CN107073064A - 含有抗真菌肽和萜烯醇的抗真菌组合物 - Google Patents
含有抗真菌肽和萜烯醇的抗真菌组合物 Download PDFInfo
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- CN107073064A CN107073064A CN201580048862.4A CN201580048862A CN107073064A CN 107073064 A CN107073064 A CN 107073064A CN 201580048862 A CN201580048862 A CN 201580048862A CN 107073064 A CN107073064 A CN 107073064A
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- arg arg
- nucleoprotamine
- hydrolysate
- antifungal activity
- antifungal
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Abstract
本发明通过作为具有抗真菌活性的组合物的有效成分组合使用鱼精蛋白的水解物和萜烯醇,可以提供一种作为有效成分包含作为鱼精蛋白水解物的肽的具有抗真菌活性的组合物,其抗真菌活性得到进一步增强,并且压缩了成本,适于产业化。
Description
技术领域
本发明涉及一种包含鱼精蛋白水解物与萜烯醇的组合的具有抗真菌活性的组合物。该抗真菌活性组合物可以在用于进行真菌感染症的预防、治疗的功能性食品、化妆品及药品或准医药品等中广泛地利用。
背景技术
酵母及丝状菌为真核生物,与属于原核生物的细菌不同,被称作真菌。这些真菌中的某种对于人显示出病原性,成为真菌感染症的病原菌。已知在真菌当中,念珠菌属的真菌在人的消化管中广泛地发育,通常不显示出病原性,然而随着宿主机体防御能力的降低,会引起各种各样的感染症。特别是,口腔及咽、食道念珠菌症是随着唾液分泌的降低、糖尿病、抗生素或免疫抑制剂的长期给药、口腔卫生管理的降低等而常发的疾病。
以往,对于作为内用抗真菌剂用于真菌症的治疗中的抗真菌剂,在临床中使用多烯系的两性霉素B、氟吡啶系的氟胞嘧啶、咪唑系(唑系)的咪康唑及三唑系(唑系)的氟康唑、唑系的伊曲康唑等。成为这些抗真菌剂的对象的病原真菌的种类和药剂感受性随着各个抗真菌剂而不同,对于这些成为对象的病原真菌的种类,例如念珠菌属、隐球菌属、帚状曲霉属、毛癣菌属、马拉色霉菌属、球孢子菌属等为代表性的种类。但是,在使用了这些抗真菌剂的治疗中,虽然暂时性地治愈由真菌造成的感染,然而会有大多数可以看到复发、随着长期使用而出现抗药菌等问题,因此希望引入新的治疗法。另外,在老年人、特别是假牙佩戴者中可以看到的口腔念珠菌症等是只要引起易感染性的原因没有被去除、则即使暂时有疗效也会复发的疾病,需要开发出替代抗真菌剂的口内清洗剂或功能性食品等新的预防法(非专利文献1)。
另一方面,鱼精蛋白是从鱼类的精巣(鱼白)得到的具有抗菌活性的碱性蛋白质,是来自于天然物的食品防腐剂(专利文献1)。成为鱼精蛋白的原料的鱼白被作为火锅类食物用的食材食用等,自古以来就有食用经验,实施过对小鼠的急性毒性试验、对大鼠的亚慢性毒性试验等(非专利文献2),其安全性得到了确认,由于此等原因,鱼精蛋白是在安全方面优异的抗菌剂(非专利文献3)。已知鱼精蛋白在微生物当中,对芽孢杆菌属、乳酸菌等革兰氏阳性细菌也显示出特别强的抗菌活性(非专利文献4),对酵母、丝状菌的抗真菌活性非常弱(非专利文献5)。
为了提高鱼精蛋白的抗真菌活性,已知有将鱼精蛋白水解的方法,报告过其水解物中所含的以下的(1)~(3)的各肽或其盐具有抗真菌活性(专利文献1)。
(1)由以Ile Arg Arg Arg Arg Pro Arg Arg表示的序列编号:1的氨基酸序列构成的肽或其盐。
(2)由以Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg表示的序列编号:2的氨基酸序列构成的肽或其盐。
(3)由以Val Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg表示的序列编号:3的氨基酸序列构成的肽或其盐。
