CN1156404A - 抗微生物水包油乳液 - Google Patents
抗微生物水包油乳液 Download PDFInfo
- Publication number
- CN1156404A CN1156404A CN95194248A CN95194248A CN1156404A CN 1156404 A CN1156404 A CN 1156404A CN 95194248 A CN95194248 A CN 95194248A CN 95194248 A CN95194248 A CN 95194248A CN 1156404 A CN1156404 A CN 1156404A
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- Prior art keywords
- oil
- emulsion
- virus
- water
- antimicrobial
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Abstract
本发明公开了一种水包油抗微生物乳液,它包含一个选自如下种类的,作为主要乳化剂的成分:甘油一油酸酯,甘油三油酸酯,甘油一月桂酸酯,和甘油二月桂酸酯,还包含一个作为正电荷生成剂的,具有C12-C16链的阳离子含卤素化合物。该乳液还可以任选地包含一个固醇,优选地是植物固醇。用于本发明优选的具有C12-C16链的阳离子含卤素化合物包括:十六烷基吡啶鎓氯化物,十六烷基吡啶鎓溴化物,十六烷基三甲基铵溴化物,十六烷基二甲基乙基铵溴化物和氯苄烷铵。该抗微生物乳液可以以药剂的形式用于抑制多种传染性病原体的生长,包括细菌、真菌和病毒。
Description
发明背景
本发明涉及一种有抗微生物作用的,含脂质的水包油乳液,它能通过接触使传染性病原体灭活。
人们已经知道,如果通过机械搅动,例如用超匀化器(ultra-disperser),将一种水不混溶性液相混入水相中,那末,为了形成稳定的水包油分散体,常常需要加入乳化剂,其分子吸附在油微滴表面,形成一种连续的膜,使二个相邻的微滴不能直接接触。油滴内还可以包含能溶于有机介质的物质,如固醇。
除了分散在水相中的分散的油微滴外,水包油乳液中还可以包含其它脂质结构,例如小的脂囊泡(即通常是由几个基本同心的并由水相层使其彼此隔开的脂双层组成的脂质球),微胞(micelle,如由50-200个两亲分子形成一个小簇,其极性头部基团向外面对着水相,而非极性尾部向里与水相分隔开),或者片层状结构(其每个微粒是由平行的甘油酯双层组成的脂质分散体,由水薄层分隔开)。这些脂质结构是由于疏水作用力驱使非极性残基(即长碳氢链)远离水而形成的。
病原性细菌、病毒或真菌侵入的入口主要是皮肤和粘膜,以及上、下呼吸道。任何感染的第一步都是传染性病原体在皮肤或粘膜上附着或移生,然后侵入并在体内散布开。因此,本发明的目的是提供一种抗微生物乳液,它能通过接触来破坏微生物的膜结构,从而使传染性病原体灭活。
发明概述
本发明提供一种用于通过接触灭活传染性病原体的,稳定的抗微生物水包油乳液。该乳液包含分散在水“连续相”中的含脂质油“不连续相”的带正电荷的微滴。据信,油不连续相是通过破坏传染性病原体的膜结构而使其灭活的。该乳液对细菌、病毒和酵母菌具有广谱抗微生物活性。
本发明的抗微生物乳液主要由分散在水连续相(如水)中的带正电荷的油不连续相微滴组成。不连续相含有选自如下种类的甘油酯:甘油一油酸酯(GMO),甘油三油酸酯(GTO),甘油一月桂酸酯(GMO)和甘油二月桂酸酯(GTL),还含有一个作为正电荷生成剂的阳离子含卤素化合物,优选的是具有C12-C16链的阳离子含卤素化合物。微滴中还可含有固醇,如胆固醇或植物固醇。该微滴看来是通过与包含在细菌、病毒或真菌膜中的带负电荷的蛋白质相结合,从而破坏其膜结构并杀灭病原体的。
当例如吞服、吸入或用于皮肤时,本发明的抗微生物乳液是无毒性和安全的。这个结果是出乎预料的,因为很多具有C12-C16链的阳离子含卤素化合物,如果单独给药都是极毒的。例如,本发明优选的阳离子含卤素化合物,十六烷基吡啶鎓氯化物(CPC)对上呼吸道、粘膜和皮肤组织有严重的刺激作用,并导致严重的损伤。但是,当以本发明的乳液形式给药时,没有发生这种有害的作用。并且,本发明的乳液,对加热或暴露于相当强度的酸和碱都是稳定的。
油不连续相的正电荷是由具有C12-C16链的阳离子含卤素化合物提供的。在一个优选的实施方案中,具有C12-C16链的阳离子含卤素化合物选自:十六烷基吡啶鎓氯化物(CPC),十六烷基吡啶鎓溴化物(CPB),十六烷基三甲基铵溴化物(CTAB),十六烷基二甲基乙基铵溴化物(CDEAB)。能使用的具有C12-C16链的其它阳离子含卤素化合物包括:十六烷基三甲基铵氯化物,十六烷基苄基二甲基铵氯化物,十六烷基三丁基鏻溴化物,十二烷基三甲基铵溴化物和十四烷基三甲基铵溴化物。
油不连续相还可包含至少一种选自如下种类的固醇:胆固醇、胆固醇衍生物、氢化可的松、植物固醇、以及它们的混合物。在此所用的术语“胆固醇衍生物”,包括但不限于胆固醇的硫酸酯或磷酸酯衍生物。优选的固醇包括植物固醇,如大豆固醇。
能用于形成本发明抗微生物水包油乳液的油,包括广泛种类的水不混溶物质,例如大豆油,鳄梨油,角鲨烯油,芝麻油,橄榄油,卡诺拉(canola)油,玉米油,菜籽油,红花油,葵花籽油,鱼油,香料油,水不溶性维生素,以及它们的混合物。在本发明的一个优选的实施方案中,油是一种有香味的油如薄荷油。
在本发明的另一个实施方案中,乳液中的至少一部分可能以如下脂质结构形式存在,包括但不限于:单层,多层和少层的脂囊泡、微胞和片层状结构。
