎氯铵和铋盐来阻止抗生素抗性生物体形成。
迄今还没有关于联用(a)由脂肪酸与酯化的碱性氨基酸缩合而成的阳离子表面活性剂和(b)抗生素的报道。例如,联用LAE和抗生素,致使针对更广谱生物体、尤其是抗生素抗体细菌的抗微生物活性增强。
发明概述
本文描述的是抗微生物组合物,其包括(a)由脂肪酸与酯化的碱性氨基酸缩合而成的阳离子表面活性剂,例如月桂酰精氨酸酯和(b)一种以上抗生素,例如β-内酰胺类抗生素类、多肽类和喹诺酮类。上述组合物可以单独作为抗微生物制剂使用,或者与医疗用品或医疗装置联用。
发明详述
本发明指的是抗微生物组合物,其包括(a)由脂肪酸与酯化的碱性氨基酸缩合而成的阳离子表面活性剂和(b)一种以上抗生素。更具体地说,本发明指的是可以与医疗装置联用的抗微生物组合物,其包括月桂酰精氨酸酯(LAE)和一种以上抗生素,其中通过掺入(incorporate)月桂酰精氨酸酯(LAE)和抗生素,所述装置的抗微生物性能得到改进。已经发现的是,上述组合物表现协同抗微生物作用。
本发明使用的术语“协同”意指应用两种以上药剂所产生的生物效应比单独应用这些药剂所产生的生物效应的总和更大。
本文所述的阳离子表面活性剂由脂肪酸与酯化的碱性氨基酸缩合而成。更具体地说,所述阳离子表面活性剂指的是由脂肪酸与酯化的碱性氨基酸缩合而成的具有下式的一类化合物:
其中X是Br、Cl或HSO4;R1是来自通过酰胺键与α-氨基酸基连接的8-14个碳原子饱和脂肪酸或羟基酸的直链烷基;R2是1-18个碳原子的直链或支链烷基或芳基;R3是以下中的一种:
—NH3
而n可以为0-4。
这类阳离子表面活性剂的特例是月桂酰精氨酸酯(LAE,由Lamirsa Laboratories,Barcelona,Spain制造)。月桂酰精氨酸酯——由月桂酸和精氨酸衍生的阳离子防腐剂、更具体地说是单盐酸精氨酸的月桂酰胺的乙酯,可以用于起抗微生物生长的保护作用。LAE的化学结构如式(III)所示:
本文所指的抗生素是天然来自真菌或细菌或者合成的破坏或抑制微生物生长的物质。抗生素的一般种类包括但不限于β-内酰胺类抗生素、多肽类和喹诺酮类。更具体地说,所述抗生素可以选自:青霉素类、头孢菌素类、碳青霉烯类、β-内酰胺类抗生素类、氨基糖苷类、酰胺醇类(amphenicols)、安莎霉素类、大环内酯类、林可霉素类、糖肽类、多肽类、四环素类、氯霉素类、喹诺酮类、梭链孢素类、磺酰胺类、砜类、硝基呋喃类、二氨基嘧啶类、甲氧苄啶类、利福霉素类、喹噁啉类(oxalines)、链阳性菌素类、脂肽类、酮内酯类、多烯类、唑类、棘球白素类、及它们的任何组合。抗生素,特别是β-内酰胺类抗生素、多肽类和喹诺酮类、或其混合物对广谱微生物特别有效,即对各种各样微生物有效,尤其是对革兰氏阴性细菌和革兰氏阳性细菌。
在一组具体的非限定性实施方案中,所述抗微生物组合物包含(a)由脂肪酸和酯化的碱性氨基酸缩合而成的阳离子表面活性剂和(b)一种以上抗生素,作为单独的抗微生物组合物制剂,与任何医疗装置或具体应用无关。本发明抗微生物组合物制剂可以是液态(例如溶液)或固态(例如粉末)。例如,所述抗微生物组合物可以直接应用到伤口。
已经发现,LAE与一种以上抗生素组合比单独LAE或单独抗生素活性更好,LAE起抗微生物增强剂(enhancing agent)作用。本发明抗微生物组合物的特征在于其协同作用,协同作用是指两种以上组分共同作用比它们单独使用时的作用总和更大的现象。现在已经发现LAE与一种以上抗生素结合的抗微生物活性比相同剂量的上述每种组分单独使用时所表现的活性更高。上述LAE活性增强作用可以通过其破坏微生物细胞膜的作用模式来解释。