另一方面,通过将鱼精蛋白水解而得的包含特定的氨基酸序列的肽虽然在生物体外显示出高的抗菌活性,然而在生物体内的特别是高盐浓度下可以看到活性降低的趋势(非专利文献1)。因而,为了提高生物体内的抗菌活性,报告过合成肽而进行环状化的方法(非专利文献6)。
另一方面,已知某种植物精油或精油成分会提高其他的药剂的皮肤渗透性。报告过若为了提高以往的抗真菌剂的治疗效果而将抗真菌剂与具有抗真菌活性的精油或萜烯醇并用,则药剂的皮肤透过性提高,其血中浓度明显升高(专利文献2)。此处所说的所谓萜烯醇,是指1个分子中的碳原子数为10个的单萜烯醇、和15个的倍半萜烯醇。例如,玫瑰草油及其主成分的香叶醇分别明显地提高向皮肤给药的抗真菌剂特比萘芬的血中浓度,另外,对于薰衣草油及其主成分的里那醇、广藿香油及其主成分的广藿香醇、钓樟油及其副成分的橙花叔醇,也已知虽然程度各自不同然而也具有相同的效果(专利文献2)。
皮肤或粘膜的念珠菌症、特别是老年人的口腔念珠菌症、以及女性的阴道念珠菌症各自的发病频率非常高,一般是通过使抗真菌药直接接触患部来进行治疗,然而属于难治病,且容易反复发作。由此,为了抑制复发而长期使用药剂,其结果是,产生肝功能障碍等副作用,或出现抗药菌的风险变大。
现有技术文献
专利文献
专利文献1:日本专利第4520477号说明书
专利文献2:日本特开2010-126532号公报
非专利文献
非专利文献1:安部茂:小鼠口腔念珠菌症模型的开发及其应用(マウス口腔カンジダ症モデルの開発とその応用),真菌志45,227-231(2004)
非专利文献2:多田幸恵等:天然防腐剂鱼白蛋白对大鼠的亚慢性毒性试验,东京都立卫生研究所研究年报,(天然保存料しらこたん白のラットによる亜慢性毒性試験,東京都立衛生研究所研究年報)49,267-276(1998)
非专利文献3:庵原启司,根本Erika:鱼白蛋白(鱼精蛋白)在食品中的利用(根本えりか:しらこたん白(プロタミン)の食品への利用),月刊Food Chemical 4月号,24-32(2006)
非专利文献4:Bulletin of the Japanese Society of Scientific Fisheries,50,1715(1984)
非专利文献5:Bulletin of the Japanese Society of Scientific Fisheries,52,1061(1986)
非专利文献6:第57次日本医真菌学会总会·学术集会抄录集(第57回日本医真菌学会総会·学術集会抄録集),98(2013)
发明内容
发明所要解决的问题
利用了通过将鱼精蛋白水解而得的肽或精油成分的治疗出现副作用或抗药菌的危险低,这一点是优势,然而如此一来这样的来自于天然的成分会有抗真菌活性低于以被化学合成的非肽化合物作为有效成分的抗真菌剂的情况,此种情况下,需要使抗真菌活性进一步增强。另外,如非专利文献6中公开所示,用于确保生物体内的高盐浓度下的活性的肽的环状化会在被环状化了的肽的合成中增加成本,因此是不适于压缩成本的抗真菌剂的产业化的方法。
本发明的目的在于,提供一种作为有效成分包含鱼精蛋白水解物的具有抗真菌活性的组合物,其抗真菌活性得到进一步增强,并且压缩了成本,适于产业化。
用于解决问题的方法
本发明的具有抗真菌活性的组合物(抗真菌组合物)的特征在于,作为有效成分包含鱼精蛋白水解物和萜烯醇。
本发明还包含以下的各方式。
(1)一种抗真菌剂,其包含上述的抗真菌组合物。
(2)一种食品,其包含上述的抗真菌组合物。
(3)一种药品或准医药品,其包含上述的抗真菌组合物。
(4)一种化妆品,其包含上述的抗真菌组合物。
(5)一种方法,其作为用于获得抗真菌活性的有效成分在食品或化妆品的制造中使用上述的抗真菌组合物。
(6)一种方法,其作为用于获得抗真菌活性的有效成分在药品或准医药品的制造中使用上述的抗真菌组合物。
发明效果