本发明的抗微生物乳液可以以例如药剂的形式(例如乳油,溶液和悬液)用于抑制多种传染性病原体的生长,包括细菌、病毒和真菌。因此本发明也提供了一种适合于药用的抗微生物制剂,它由本发明的抗微生物乳液和药用载体组成。该制剂可以以例如乳油、凝胶、喷雾剂漱口剂或脱臭剂的剂型,用于皮肤表面、粘膜或口腔表面局部给药,以治疗或预防如下的细菌感染:痤疮丙酸杆菌,淋病奈瑟氏球菌,表皮链球菌和表皮葡萄球菌。另外,该制剂也可以体内给药,例如口服或静脉内给药。以这种全身性给药法给予该制剂,能够杀灭病原性微生物,例如细菌,如幽门螺旋杆菌,以及病毒,特别是有被膜病毒。在本发明的一个优选的实施方案中,以该制剂对一个病人口服给药,用于治疗人免疫缺损病毒(HIV)感染。
因此,本发明还进一步提供了一种通过局部或全身性施用本发明的抗微生物乳液,来抑制传染性病原体生长的方法。发明详述
本发明涉及一种稳定的抗微生物水包油乳液,它是由带正电荷的油相微滴不连续在水连续相内构成的。
这里所用的术语“抗微生物”的含义是具有灭活传染性病原体的能力。在此所用的术语“灭活”包括,但不局限于,杀灭有机体或抑制有机体生长。所用的术语“传染性病原体”包括,但不局限于:真菌、病毒、细菌和移生虫。本发明的抗微生物乳液能灭活多种传染性病原体。看来,灭活是由油不连续相成分,通过瓦解病原体的膜结构完成的。
这里所用的术语“乳液”,包括水不混溶的油相与水相混合时形成的经典的水包油分散体或微滴,以及其它一些由于疏水作用力而形成的脂质结构,这种作用力驱使非极性残基(即长碳氢链)远离水,而驱使极性头部基团朝向水。这些脂质结构包括,但不局限于:单层、少层和多层的脂囊泡、微胞和片层状或六方形结构。这些其他脂质结构还含有选自如下种类的,作为主要乳化剂的甘油酯:甘油一油酸酯(GMO),甘油三油酸酯(GTO),甘油一月桂酸酯(GML)和甘油二月桂酸酯(GDL),并含有作为正电荷生成剂的含卤素的十二烷基至十六烷基阳离子化合物。这些脂质结构还可以进一步包含至少一种固醇,优选的是植物固醇。在本发明的一个优选实施方案中,GMO被用作主要乳化剂。在此所用的术语“主要乳化剂”指的是,在油不连续相中所包含的任何单一乳化剂中,按重量构成最大部分的乳化剂。
本发明的抗微生物水包油乳液,可以用本专业人员熟知的经典的乳液形成技术制成。简单地说,使脂-油相在相当大的切变力作用下与水相混合,可得到一种含直径大约1微米的油微滴的水包油乳液。更具体地说,通过将(a)一个油载体,(b)一个选自如下种类的甘油酯:GMO,GTO,GML,或GDL,和(c)一个具有C12-C16链的阳离子含卤素化合物,以及任何掺入到脂-油相中的其它相容的甘油酯或乳化剂如多乙氧基醚60,和任何固醇或其它亲油物质混合,形成带正电荷的含脂的油不连续相。
一旦形成了脂-油相,就可以将其同水相(例如水、盐水或任何其它能使脂质水合化的水溶液)一起加热、混合,脂-油相对水相的体积比大约在1∶4至1∶2的范围内,优选的是大约1∶3。用任何能产生强切变混合作用力的装置都可以使脂-油相和水相混合,包括例如:french冲压机(press),NovamixTM脂囊泡生成器(IGI公司,Buena N.J),喷射混合器,或者还可以用二个如在美国专利4,895,452和4,911,928(在此引入作为参考)中所述注射器,手工进行混合。
本发明的抗微生物水包油乳液具有对热、酸或碱稳定的优点。例如在后面实施例7中所示,当被煮沸或者用1N硝酸或1N NaOH处理时,都未使本发明的乳液发生明显的改变或被破坏。这种稳定性使该乳液适合于医用给药,甚至可以体内给药。
本发明的抗微生物水包油乳液,可以用于以接触的方式灭活多种传染性病原体。如以下实施例中所述,能被本发明的乳液灭活的微生物包括多种细菌、真菌和病毒。更具体地说,在此公开的乳液可作为喷雾剂或漱口液局部用于灭活移生在口腔或咽喉部的细菌,如肺炎链球菌,A群β-溶血性链球菌,流感嗜血杆菌,和脑膜炎奈瑟氏球菌。对于移生在胃肠道中的细菌,如幽门卷旋杆菌,该乳液可用丸剂或液体剂型通过口服给药来灭活。对于移生在阴道中的细菌和真菌,如淋病奈瑟氏球菌,阴道加德纳氏菌,B群链球菌和白色念珠菌,该乳液可以以乳油、凝胶或栓剂剂型,通过局部用药来灭活。在此公开的乳液还可以以乳油或凝胶剂型,用于皮肤病治疗,灭活或防止痤疮丙酸杆菌,金黄色葡萄球菌,表皮葡萄球菌和B群链球菌的继发性感染。在本发明的一个优选实施方案中,本发明的抗微生物乳液被用于预防革兰氏阳性菌感染。
本发明的抗微生物水包油乳液还可以用于通过接触灭活各种病毒,特别是具有被膜的病毒。例如,在此公开的乳液可用于咽喉、口腔、性器官,皮肤或体内给药,来灭活或防止下列病毒的继发性感染:疱疹病毒(如单纯疱疹病毒1型和2型,E-B病毒,巨细胞病毒,水痘病毒,和6型人疱疹病毒),披膜病毒(如风疹病毒),黄病毒(如黄热病毒),冠状病毒(如冠状病毒),弹状病毒(如狂犬病毒),丝状病毒(如马尔堡病毒),副粘病毒(如麻疹病毒),正粘病毒(如流感病毒),布尼亚病毒(如加利福尼亚脑炎病毒),嵌沙样病毒(如淋巴细胞脉络丛脑膜炎病毒),反转录病毒(如人免疫缺损病毒1型),和肝DNA病毒(如乙型肝炎病毒)。本发明的乳液还可以用于体外灭活病毒,例如用于消毒被污染的血液制品。在本发明的一个优选实施方案中,水包油乳液被用于灭活人免疫缺损病毒(HIV)。
本发明还提供了一种适合于药用的抗微生物制剂,它是由本发明的抗微生物乳液和药用载体组成的。在此所用的术语“药用载体”是指任何适合于药用的生理学相容的载体。用这种基质和药剂作为药物活性物质是本专业人员熟知的。除非某些常规的基质或试剂与本发明的乳液是不相容的,否则可以考虑将它们用于药物制剂中。