这种增强的抗微生物活性使得所述组合物对于针对范围广的微生物具有单独使用这两种化合物所不具备的有效水平。这种结合的使用被认为对更广的抗微生物谱有效,包括但不限于:脚癣、甲癣、股癣、或头癣,金黄色葡萄球菌(S.aureus)、MRSA、MRSE、GISA、表皮葡萄球菌(S.epidermidis)、大肠杆菌(E.coli)、铜绿假单胞菌(P.aeruginosa)、肺炎克雷伯氏菌(K.pneumoniae)、洋葱假单胞菌(B.cepacia)、阴沟肠杆菌(E.cloacae)、粘质沙雷氏菌(S.marcescens)、酿脓链球菌(S.pyogenes)、无乳链球菌(S.agalacticae)、耐万古霉素粪肠球菌(E.faecalis-Vancomycin Resistant)、粪肠球菌(E.faecium)、白色念珠菌(C.albicans)和枯草芽孢杆菌(B.subtilis)、沙门氏菌(Salmonella sp.)、变形菌(Proteus sp.)、不动杆菌(Acinetobactersp.)、黑曲霉(Aspergillus niger)。
为了展示所述抗菌组合物的协同作用,单独的抗微生物组合物可以包含基于组合物总重量约0.001%至约1%(重量)的LAE,和相对于组合物总重量约0.001%至约1%(重量)的抗生素。更优选本发明的抗微生物组合物包含基于组合物总重量约0.01%至约0.1%(重量)的LAE,和相对于组合物总重量约0.01%至约0.1%(重量)的抗生素。
在另一组非限定性实施方案中,本发明提供掺有抗微生物组合物的医疗装置。本文所用术语“掺入”、“已掺入”或“经掺入”意指用物理或化学方法使所述组合物与医疗装置结合。实例包括但不限于用抗微生物组合物灌注、浸渍、浸泡或涂布医疗装置或者向制成医疗装置的材料加入抗微生物组合物来制造医疗装置。可以依照本发明处理的医疗装置由生物医学聚合物制成、或者被生物医学聚合物覆盖或处理,其包括但不限于:微胶囊、敷料、植入物、伤口愈合剂(wound closure)、U形钉、网、药物控释体系、伤口覆盖物、填料、缝合线、组织粘合剂(tissue adhesive)、组织密封剂(tissue sealant)、可吸收和不可吸收的止血器(hemostat)、包括导尿管和导血管的导管(例如,外周和中心的导血管)、伤口引流管、动脉移植物、软组织片(例如聚四氟乙烯(“PTFE”)软组织片)、手套、分流器、移植片固定模、气管导管、创伤敷料、导线和假体装置(例如心瓣膜和LVAD)。本发明可以进一步应用于美国专利第3,839,297、4,027,676、4,185,637和4,201,216号中已制造的医疗用品中,以上专利内容如其阐述的完整性引入本文作为参考。
例如,当所述医疗用品是水凝胶、例如Nu-Gel水凝胶(可市购自Johnson & Johnson Medical,a divison of Ethicon,Inc.,Gargrave,U.K.)时,LAE的量可以是约0.001-100μg/cm2,优选约0.01-50μg/cm2,而抗生素的量可以是约0.001-1000μg/cm2,优选约0.01-100μg/cm。
尽管以下的实施例证明了本发明某些实施方案,但并不解释为限制本发明保护范围,而是有助于完整地描述本发明。
实施例1
抗生素-LAE组合物体外协同作用的评价
LAE和抗生素的协同作用由表1和表2出示的结果阐明,通过以下实验方案测定。在无菌盐水中制得浓度为1000ppm的月桂酰精氨酸酯(LAE)和抗生素溶液。随后制备上述两种贮备液的无菌盐水连续稀释液。将0.05ml的每种稀释液加入到0.95ml细菌培养物(含有106CFU/ml胰胨豆胨培养液)中。对照含有测试培养物中的相当量盐水而不含抗生素和LAE。使测试培养物在37℃下培养24小时,通过含失活剂的Trypticase soy agar(BBL)上平板计数计总活菌数。所述琼脂平板在37℃下培养48小时,记为菌落形成单位(CFU/ml)。以金黄色葡萄球菌(S.aureus)为例,对照培养物在没有月桂酰精氨酸酯(LAE)或抗生素存在下生长到1.1×109cfu/ml。