根据本发明,利用因鱼精蛋白的水解而得的鱼精蛋白水解物与萜烯醇的协同作用,抗真菌活性得到明显的提高,可以提供没有抗药菌的出现或副作用的问题、并且安全性极高的具有抗真菌活性的组合物。作为抗真菌组合物,可以考虑作为具有抗真菌效果的口腔护理材料(含漱剂、牙膏、假牙清洗剂等)、针对包括褥疮、阴道念珠菌症或食道念珠菌症等的真菌感染症的药品(抗真菌剂)、准医药品(漱口剂、口腔清洗剂、药用牙膏等)、化妆品(软膏、液剂、悬浮剂、乳剂、气溶胶、泡沫剂、颗粒剂、粉末剂、片剂、胶囊等)的利用。口腔念珠菌症是尤其会在老年人、口腔干燥症患者中发作的症状,在今后的老龄化社会中的需求很大。另外,不仅可以有效地应用于口腔念珠菌症,还可以有效地应用于褥疮、阴道念珠菌症或食道念珠菌症等念珠菌症、马拉色霉菌症、以及隐球菌症等其他的真菌感染症,可以实现由此带来的病状的改善、治疗、以及感染的预防。另外,由于鱼精蛋白被收录于食品防腐剂的现有添加物表格中,因此不仅可以作为药品、准医药品利用,还可以作为口内清洗剂或健康食品、特定保健用食品等功能性食品利用,对于患者而言也有容易获取、容易使用的优点。
附图说明
图1是表示鱼精蛋白水解物与桧木醇的并用下的体外评价中的抗菌活性的相对值的图。
图2是表示鱼精蛋白水解物与4-萜烯醇的并用下的体外评价中的抗菌活性的相对值的图。
图3是表示鱼精蛋白水解物与香叶醇的并用下的体外评价中的抗菌活性的相对值的图。
图4是表示鱼精蛋白水解物与薄荷醇的并用下的体外评价中的抗菌活性的相对值的图。
图5是表示鱼精蛋白水解物与肉桂醛的并用下的体外评价中的抗菌活性的相对值的图。
图6是表示鱼精蛋白水解物与癸酸的并用下的体外评价中的抗菌活性的相对值的图。
图7是表示鱼精蛋白水解物单独使用的体外评价中的抗菌活性的相对值的图。
图8是表示鱼精蛋白水解物与桧木醇的并用下的体内评价中的舌评分的值的图(*:Steel Dwass的方法中p<0.05)。
图9是表示由鱼精蛋白水解物与桧木醇的并用造成的体外评价的结果的图。
图10是表示由鱼精蛋白水解物与桧木醇的并用造成的体外评价的结果的图。
图11是表示各种鱼精蛋白分解物的体外评价的结果的图。
图12是表示由鱼精蛋白水解物与桧木醇的并用造成的舌组织切片的光学显微镜观察的结果的图。
具体实施方式
本发明人等为了解决上述的来自于天然的成分所存在的问题,发现通过将对鱼精蛋白进行水解而得到的鱼精蛋白水解物与萜烯醇并用,可以明显地增强抗真菌活性,其增强效果是在由单纯的并用带来的相加作用以上的协同作用,从而形成了本发明。
已知鱼精蛋白水解物和萜烯醇分别可以单独地发挥抗念珠菌作用,然而迄今为止没有报告过若将它们一起使用则会协同地提高抗真菌活性的见解。一般而言,对微生物并用抗菌物质时的协同作用的定义是指显示出明显大于2种药的独自作用之和的作用的情况。作为评价有无协同作用的基准,可以举出由2种药的MIC值求出的FIC系数(fractionalinhibitory concentration index)作为一例。FIC系数可以利用以下的式(1)求出。
FIC系数的求法:
FIC系数=A1/A0+B1/B0····(1)
A0:A药单独使用的MIC
A1:A药、B药并用时的A药的MIC
B0:B药单独使用的MIC
B1:A药、B药并用时的B药的MIC
基于FIC系数的并用效果的评价:
FIC≤0.5:协同作用
0.5<FIC≤1.0:相加作用
1.0<FIC≤2.0:无关
2.0<FIC:拮抗作用
此外,本发明人等发现,由鱼精蛋白水解物与萜烯醇的并用带来的抗真菌活性增强的协同作用不仅在以往的体外评价体系中得到发挥,而且在使用了口腔念珠菌症模型小鼠的生物体模型中也得到发挥,从而完成了本发明。即发现,利用若使小鼠出现口腔念珠菌症则可以在舌中观察到白苔(念珠菌的菌丝)的现象,并用鱼精蛋白水解物和萜烯醇而经口给药,由此可以明显地抑制白苔在小鼠舌上的形成,可以协同地增强抗真菌活性。另外,本发明人等确认,鱼精蛋白水解物具有对于马拉色霉菌属的真菌的抗菌活性。
在上述的协同作用的研究时,首先,利用体外评价体系筛选了与鱼精蛋白水解物并用的候选材料的精油类。其结果是确认,通过将鱼精蛋白水解物与桧木醇、4-萜烯醇、香叶醇、薄荷醇等萜烯醇类并用,可以协同地增强抗真菌活性。另一方面,若是与肉桂醛、癸酸等不是分类为萜烯醇的精油类并用,则看不到抗真菌活性的增强。因而,利用使用了口腔念珠菌症模型小鼠的生物体模型评价了鱼精蛋白水解物与桧木醇的并用,其结果是确认,可以看到由协同作用造成的舌评分的明显改善,即使在生物体内的高盐浓度下也可以维持协同活性。根据以上内容可以发现,鱼精蛋白水解物与萜烯醇的并用即使是与以往的使用肽组合物、精油类时的使用量相同程度或远低于其的用量,也可以增强抗真菌活性,因此本发明人等认为在实用方面与以往技术相比具有进步性,从而形成了本发明。
下面,对本发明进行详细记述。