本发明还进一步提供了通过局部或全身性给予本发明的抗微生物乳液来抑制传染性病原体生长的方法,优选地是以药物制剂的形式给药。在此所用的术语“局部”,包括用于粘膜、口腔表面、皮肤、内耳表面或者身体任何孔道的表面,如阴道或直肠。在此所用的术语“全身性”包括任何形式的体内给药,包括但不局限于口服和静脉内给药。
以下的实施例将阐明本发明的功效。
实施例实施例1-GMO和GMS水包油乳液制备:
在此实施例中,制备了一系列具有以GMO或GMS作为主要乳化剂的,带正电荷和带负电荷的含脂质水包油乳液。并选择几个乳液对其纯度、pH和油微滴大小进行了鉴定。
表1显示了用于构成几个带电荷的GMO和GMS水包油乳液脂-油相的各种化学成分的用量,它们是以甘油一油酸酯(GMO)或甘油一硬脂酸酯(GMS)作为主要的乳化剂,以十六烷基吡啶鎓氯化物(CPC),十六烷基吡啶鎓溴化物(CPB),十六烷基三甲基铵溴化物(CTAB),或二甲基二十八烷基铵溴化物(DDDAB)作为正电荷生成剂,或者以油酸作为负电荷生成剂。表1
GMO/ GMO/ GMO/ GMS/ GMO/ GMS/
CPC CPB CTAB DDDAB OLEIC CPCGMO 3.43g 3.43g 3.43g ----- 3.43g -----GMS ----- ----- ----- 3.43g ----- 3.43g大豆固醇或 0.96g 0.96g 0.96g 0.96g 0.96g 0.96g胆固醇吐温60 0.84g 0.84g 0.84g 0.84g 0.84g 0.84g大豆油 11g 11g 11g 11g 11g 11gCPC 130mg ----- ----- ----- ----- 130mgCPB ----- 150mg ----- ----- ----- -----CTAB ----- ----- 140mg ----- ----- -----DDDAB ----- ----- ----- 240mg ----- -----油酸 ----- ----- ----- ----- 108mg -----
为了制备如上表1所示的带电荷的乳液,先将含下列成分的脂-油相在86℃加热大约1小时:约12-21%重量的GMO或GMS,0.8-0.9%重量的阳离子含卤素化合物(或0.7%重量的油酸),67-80%重量的载体油如大豆油,3-5%重量的吐温60(聚氧乙烯20脱水山梨醇一硬脂酸酯),和3-6%重量的大豆固醇。然后在65℃,用5ml喷射机(syringe machine)将此脂-油相与含水的水相混合,方法如美国专利No.4,895,452所述,体积比为13份脂-油比37份水。
表2显示表1所示乳液的pH值。表2同时显示了乳液中脂-油微滴的大小,这是用配有循环水浴的库尔特LS 130激光定径仪测定的。表2乳液的 平均库尔特大小 平均大小化学成分 电荷 pH (微米) (微米)GMO/CPC 正 3.72 1.049 0.720-1.401GMO/CPB 正 4.31 0.891 0.680-1.124GMO/CTAB 正 4.82 1.143 0.647-1.358GMS/DDDAB 正 5.86 1.080 O.694-1.532GMO/油酸 负 4.45 1.078 0.738-1.448GMS/CPC 正 3.72 1.047 0.677-1.497实施例2-10N GMO水包油乳液制备:
在此实施例中,制备了一系列带正电荷的水包油乳液,它们都是以GMO作为主要乳化剂,并且与实施例1相比较,具有高于10倍百分数(10N)的阳离子含卤素化合物(十六烷基吡啶鎓氯化物(CPC),十六烷基吡啶鎓溴化物(CPB),十六烷基三甲基铵溴化物(CTAB),十六烷基二甲基乙基铵溴化物(CDEAB)和氯苄烷铵(BAC))作为正电荷生成剂。
表3显示用于构成带正电荷的10N GMO乳液的脂-油相的各种化学成分的用量。表3 带正电荷的10N乳液乳液的 GMO/ GMO/ GMO/ GMO/ GMO/化学成分 CPC CPB CTAB CDEAB BACGMO 3.43g 3.43g 3.43g 3.43g 3.43g大豆固醇或 0.96g 0.96g 0.96g 0.96g 0.96g胆固醇吐温60 0.84g 0.84g 0.84g 0.84g 0.84g大豆油 11g 11g 11g 11g 11gCPC 1.3g ----- ----- ----- -----CPB ----- 1.5g ----- ----- -----CTAB ----- ----- 1.4g ----- -----CDEAB ----- ----- ----- 1.3g -----BAC ----- ----- ----- ----- 1.3g
为了制备如表3所示的10N乳液,可先将含下列成分的脂-油相在86℃加热大约1小时:约19%重量的GMO,62%重量的载体油如大豆油,4.7%重量的吐温60(聚氧乙烯20脱水山梨醇一硬脂酸酯),5.4%重量的大豆固醇,和7.4-8.4%重量的阳离子去污剂。然后在65℃,用5ml喷射机将此脂-油相与含水的水相混合(如美国专利4,895,452,其方法在此引入作为参考),体积比为13份脂-油比37份水。实施例3-GMO和GMS水包油乳液对金黄色葡萄球菌8型的杀微生物活性:
在此实施例中,对表1所示的每种GMO和GMS乳液的杀微生物活性进行了比较。为此目的,可按如下方法测定每种乳液杀灭金黄色葡萄球菌8型的能力:
将细菌接种于液体培养基内(胰蛋白酶解酪蛋白大豆液体培养基或Schaedler’s液体培养基),37℃培养1-7小时。再在波长650nm测定每个液体培养物的光密度,并对每个培养物进行定量。然后取1毫升每个细菌培养物与1毫升乳液混合,或者与水混合作对照,作用10分钟或30分钟。然后对每个混合物作双份定量培养。将含有细菌的平板在37℃培养18小时,然后进行计数。