表1.LAE与抗生素对金黄色葡萄球菌(S.aureus)的体外协同作用
表2.LAE与抗生素对铜绿假单胞菌(P.aeruginosa)的体外协同作用
这些结果显示月桂酰精氨酸酯(LAE)与抗生素的协同作用。与对照相比,单独加入10ppm月桂酰精氨酸酯(LAE)导致少于半个对数减少值(log reduction)。与对照相比,单独加入抗生素所导致的是,对于10ppm头孢唑林和10ppm多粘菌素B而言活菌对数减少值小于1,对于0.2ppm左氧氟沙星而言活菌对数减少值为5。如表1和2中所示,与单独使用相同浓度的LAE或抗生素所提供的(0.2-5log)相比,LAE与上述抗生素联合对于抗革兰氏阳性和革兰氏阴性细菌都提供了大很多的对数减少值(9log)。
实施例2
使用实施例1描述的相同实验方案,测定LAE与抗生素针对临床上主要的抗性细菌——耐甲氧苯青霉素金黄色葡萄球菌(MRSA)和耐甲氧苯青霉素表皮葡萄球菌(MRSE)的体外协同作用。结果列在表3中。所用的MRSE是MRSE 700563和MRSE 51625。所用的MRSA是MRSA-002和MRSA-006。(来自内部培养物收集)
表3.LAE与抗生素对耐甲氧苯青霉素金黄色葡萄球菌(MRSA)和耐甲氧苯青霉素表皮葡萄球菌(MRSE)的体外协同作用
实施例3
当LAE与抗生素组合物被掺入医疗装置例如Nu-Gel水凝胶(Johnson & Johnson Medical,Divison of Ethicon,Inc.,Gargrave,U.K.)中时,观测到此组合物的协同作用。根据实施例1制备含有LAE和/或抗生素的溶液。将所述水凝胶切成0.7×0.7cm的正方形并浸没在实施例1和2中所述已制备的LAE和抗生素贮备液中10min。处理后的水凝胶方块在室温下干燥10min,然后放在经接种耐甲氧苯青霉素金黄色葡萄球菌(MRSA)和耐甲氧苯青霉素表皮葡萄球菌(MRSE)的TSA琼脂平板上。该平板在37℃下培养48小时。
测量抑菌区——定义为以毫米计从方块四条边到在方块周围清晰区域的四条边的平均距离。表4中出示的结果表明,与单独使用LAE和抗生素相比,月桂酰精氨酸酯(LAE)与抗生素的联合对耐甲氧苯青霉素金黄色葡萄球菌(MRSA)和耐甲氧苯青霉素表皮葡萄球菌(MRSE)具有改良的抗菌活性。未处理的水凝胶方块与用LAE或抗生素单独处理的水凝胶方块均没形成抑菌区,而用LAE与抗生素联合处理的方块显示清晰抑菌区。
这种协同作用证明:通过使LAE和一种以上抗生素的组合以这些药剂单独使用时有效的浓度掺入,可以制造出针对抗生素抗性细菌功效好的医疗装置。
Claims (12)
3.权利要求1的抗微生物组合物,其中所述抗生素为头孢唑林、多粘菌素B、左氧氟沙星、及其任意组合。
5.权利要求4的抗微生物组合物,其中所述抗生素为头孢唑林、多粘菌素B、左氧氟沙星、及其任意组合。
6.权利要求4的抗微生物组合物,其中基于所述组合物总重量,月桂酰精氨酸酯的浓度为0.001%-1%重量,所述抗生素的浓度为0.001%-1%重量。
7.权利要求4的抗微生物组合物,其中基于所述组合物总重量,所述月桂酰精氨酸酯和抗生素的浓度为0.01%-0.1%重量,所述抗生素化合物的浓度为0.01%-0.1%重量。
9.权利要求8的医疗装置,其中所述阳离子表面活性剂是月桂酰精氨酸酯,根据下式:
10.权利要求8的医疗装置,其中所述抗生素为头孢唑林、多粘菌素B、左氧氟沙星、及其任意组合。
12.权利要求11的医疗装置,其中所述抗生素为头孢唑林、多粘菌素B、左氧氟沙星、及其任意组合。
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