作为鱼精蛋白水解物的原料的鱼精蛋白是在大马哈鱼、鲱鱼、鳟鱼等鱼类的精子核中结合有脱氧核糖核酸的作为核鱼精蛋白存在的强碱性蛋白质,根据原料的不同,例如被称作大马哈鱼精蛋白(大马哈鱼)、鲱鱼精蛋白(鲱鱼)等,结构分别略有不同,然而任意一种鱼精蛋白均可以使用。
作为鱼精蛋白的水解方法,可以使用酸、碱、蛋白质分解酶,或者也可以利用基于它们的组合的分解,优选使用蛋白质分解酶。更具体而言如下所示。
在利用酸或碱的水解中,在强酸或强碱下对鱼精蛋白在可以获得作为目标的大小(长度)的肽的条件下进行加热处理后,进行中和,由此可以得到作为目标的大小(长度)的肽。
向鱼精蛋白中加入去离子水,加入氢氧化钠或盐酸而将pH调整为可以获得酶活性的pH,优选调整为最佳pH。将反应溶液加温到可以获得酶活性的温度、优选为酶的最佳温度后,添加酶,一边搅拌一边进行酶反应。反应结束后,将反应液加温到80~100℃而使之加热失活5~60分钟,将pH调整为中性区后,冷冻干燥反应液,就可以得到鱼精蛋白水解物。水解酶反应进行至可以得到由5~14个左右的氨基酸残基构成的富含精氨酸的肽,优选利用酶的加热失活使之停止。
可以将如上所述地得到的鱼精蛋白水解物中所含的各成分作为抗真菌用组合物的有效成分利用。因而,鱼精蛋白水解物可以以下面举出的形态进行利用。
(1)在上述的酶加热失活后进行了pH调整的反应液
(2)上述的反应液的冷冻干燥品
(3)从上述的反应液或冷冻干燥品中除去酶蛋白而得的调制物
(4)将上述的反应液、冷冻干燥品或调制物中的肽变换为所期望的盐的形态而得的调制物。
作为本发明中可以在水解中使用的蛋白质分解酶,例如可以举出芽孢杆菌(Bacillus)属(例如枯草芽孢杆菌(Bacillus subtilis)、嗜热蛋白溶解杆菌(Bacillusthermoproteolyticus)、地衣形芽孢杆菌(Bacillus licheniformis)等所产生的酶、曲霉(Aspergillus)属(例如米曲霉(Aspergillus oryzae)、黑曲霉(Aspergillus niger)、蜂蜜曲霉(Aspergillus melleus)等)所产生的酶、根霉(Rhizopus)属(例如雪白根霉(Rhizopusniveus)、戴尔根霉(Rhizopus de lemar)等)所产生的酶、胃蛋白酶、胰酶、木瓜蛋白酶等。这些酶可以单独使用,或者组合使用2种以上。另外,蛋白质分解酶被分类为特异性地识别并切断蛋白质的内部序列的肽链内切酶、和从末端每次切断1~2个氨基酸残基的肽链端解酶。因而,根据需要,可以利用肽链内切酶与肽链端解酶的组合,生成各种各样的肽链。在利用酶进行水解的情况下,相对于底物,添加0.001~10质量%的酶,将溶液水解为所使用的酶的最佳pH。
鱼精蛋白水解物中所含的肽根据需要可以制成与无机酸或有机酸的盐、与无机碱或有机碱的盐的形态,作为抗真菌剂的有效成分使用。作为酸、碱,可以根据盐的用途来选择,若考虑在食品、化妆品、药品等中的用途,则优选以下举出的药学上容许的盐。作为酸加成盐,例如可以举出盐酸盐、硝酸盐、硫酸盐、甲磺酸盐、对甲苯磺酸盐、以及与乙二酸、丙二酸、丁二酸、马来酸、或富马酸等二羧酸的盐、以及与乙酸、丙酸、或丁酸等单羧酸的盐等。另外,适于本发明中得到的肽化合物的盐的形成的无机碱例如为氨、钠、锂、钙、镁、铝等的氢氧化物、碳酸盐及重碳酸盐等。作为与有机碱的盐,例如可以举出甲胺、二甲胺、三乙胺之类的单-、二-及三-烷基胺盐、单-、二-及三-羟基烷基胺盐、胍盐、N-甲基葡萄糖胺盐等。肽成分被变换为盐的形态的鱼精蛋白水解物也包含于本发明的鱼精蛋白水解物中。
本发明的具有抗真菌活性的组合物、即抗真菌组合物作为抗真菌活性的有效成分包含鱼精蛋白水解物和萜烯醇,优选抗真菌活性的有效成分由鱼精蛋白水解物和萜烯醇构成。
作为利用鱼精蛋白的水解处理得到的具有抗真菌活性的肽,可以举出分类为以下的(1)~(6)的肽。因而,作为与萜烯醇组合的鱼精蛋白水解物,优选包含选自以下的(1)~(6)中的至少1种肽化合物(即肽或其盐)。
(1)由以Ile Arg Arg Arg Arg Pro Arg Arg表示的序列编号:1的氨基酸序列构成的肽及其盐。
(2)由以Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg表示的序列编号:2的氨基酸序列构成的肽及其盐。