按如下公式测定被杀灭细菌的百分数:A=接种的细菌总数B=与乳液混合后计数的细菌总数。
表4列出了每种乳液或水与2×107个细菌混合培养10分钟或30分钟后,金黄色葡萄球菌被杀灭的百分数。表4制剂的 培养10分钟后的 培养30分钟后的化学成分 灭活百分数(%) 灭活百分数(%)GMO/CPC 100 100GMO/CPB 100 100GMO/CTAB 99.99 99.99GMO/DDDAB 65 0GMO/油酸 0 0GMS/CPC 65 0只有对照 50 0
从表4可以看出,带正电荷的甘油一油酸酯(GMO)乳液能灭活金黄色葡萄球菌8型,而带正电荷的甘油一硬脂酸酯(GMS/CPC)乳液对此没有灭活作用。此外,只是含有氯或溴的具有C12-C16链的阳离子化合物,即CPC、CPB或CTAB的乳液有显著的杀微生物活性,含有二-十八烷基阳离子化合物(DDDAB)或油酸(具有负电荷)的乳液没有明显的杀微生物活性。因此表明,用含有氯或溴,并含有具C12-C16链阳离子化合物的GMO乳液,对灭活这种细菌,金黄色葡萄球菌,更有效。
为了测定在本发明的乳液中,改变其电荷生成剂浓度的影响,也可以用含有不同浓度CPC的GMO乳液,测定它们对金黄色葡萄球菌8型的杀微生物活性。表5显示GMO乳液与107细菌混合培养10分钟或30分钟后,被杀灭的金黄色葡萄球菌的百分数。表5
金黄色葡萄球菌8型 培养 培养乳液的 的起始接种量 10分钟后的 30分钟后的化学成分 灭活百分数 灭活百分数GMO/CPC 10,000,000CFU 100 100
[1.8mg/ml乳液]GMO/CPC 10,000,000CFU 99.5 100
[0.9mg/ml乳液]GMO/CPC 10,000,000CFU 54 99.5
[0.45mg/ml乳液]GMO/CPC 10,000,000CFU 39 32
[0.23mg/ml乳液]GMO/CPC 10,000,000CFU 0 0
[0.028mg/ml乳液]GMO 10,000,000CFU 0 0GMO/油酸 10,000,000CFU 0 0只有水 10,000,000CFU 10 0
表5表明,金黄色葡萄球菌8型菌对每毫升乳液CPC浓度大于0.23mg的GMO/CPC乳液的杀微生物作用是敏感的。实施例4-GMO水包油乳液对细菌和酵母菌的杀微生物活性
在此实施例中,测定了实施例1中制备的,表1中所示的GMO/CPC乳液杀灭各种细菌和酵母菌的能力。
用上面实施例3所述的测定法,测定GMO/CPC乳液对多种细菌和真菌的杀微生物能力,方法仅作了如下改变:
先将酵母菌接种于Sabouraud’s液体培养基中,在30℃培养6小时,再与GMO/CPC乳液混合作用10分钟或30分钟,然后作平板接种,在37℃培养18小时后作计数测定。
将痤疮丙酸杆菌在Schaedler’s液体培养基中厌氧培养24小时,与乳液混合作用10分钟或30分钟,然后在含有5%羊血的胰蛋白酶解酪蛋白大豆琼脂板培养基上作平板接种,厌氧培养72小时后作计数测定。
将阴道加德纳氏菌在含有5%羊血的胰蛋白酶解酪蛋白大豆琼脂板培养基上作平板接种后,在含5%CO2的空气中,37℃培养72小时。从平板培养基上刮取菌落,接种于Schaedler’s液体培养基中,形成0.5McFarland标准密度。然后将这种液体培养基和细菌的混合物与乳液混合培养10分钟或30分钟,再在含5%羊血的胰蛋白酶解酪蛋白大豆琼脂板培养基上作平板接种。将平板在含5%CO2的空气中,37℃培养72小时后,进行菌落计数。
表6列出了GMO/CPC乳液与105-108细菌混合培养10分钟或30分钟后,被杀灭的革兰氏阳性菌百分数。对被列出的细菌通常可作如下分类:(a)移生在皮肤上的细菌,包括:金黄色葡萄球菌(8型),金黄色葡萄球菌(5型),表皮葡萄球菌(977株),B群链球菌(荚膜III型),A群链球菌(β-溶血性),和痤疮丙酸杆菌;(b)移生在口咽部的细菌,包括:A群链球菌(β-溶血性)肺炎链球菌(5型)和变异链球菌,以及(c)移生或感染阴道的细菌,包括阴道加德纳氏菌,和B群链球菌(荚膜III型)。表6
培养 培养
接种量 10分钟后的 30分钟后的革兰氏阳性菌 (CFU)* 灭活百分数 灭活百分数金黄色葡萄球菌 2×107 99.99 99.99(8型/菌血症分离物)金黄色葡萄球菌 9×106 100 99.99(5型菌血症分离物)表皮葡萄球菌 8×105 100 100(977株)B群链球菌 2.9×107 99.99 100(荚膜III型)A群β溶血性 3.3×107 99.99 99.99(1型)链球菌(ATCC 12344)单核细胞增生 1.3×108 99.99 99.99李斯特氏菌(2型)(ATCC 19112)肺炎链球菌 6.4×107 100 100(5型)(ATCC 6305)变异链球菌 6.5×106 96.2 96.8(ATCC 25179)痤疮丙酸杆菌 1.2×108 100 100(ATCC 6919)粪链球菌 3.7×107 99.36 99.98(ATCC 19433)阴道加德纳氏菌 5.5×107 100 100(ATCC 14018)嗜酸乳酸杆菌 5.0×105 100 100(ATCC 4356)*CFU=菌落形成单位
表6表明,能对人引起严重临床感染的所有革兰氏阳性菌,对GMO/CPC乳液的杀微生物作用都非常敏感。
表7显示GMO/CPC乳液与105-108革兰氏阴性菌混合培养10分钟或30分钟后杀菌百分数。表中的革兰氏阴性菌包括移生在口咽部的如流感嗜血杆菌(荚膜6型)和脑膜炎奈瑟氏菌6型,移生在胃肠道的如幽门卷旋杆菌以及移生在阴道的如淋病奈瑟氏菌。表7
培养 培养