(3)由以Val Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg表示的序列编号:3的氨基酸序列构成的肽及其盐。
(4)由序列编号:1的氨基酸序列中缺失了1到6个氨基酸的氨基酸序列构成的肽或其盐。
(5)由序列编号:3的氨基酸序列中缺失了1到4个氨基酸的氨基酸序列构成的肽或其盐。
(6)由序列编号:3的缺失序列以Arg Arg Arg Arg Arg Arg Gly Gly Arg ArgArg Arg(序列编号:4)、Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg(序列编号:5)、或Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg(序列编号:6)表示的氨基酸序列构成的肽或其盐。
另外,作为鱼精蛋白水解物,更优选包含选自上述(1)~(3)中的至少1种肽化合物的鱼精蛋白水解物,进一步优选为包含选自上述(1)中的至少1种肽化合物、选自上述(2)中的至少1种肽化合物、和选自上述(3)中的至少1种肽化合物的鱼精蛋白水解物。
而且,也可以将不同组成的具有抗真菌活性的鱼精蛋白水解物的2种以上混合使用。
继而,作为本发明中所用的萜烯醇,优选1个分子中的碳原子数为10个的单萜烯醇、或15个的倍半萜烯醇。虽然还有其他具有抗真菌活性的精油及精油成分,然而均报告过副作用,在安全性方面有问题。例如,桂皮油及作为其成分的肉桂醛、香茅草油及作为其成分的柠檬醛、百里香油及作为其成分的百里酚、牛至油及作为其成分的香芹酚的皮肤刺激性均很强。另外,迷迭香油及作为其成分的樟脑、留兰香油及作为其成分的香芹酮等也有抗真菌活性,然而均报告过对中枢神经系统的刺激作用。但是,香叶醇、里那醇、橙花叔醇之类的萜烯醇没有应当特别注意的副作用,安全性高。另外如前所述,抗真菌活性也高,因此最适于与鱼精蛋白水解物并用。
本发明中所用的植物精油及其成分如下所示。桧木油与作为其主成分的桧木醇、茶树油与作为其主成分的4-萜烯醇、玫瑰草油与作为其主成分的香叶醇、薄荷油与作为其主成分的薄荷醇及其衍生物、薰衣草油与作为其主成分的里那醇、广藿香油与作为其主成分的广藿香醇、钓樟油与作为其副成分的橙花叔醇。而且,作为薄荷醇衍生物,可以举出乳酸薄荷酯、薄荷氧基丙二醇、羟基丁酸薄荷酯、薄荷氧基呋喃、薄荷基葡糖苷等。另外玫瑰木油、玫瑰天竺葵油、柠檬桉叶油、胡椒薄荷油、橙花油之类的植物精油也分别可以期待相同的效果地使用。
作为单萜烯醇,优选使用选自桧木醇、香叶醇、4-萜烯醇、薄荷醇、薄荷醇衍生物及里那醇中的至少1种。单萜烯醇更优选为桧木醇、香叶醇、4-萜烯醇、薄荷醇、薄荷醇衍生物或里那醇。
倍半萜烯醇优选为广藿香醇和/或橙花叔醇。
本发明的抗真菌组合物例如可以在精油或精油成分中直接溶解或悬浮鱼精蛋白水解物的原末(例如冷冻干燥品)而得到。虽然也可以将如此得到的组合物作为抗真菌剂给药,然而在实用上软膏或凝胶剂之类的涂布剂、或喷雾制品之类的外用剂的形态更容易使用。本发明的抗真菌组合物可以与其给药形态对应地含有赋形剂、稀释剂、载体(carrier)等的至少1种。
精油或精油成分可以通过使用乙醇、丙二醇之类的适当的溶剂而作为完全透明的液体制备。另外也可以使用凝胶性质等水性凝胶剂或增溶剂(Solbiraizer)之类的精油分散剂悬浮在水中。在以个人或家庭使用的情况下,考虑刺激性、经济性而将精油或精油成分预先稀释在媒介油(carrier oil)中后给药是实际的做法。作为用于该操作的媒介油,可以举出炉油、荷荷巴油、甜杏仁油、苦楝油、圣约翰药草浸泡油等植物油。另外通过向热水中加入抗真菌组合物并实施足浴也可以期待相同的效果。
本发明的以鱼精蛋白水解物和萜烯醇双方作为有效成分的抗真菌组合物对至少一种真菌具有高抗真菌活性,特别是优选以成为真菌感染症的病原菌的念珠菌(Candida)属、马拉色霉菌(Malassezia)属的真菌作为对象,除此以外,例如,也可以将隐球菌(Cryptococcus)属、曲霉(Aspergillus)属、毛癣菌(Trichophyton)属、球孢子菌(Coccidioides)属等作为对象。可以使用属于这些属的真菌株,利用常法,例如基于后述的实施例中举出的方法确认本发明的抗真菌活性。
对于肽化合物而言,由于认为难以出现抗药菌,因此鱼精蛋白水解物适于作为真菌症预防剂的主成分使用。另外,鱼精蛋白水解物及萜烯醇的安全性也得到确认,它们适于用作抗真菌组合物的有效成分。通过作为抗真菌剂的有效成分使食品、药品、准医药品、化妆品中含有本发明的抗真菌组合物,就可以获得真菌感染症的预防、缓解或治疗等效果。此外,可以将本发明的抗真菌组合物作为真菌感染症的预防和/或治疗用的组合物的有效成分利用。本发明的抗真菌组合物可以作为包括将本发明的抗真菌组合物的有效量向真菌感染症的预防和/或治疗对象者给药的操作的真菌感染症的预防和/或治疗方法中的有效成分利用。
对于抗真菌组合物的形态没有特别限定。例如,作为内用剂或外用剂的典型形态,可以举出软膏、液剂、悬浮剂、乳剂、气溶胶、泡沫剂、颗粒剂、粉末剂、片剂、胶囊、喷雾剂。另外,为了用于注射等中,也可以制成用于在即将使用前溶解于生理盐水或适当的缓冲液(例如PBS)等中而制备药液的冷冻干燥物、造粒物。抗真菌剂中所含的载体根据抗真菌剂的形态而不同。而且,以鱼精蛋白水解物及萜烯醇(有效成分)、以及各种载体(副成分)作为材料制备各种形态的药剂(组合物)的制剂过程本身只要依照以往公知的方法即可,该制剂方法本身并非对本发明附加特征的内容,因此省略详细的说明。作为与配方有关的详细的信息源,例如可以举出Comprehensive Medicinal Chemistry、CorwinHansch主编、PergamonPress出版(1990)。
抗真菌组合物中的作为有效成分的具有抗真菌活性的鱼精蛋白水解物和萜烯醇的含量可以根据其用途,从能够获得本发明中作为目标的它们的协同作用的范围中选择。此外,对于在成为赋予作为抗真菌剂的功能的对象的药品、准医药品、食品及化妆品中的这些有效成分的配合量,也可以同样地从能够获得协同作用的范围中选择。
利用本发明提供的抗真菌组合物可以以与其形态及目的对应的方法、用量使用。例如,利用本发明提供的抗真菌组合物可以作为液剂通过向静脉内、肌肉内、皮下、皮内或腹腔内的注射或灌肠来向患者给药。或者可以将片剂等固体形态的药剂经口给药。另外,在出于皮肤表面、口腔内、阴道内、或卫生陶瓷表面的消毒(杀菌)或食品的防腐目的使用的情况下,可以将含有较多量的鱼精蛋白水解物(例如作为肽化合物的量为1~100mg/ml)的液剂向对象物的表面直接喷雾,或者用以该液剂润湿了的纱布或布、纸来擦拭对象物的表面。这些只不过是例示,可以应用与以往的以肽系抗生素或肽作为构成成分的农药、准医药品等相同的形态、使用方法。例如,对于接受放射线治疗的癌症患者、艾滋病患者,预防及治疗微生物所致的感染症是重大的关心事项。此处公开的抗真菌组合物可以对作为感染症的原因的真菌(例如念珠菌属的真菌)显示出高抗真菌作用。由此,本发明的抗真菌组合物作为抗真菌剂的主成分而言有用。
作为进行本发明的真菌感染症的预防、缓解或治疗等的方法,可以作为食品、功能性食品、药品、准医药品、化妆品使用,可以举出向口香糖、粒状糖、片状糖、薄膜、喷雾剂、健康食品、特定保健用食品、口腔或牙科卫生用器具、假牙清洗剂或假牙稳定剂组合物中的添加、含漱剂、口腔清洗剂、药用牙膏、化妆水、乳霜、粉剂、乳液、喷雾剂、涂布剂等各种形态。
实施例
下面,给出实施例而对用于实施本发明的最佳形态进行详细记述,然而本发明并不限定于以下的实施例。
以下的真菌株可以从以下的单位公开获取。而且,用于试验抗菌性的真菌株并不限定于以下所示的菌株,可以利用普遍所用的菌株。
-Candida albicans NBRC1594
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·住所:日本国〒292-0818千叶县木更津市かずさ鎌足2-5-8
(http://www.nite.go.jp/nbrc/cultures/)
-Candida albicans TIMM1768及Malassezia fur fur TIMM10020
帝京大学医真菌研究中心
住所:日本国〒192-0395东京都八王子市大塚359
(http://www.teikyo-u.ac.jp/timm/research/r01.html?page=research)
(实施例1)
(利用鱼精蛋白的酶分解的鱼精蛋白水解物的制备)