接种量 10分钟后的 30分钟后的革兰氏阴性菌 (菌落形成单位) 灭活百分数 灭活百分数大肠杆菌O18:K1型 2.1×107 97.1 96.7大肠杆菌O18:K-型 3.2×107 89.7 99.6大肠杆菌J5 3×107 94 85(差向异构酶缺乏型)脑膜炎黄杆菌 2.1×106 0 47.6A群(ATCC 13253)肺炎克雷伯氏菌O12K+型 5×107 98.3 99.9绿脓假单胞菌 3.8×107 99 99FD-1型绿脓假单胞菌 8×106 99.1 97.5MEP株2192流感嗜血杆菌 1×107 99.99 99.99荚膜B型(ATCVC 33533)脑膜炎奈瑟氏菌 1.6×108 100 100(ATCC 13090)淋病奈瑟氏菌 1.2×106 100 100(ATCC 9793)幽门卷旋杆菌 3×106 100 100(ATCC 43504)幽门卷旋杆菌 4.7×106 100 100(ATCC 43629)幽门卷旋杆菌 2×106 100 100(ATCC 49503)幽门卷旋杆菌 7×106 100 100(ATCC 43579)
表7表明,培养30分钟后,对所有被测定的革兰氏阴性菌,除脑膜炎黄杆菌外,至少有85%的接种细菌被灭活了。有荚膜的b型流感嗜血杆菌,b型脑膜炎奈瑟氏菌,淋病奈瑟氏菌,和幽门卷旋杆菌,对GMO/CPC乳液的杀微生物活性都非常敏感,与其它革兰氏阴性菌相比较,这些细菌都具有较粗糙的脂多糖(LPS)类。
表8显示GMO/CPC乳液与105接种量细菌混合培养10分钟或30分钟后,对二种念珠菌杀灭的百分数。表8
培养 培养
接种量 10分钟后的 30分钟后的酵母菌 (菌落形成单位) 灭活百分数 灭活百分数白色念珠菌 3.2×105 62.5 62.5(临床血分离物)热带念珠菌 5.4×105 100 100(临床血分离物)
表8表明只有与GMO/CPC乳液混合培养10-30分钟后,对白色念珠菌才有明显的灭活作用。实施例5-10N GMO乳液的杀微生物活性
在此实施例中,测定了实施例2中制备的,表3所示的带正电荷的10N GMO乳液,对二种革兰氏阳性菌,金黄色葡萄球菌8型和表皮葡萄球菌,以及二种革兰氏阴性菌,大肠杆菌和幽门卷旋杆菌的杀微生物活性,方法如下:
将0.5ml Schaedler’s液体培养基加到冷冻干燥的细菌培养物中,再将此小瓶内的全部细菌接种到5%羊血琼脂培养平板(TSA 11)上。然后将培养物在带有Campy GasPAK的厌氧培养罐中37℃培养72小时。再将取自TSA 11平板培养基的72小时培养物接种到Schaedler’s液体培养基中,培养至达到0.5 McFarland标准密度。
然后将1ml等分量该细菌培养物与1ml水包油乳液混合作用10分钟。再对每个混合物作双份定量培养,并对原始的液体培养物作一份定量培养。将含有细菌的平板培养基在带有Campy GasPaks的厌氧培养罐内37℃培养72小时,然后进行计数。按下面的公式计算被杀灭细菌的百分数,结果显示在表9内。A=接种的细菌总数B=与乳液或脂质体混合后计数的细菌数
表9列出了来自表3的10N GMO/CPC乳液与106-107细菌混合培养10分钟后,被杀灭的每种细菌的百分数。如表9中所标明,10NGMO/CPC乳液是以未稀释的形式和作了几次稀释的形式进行测定。表9细菌 稀释度 试验#1 试验#2金黄色葡萄球菌 未稀释 NT 100.00%
8型 1∶10 99.99%8×10E7 CFU/mL 1∶20 99.99%培养10分钟 1∶40 99.99%
1∶80 96.25%表皮葡萄球菌 未稀释 NT 100.00%
977 1∶10 100.00%9×10E6 CFU/mL 1∶20 100.00%培养10分钟 1∶40 99.98%
1∶80 99.97%大肠杆菌 未稀释 NT 99.99%02a,2b型 1∶10 99.99%1×10E7 CFU/mL 1∶20 99.98%培养10分钟 1∶40 94.00%
1∶80 50.00%幽门卷旋杆菌43579 未稀释 100.00% 100.00%培养10分钟 1∶10 100.00% 100.00%用于试验#1的接种物 1∶20 100.00% 100.00%5×10E6 CFU/ml用于试验#2的接种物 1∶40 99.00% 99.00%2×10E7 CFU/ml
1∶80 99.20% 99.00%NT=此数据未测定
表9显示,与直到1∶80稀释度的10N GMO/CPC乳液混合培养10分钟后,对被测定的每种细菌(除对大肠杆菌在高稀释度(即1∶40和1∶80)以外)都有96%以上的灭活作用。在1∶10的乳液稀释度,对每种细菌都有99.99-100%的灭活作用。实施例6-GMO水包油乳液和促融(fusogenic)脂囊泡对人免疫
缺损病毒(HIV)的杀病毒活性:
在此实施例中,测定了实施例1中制备的GMO/CPC乳液和按如下所述方法制备的促融脂囊泡对HIV的杀病毒活性。
为了制备促融脂囊泡,将94.5克聚氧乙烯(POE)2硬脂醚(Brij72),0.78克油酸,和36克胆固醇共同加热熔化,形成液态脂质相。然后取一份这种脂质相0.53ml,与0.47ml角鲨烯混合,形成1.0ml脂-油相。在切变混合条件下,将此脂-油相与含有4.0ml磷酸缓冲液(PBS)的水相混合,形成脂囊泡,如在美国专利4,911,928中所述。“切变混合条件”在此的含义是,相当于通过一个1mm孔的相对流速为5-50m/秒的切变力。按体积对体积的比例,此混合液包含有4份稀释剂和1份脂-油混合物,或者是11.7%脂质∶8.3%油∶80%稀释剂。
按如下方法测定GMO/CPC乳液和Brij 72促融脂囊泡对HIV的杀病毒活性:
用C8166细胞,一种HTLV-1转化的T细胞系细胞,在20ml含10%PBS和50μg/ml庆大霉素的RPMI培养基内,配制成含20×106细胞的细胞悬液,并分装成0.4ml的等份。首先取100微升(μl)1000倍稀释的HIV-1Mn病毒液与100μl无菌水或100μl GMO/CPC乳液在室温下,在振荡器上混合作用30分钟,再向每个混合制剂加入1.8ml组织培养基,得到10-1稀释液,然后配制病毒系列稀释液(10-2到10-6)。取150μl 10-1稀释液,在1.35ml RPMI培养基中再作5次系列稀释,构成从10-2到10-6的系列10倍稀释液。
然后每个稀释液取2个0.4ml等份,加到如上述配制的C8166细胞等份悬液中。将该样品在37℃培养2小时,6小时或24小时后,在磷酸盐缓冲液中洗3次,重悬在新鲜的培养基中,并将每个稀释液重复加入培养板的4个孔中。将细胞培养2周。在第7天和第14天观察细胞病变效应,并收集上清液,测定作为病毒增殖指示的p24含量。根据所测定的p24含量,计算组织培养感染剂量(TCID-50(log10))。结果如下:
对于与GMO/CPC乳液混合培养2小时的样品,同与水混合的样品相比较,在第7天病毒的TCID-50降低了4.5log,在第14天病毒的TCID-50降低了4.25log。
对于与GMO/CPC乳液混合培养6小时的样品,同与水混合的样品相比较,在第7天病毒的TCID-50降低了4.5log,在第14天病毒的TCID-50降低了5log。
对于与GMO/CPC乳液混合培养24小时的样品,同与水混合的样品相比较,在第7天和第14天病毒的TCID-50降低了4.0log;同与磷酸盐缓冲液混合的样品相比较,在第7天和第14天,TCID-50分别降低了3.75og和4.25og;同与含有POE 2硬脂醚的促融诺瓦体(novasome)混合的样品相比较,在第7天和第14天TCID-50分别降低了4.0log和4.5log。
总之,这个实施例证明,在C8166组织培养测定中,GMO/CPC乳液使HIV-1Mn的感染性降低了4.0-5.0log。这些实验可以证明这些物质对灭活病毒如HIV-1Mn的效果,也可以用任何其它有被膜病毒来作这种试验。实施例7-GMO水包油乳液的稳定性
在此实施例中,测定了实施例1中制备的GMO/CPC乳液,在加热和存在酸和碱时的稳定性,表10显示煮沸1小时对GMO/CPC乳液的崩解或聚集作用,并显示等体积1N硝酸与GMO/CPC乳液混合作用2小时,对GMO/CPC乳液的崩解或聚集作用,以及等体积1N NaOH与GMO/CPC乳液混合作用2小时,对GMO/CPC乳液的崩解或聚集作用。表10乳液的 平均库尔特大小 平均库尔特范围化学成分 处理方式 (μm) (μm)GMO/CPC 未煮沸 1.008 0.720-1.337GMO/CPC 煮沸1小时 1.167 0.654-1.517GMO/CPC 未用酸处理 1.008 0.720-1.337GMO/CPC 1N硝酸 1.062 0.675-1.569
2小时GMO/CPC 未用碱处理 1.008 0.720-1.337GMO/CPC 1N NaOH 0.804 0.658-0.969
2小时
表10显示:(a)煮沸1小时未引起乳液发生明显的崩解或微滴大小改变;(b)用1N硝酸处理2小时,GMO/CPC乳液微滴大小或聚集状态未发生明显改变;(C)用1N NaOH处理2小时,引起乳液平均微滴大小降低20%,未瓦解乳液,也未发生聚集作用。
上述实施例1-7显然表明,本发明的抗微生物水包油乳液对多种病毒细菌和酵母菌有显著的杀微生物活性,甚至只需要极低浓度的阳离子含卤素化合物如CPC。并且本发明的乳液对热、酸、碱是稳定的,使它们非常适用于医用给药,无论是局部、口服或全身性给药都可以。
本领域的技术人员将会认识到,或者仅用常规实验就能确定出许多本发明特异性实施方案的等效物。这些等效物将被包括在权利要求之中。
Claims (34)
1.一种含有带正电荷油不连续相微滴的水包油抗微生物乳液,其中不连续相微滴是分散在连续水相中的,该乳液包含:
a.一种油;
b.一种甘油酯;
c.一种具有C12-C16链的阳离子含卤素化合物。
2.权利要求1的抗微生物乳液,其中的甘油酯选自:甘油一油酸酯,甘油三油酸酯,甘油一月桂酸酯和甘油二月桂酸酯。
3.权利要求1的抗微生物乳液,其中的油选自:大豆油,角鲨烯油,芝麻油,橄榄油,卡诺拉油,玉米油,菜籽油,红花油,葵花油,鱼油,鳄梨油,香料油,水不溶性维生素,以及它们的混合物。
4.权利要求1的抗微生物乳液,其中的卤素选自溴、氯、氟。
5.权利要求1的抗微生物乳液,其中的具有C12-C16链的阳离子含卤素化合物选自:十六烷基吡啶鎓氯化物,十六烷基吡啶鎓溴化物,十六烷基三甲基铵溴化物,十六烷基三甲基铵氯化物,十六烷基二甲基乙基铵溴化物,十六烷基苄基二甲基铵氯化物,十六烷基三丁基鏻溴化物,十二烷基三甲基铵溴化物和十四烷基三甲基铵溴化物。
6.权利要求1的抗微生物乳液,其中的乳液还含有至少一种选自如下种类的固醇:胆固醇,胆固醇衍生物,氢化可的松,植物固醇,以及它们的混合物。
7.权利要求1的抗微生物乳液,其中乳液的至少一部分是以选自如下种类的带正电荷的脂质结构形式存在:单层,多层和少层的脂囊泡,微胞和片层状结构。
8.一种适合于医用给药的抗微生物制剂,其包含权利要求1的抗微生物乳液和药用载体。
9.一种含有带正电荷油不连续相微滴的水包油抗微生物乳液,其中不连续相微滴是分散在连续水相中的,该乳液包含:
a.一种选自下列种类的油:大豆油,角鲨烯油,角鲨烷油,芝麻油,橄榄油,卡诺拉油,玉米油,菜籽油,红花油,葵花油,鱼油,鳄梨油,香料油,水不溶性维生素,以及它们的混合物。
b.甘油一油酸酯;
c.十六烷基吡啶鏻氯化物。
10.一种适合于医用给药的抗微生物制剂,其包含权利要求9的抗微生物乳液和药用载体。
11.一种抑制传染性病原体生长的方法,其包括局部应用水包油抗微生物乳液的步骤,所说的抗微生物乳液是以分散在连续水相中的带正电荷的油不连续相微滴的形式存在的,该乳液包含:
a.一种油,
b.一种甘油酯;和
c.一种具有C12-C16链的阳离子含卤素化合物。
12.权利要求11的方法,其中作为主要乳化剂的甘油酯选自:甘油一油酸酯,甘油三油酸酯,甘油一月桂酸酯和甘油二月桂酸酯。
13.权利要求11的方法,其中的卤素选自溴、氯和氟。
14.权利要求11的方法,其中具有C12-C16链的阳离子含卤素化合物选自:十六烷基吡啶鎓氯化物,十六烷基吡啶鎓溴化物,十六烷基三甲基铵溴化物,十六烷基二甲基乙基铵溴化物和氯苄烷铵。
15.权利要求11的方法,其中的油选自:大豆油,角鲨烯油,芝麻油,橄榄油,卡诺拉油,玉米油,菜籽油,红花油,葵花油,鱼油,鳄梨油,香料油,水不溶性维生素,以及它们的混合物。
16.权利要求11的方法,其中乳液还含有至少一种选自如下种类的固醇:胆固醇,胆固醇衍生物,氢化可的松,植物固醇,以及它们的混合物。
17.权利要求11的方法,其中所说的局部应用包括口腔应用。
18.权利要求11的方法,其中所说的局部应用包括经吸入应用于粘膜。
19.权利要求11的方法,其中所说的局部应用包括阴道内应用。
20.权利要求11的方法,其中传染性病原体是细菌。
21.权利要求11的方法,其中传染性病原体是真菌。
22.权利要求11的方法,其中传染性病原体是病毒。
23.权利要求22的方法,其中病毒是被膜病毒。
24.权利要求23的方法,其中的被膜病毒是HIV。
25.权利要求23的方法,其中的被膜病毒选自:疱疹病毒,披膜病毒,黄病毒,冠状病毒,弹状病毒,丝状病毒,副粘病毒,正粘病毒,布尼亚病毒,嵌沙样病毒,反转录病毒和肝DNA病毒。
26.一种抑制传染性病原体生长的方法,其包括将水包油抗微生物乳液局部应用于含有传染性病原体部位,该抗微生物乳液是以分散在连续水相中的带正电荷的油不连续相微滴的形式存在的,该乳液包含:
a.一种选自下列种类的油:大豆油,角鲨烷油,芝麻油,橄榄油,卡诺拉油,玉米油,菜籽油,红花油,葵花油,鱼油,鳄梨油,香料油,水不溶性维生素,以及它们的混合物;
b.甘油一油酸酯;和
c.十六烷基吡啶鎓氯化物。
27.一种抑制体内传染性病原体生长的方法,其包括对患者全身性施用一种水包油抗微生物乳液的步骤,该抗微生物乳液是以分散在连续水相中的带正电荷的油不连续相微滴的形式存在的,该乳液包含:
a.一种选自如下种类的油:大豆油,角鲨烯油,芝麻油,橄榄油,卡诺拉油,玉米油,菜籽油,红花油,葵花油,鱼油,鳄梨油,香料油,水不溶性维生素,以及它们的混合物;
b.一种选自如下种类的甘油酯:甘油一油酸酯,甘油三油酸酯,甘油一月桂酸酯,甘油二月桂酸酯;和
c.一种选自如下种类的具有C12-C16链的阳离子含卤素化合物:十六烷基吡啶鎓氯化物,十六烷基吡啶鎓溴化物,十六烷基三甲基铵溴化物,十六烷基二甲基乙基铵溴化物和氯苄烷铵。
28.权利要求27的方法,其中乳液还含有至少一种选自下列种类的固醇:胆固醇,胆固醇衍生物,氢化可的松,植物固醇,以及它们的混合物。
29.权利要求27的方法,其中所说的全身性施用包括肠内给药。
30.权利要求27的方法,其中病原体选自细菌、真菌和病毒。
31.一种治疗患者病原体感染的方法,其包括对患者全身性施用一种水包油抗微生物乳液的步骤,所述乳液含有分散在连续水相中的带正电荷的油不连续相微滴,该乳液包含:
a.一种油,
b.甘油一油酸酯;和
c.十六烷基吡啶鎓氯化物。
32.一种在体外灭活传染性病原体的方法,其包括使病原体与水包油抗微生物乳液接触的步骤,该乳液是以分散在连续水相中的带正电荷的油不连续相微滴的形式存在的,该乳液包含:
a.一种选自如下种类的油:大豆油,角鲨烷油,芝麻油,橄榄油,卡诺拉油,玉米油,菜籽油,红花油,葵花油,鱼油,凡士林,鳄梨油,甘油三酯的油和脂,香料油,水不溶性维生素,以及它们的混合物;
b.一种选自如下种类的甘油酯:甘油一油酸酯,甘油三油酸酯,甘油一月桂酸酯,和甘油二月桂酸酯;和
c.一种选自如下种类的具有C12-C16链的阳离子含卤素化合物:十六烷基吡啶鎓氯化物,十六烷基吡啶鎓溴化物和十六烷基三甲基铵溴化物。
33.权利要求32的方法,其中的病原体是病毒。
34.权利要求33的方法,其中的病毒是HIV。
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US08/246,868 US5547677A (en) | 1994-05-20 | 1994-05-20 | Antimicrobial oil-in-water emulsions |
US08/322,827 US5549901A (en) | 1994-05-20 | 1994-10-13 | Antimicrobial oil-in-water emulsions |
US32973094A | 1994-10-26 | 1994-10-26 | |
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US08/322,827 | 1994-10-26 | ||
US08/329/730 | 1994-10-26 |
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WO (2) | WO1995031956A1 (zh) |
Cited By (3)
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- 1995-05-18 CA CA002190604A patent/CA2190604A1/en not_active Abandoned