向来自于白鲑(大马哈鱼(Oncorhynchus keta))的鱼白的鱼精蛋白(Proserve;(株)Maruha Nichiro制)50g中加入去离子水80mL,并加入氢氧化钠而调整为pH8.0。加温到65℃后,添加嗜热菌蛋白酶(Nacalai Tesque(株)制,来自嗜热蛋白溶解杆菌(Bacillusthermoproteolyticus))1.5mg,一边搅拌2小时一边进行酶反应。反应结束后,将反应液加温到95℃而使之加热失活30分钟,将pH调整为8.5。其后,冷冻干燥反应液,得到鱼精蛋白水解物。
(实施例2)
(鱼精蛋白水解物的活性级分的分离收集和活性肽的分析)
将依照实施例1制备的鱼精蛋白水解物用去离子水制成50000ppm溶液后,使用HPLC在下述的分离条件下分离收集各级分。使用Candida albicans NBRC1594评价该级分的抗念珠菌活性,得到2个级分的活性级分。继而,将该活性级分用于LCMS-IT-TOF分析,确定了以下的3个肽的结构。
(1)Ile Arg Arg Arg Arg Pro Arg Arg(8个残基;分子量1164.7541)
(2)Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg(13个残基;分子量1780.0966)
(3)Val Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg(14个残基;分子量1879.1650)。
<HPLC分离条件>
·HPLC系统:(株)岛津制作所制Prominence系列(系统控制器:CBM-20A、自动进样器:SIL-10AF、输液泵:LC-8A×2台、柱温箱:CTO-20A、PDA检测器:SPD-M20A(测定波长190~400nm))
·流速:1.0mL/min
·流动相A:0.1%三氟乙酸
·流动相B:乙腈
·色谱柱:Inertsil ODS-2 5μm 4.6mm×250mm(GL Science制)
·梯度:用0~60分钟从B液0容量%到B液15容量%的线性梯度。
·检测波长:214nm。
<LCMS-IT-TOF解析条件>
·HPLC系统:(株)岛津制作所制Prominence系列(系统控制器:CBM-20A、自动进样器:SIL-20A、输液泵:LC-20AB Binary pump、柱温箱:CTO-20A、PDA检测器:SPD-M20A(测定波长190~400nm))
·流速:0.2mL/min
·流动相A:0.1%甲酸(关东化学制,LC-MS用)
·流动相B:乙腈(关东化学制,LC-MS用)
·色谱柱:Atlantis HILIC Silica,3μm Column(Waters制)
·梯度:用0~30分钟从B液60容量%到B液0容量%的线性梯度。
·注入量:10μL
·IT-TOFMS系统:(株)岛津制作所制LCMS-IT-TOF(离子化模式:ESI-、雾化气体流量:1.5L/min、Drying gas压力0.15Mpa、施加电压4.5kV、CDL温度:200℃、BH温度:200℃、测定范围MS:m/z 500~2,000)。
(实施例3)
(协同作用材料的体外筛选)
·菌株
Candida albicans TIMM1768
·试验物质
将桧木醇((有)Kiseitec制)、4-萜烯醇(东京化成工业(株)制)、香叶醇(关东化学(株)制)、薄荷醇(和光纯药工业(株)制)、肉桂醛(和光纯药工业(株)制)、癸酸(和光纯药工业(株)制)分别溶解于RPMI培养基中,使得试验物质中的浓度为0.008、0.04、0.2、1mg/mL,并溶解依照实施例1制备的鱼精蛋白水解物,使得试验物质中的鱼精蛋白水解物的浓度为0、0.125、2.0mg/mL,用于试验。另外,将鱼精蛋白水解物单独的0.002、0.008、0.031、0.125、0.5、2、8、32mg/mL溶液用于试验。
·评价方法
将C.albicans TIMM1768株以达到2.5×105cells/well的方式向96well微孔板中各添加200μL,在5%CO2下、37℃培养2.5~3.5小时。培养后,抽吸除去培养基,添加200μL/well的各试验物质。在37℃静置10分钟后,抽吸除去样品溶液,加入200μL/well的RPMI培养基,在5%CO2下、37℃培养2.5小时。培养后,进行结晶紫染色并测定出620nm的吸光度。抗菌活性是以将空白的吸光度设为1时的各试验区的相对值来表示。
·结果