- 1995-05-18 JP JP7530417A patent/JPH10500686A/ja active Pending
- 1995-05-18 AU AU25936/95A patent/AU2593695A/en not_active Abandoned
- 1995-05-18 DE DE69527624T patent/DE69527624T2/de not_active Expired - Fee Related
- 1995-05-18 EP EP95920505A patent/EP0765151B1/en not_active Expired - Lifetime
- 1995-05-18 CA CA002190606A patent/CA2190606A1/en not_active Abandoned
- 1995-05-18 WO PCT/US1995/006234 patent/WO1995031956A1/en active IP Right Grant
- 1995-05-18 AU AU25937/95A patent/AU687562B2/en not_active Ceased
- 1995-05-18 ES ES95920506T patent/ES2180636T3/es not_active Expired - Lifetime
- 1995-05-18 US US08/443,937 patent/US5618840A/en not_active Expired - Lifetime
- 1995-05-18 BR BR9507669A patent/BR9507669A/pt not_active IP Right Cessation
- 1995-05-18 CN CN95194252A patent/CN1159158A/zh active Pending
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- 1995-05-18 JP JP7530418A patent/JPH10500687A/ja active Pending
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- 1995-05-18 CN CNB951942484A patent/CN1158069C/zh not_active Expired - Fee Related
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1878536B (zh) * | 2003-09-09 | 2014-11-26 | 3M创新有限公司 | 抗菌组合物和方法 |
CN103260403A (zh) * | 2010-12-29 | 2013-08-21 | 美国石膏公司 | 抗微生物施胶乳液及由其制造的石膏面板 |
CN103260403B (zh) * | 2010-12-29 | 2015-08-19 | 美国石膏公司 | 抗微生物施胶乳液及由其制造的石膏面板 |
WO2017063150A1 (zh) * | 2015-10-14 | 2017-04-20 | 高雄医学大学 | 酪梨萃取物、avocadenol B及(2R,4R)-1,2,4-三羟基十七碳-16-炔的用途,以及包含酪梨萃取物的保健食品 |
Also Published As
Publication number | Publication date |
---|---|
ES2180636T3 (es) | 2003-02-16 |
WO1995031966A1 (en) | 1995-11-30 |
AU2593695A (en) | 1995-12-18 |
EP0760650B1 (en) | 2002-07-31 |
BR9507742A (pt) | 1997-10-07 |
EP0760650A1 (en) | 1997-03-12 |
EP0765151A1 (en) | 1997-04-02 |
WO1995031956A1 (en) | 1995-11-30 |
AU2593795A (en) | 1995-12-18 |
CN1159158A (zh) | 1997-09-10 |
DE69527624D1 (de) | 2002-09-05 |
AU687562B2 (en) | 1998-02-26 |
CA2190606A1 (en) | 1995-11-30 |
DE69524953D1 (de) | 2002-02-14 |
US5618840A (en) | 1997-04-08 |
DE69527624T2 (de) | 2003-04-03 |
DE69524953T2 (de) | 2002-08-29 |
BR9507669A (pt) | 1997-10-07 |
EP0765151B1 (en) | 2002-01-09 |
CN1158069C (zh) | 2004-07-21 |
CA2190604A1 (en) | 1995-11-30 |
EP0760650A4 (en) | 1998-11-25 |
JPH10500687A (ja) | 1998-01-20 |
EP0765151A4 (en) | 1998-11-25 |
JPH10500686A (ja) | 1998-01-20 |
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