图1~6中表示出由鱼精蛋白水解物与萜烯醇类的并用带来的体外评价的结果,图7中表示出鱼精蛋白水解物单独使用的体外评价的结果。图1~6中,◆表示萜烯醇类单独使用的结果,■表示与鱼精蛋白水解物0.125mg/ml并用的结果,▲表示与鱼精蛋白水解物2.0mg/ml并用时的结果。
桧木醇即使在单独使用时也显示出抗菌活性,被认为可以看到由与鱼精蛋白水解物的组合带来的活性增强的协同作用。4-萜烯醇和香叶醇、薄荷醇虽然单独使用时的活性低,然而会因与鱼精蛋白水解物的并用而略微增强活性,因此被认为具有协同作用。肉桂醛、癸酸在单独使用时基本上不显示出抗菌活性,也没有看到由与鱼精蛋白水解物的并用带来的协同作用。而且,虽然已知癸酸显示出强的抗真菌活性,然而此次的体外评价体系为了模拟生物体内,将药剂与菌的接触时间设定为非常短的10分钟,因此可以认为癸酸无法发挥充分的抗真菌作用。
根据以上的结果可以确认,鱼精蛋白水解物在精油当中与桧木醇、4-萜烯醇、香叶醇等萜烯醇类显示出协同作用。
(实施例4)
(体内评价体系中的效果确认)
·菌株
Candida albicans TIMM1768
·实验动物
ICR小鼠、雌性、6周龄(日本Charles River(株))
·试验物质
依照实施例1制备的鱼精蛋白水解物
桧木醇((有)Kiseitec制)
·组构成
阴性对照(1%甲基纤维素)6只
鱼精蛋白水解物25mg/mL(1%Tween 80)6只
桧木醇0.4mg/mL(1%Tween 80)6只
桧木醇2mg/mL(1%Tween 80)6只
鱼精蛋白水解物25mg/mL+桧木醇0.4mg/mL(1%Tween 80)6只
鱼精蛋白水解物25mg/mL+桧木醇2mg/mL(1%Tween 80)6只
·评价方法
在C.albicans的感染前一天,皮下注射100mg/kg的免疫抑制剂(氢化泼尼松)。为了防止C.albicans以外的感染,使自来水中含有15mg/mL的盐酸金霉素,使之自由摄取。在感染当天,肌肉注射14.4mg/kg的氯丙嗪盐酸盐后,以使C.albicans为2×108cells/mL的方式用FBS-RPMI液体培养基稀释,将稀释了的菌液用棉棒涂布于小鼠口腔内。在感染3、24、27小时后,使用经口探棒给予50μL的各试验物质。在感染48小时后,使小鼠安乐死,进行了舌症状的评分。而且,舌评分是若利用目视在舌中完全看不到白苔则设为0分,若在舌的20%以下的部分看到白苔则设为1分,若为21~90%则设为2分,若为91%以上则设为3分,若在91%以上并且呈层状地看到白苔则设为4分。
·结果
图8中表示出由鱼精蛋白水解物与桧木醇的并用造成的体内评价的结果。对于舌评分,在鱼精蛋白水解物25mg/mL与桧木醇2.0mg/mL的组合中可以看到明显的评分的改善,与分别单独地给药的情况相比舌评分改善,可以看到由协同作用造成的抗真菌活性的增强。由于鱼精蛋白水解物被暗示过以低浓度附着于菌体表面而显示出抑菌作用的作用机理,另一方的桧木醇被报告过膜功能的阻碍和呼吸的抑制作用,根据这些机理的差别,可以认为鱼精蛋白水解物与桧木醇的并用并非单纯的相加作用,而是发挥出协同作用后增强了抗菌活性。
(参考例1)
(利用马拉色霉菌的效果确认)
·菌株
Malassezia fur fur TIMM10020
·评价方法
将在MLNA培养基中培养的Malassezia fur fur用生理盐水调整为MacFarland1.0,将该调整液100μL、橄榄油50μL涂布在MLNA琼脂平板上。在皿中央向厚8mm的抗生素测试用纸片滴下试验试样(将鱼精蛋白水解物用灭菌水调整为40mg/mL)50μL,在32℃培养7天。
·结果
在滴下了50μL的鱼精蛋白水解物40mg/mL的纸片的周围,看到了14mm×14mm(纸片为8mm)的阻止圆。在对照的灭菌水中没有看到阻止圆,因此确认鱼精蛋白水解物具有对马拉色霉菌的抗菌效果。
(实施例5)
(关于与桧木醇的并用的详细分析)
·菌株
Candida albicans TIMM1768
·试验物质
将桧木醇((有)Kiseitec制)溶解于RPMI培养基中,使试验物质中的浓度为0、0.004、0.008、0.016、0.031、0.063、0.125、0.25、0.5、1μg/mL,将依照实施例1制备的鱼精蛋白水解物溶解,使试验物质中的鱼精蛋白水解物的浓度为0、0.156、0.313、0.625、1.25、2.5、5、10μg/mL,用于试验。
·评价方法
将C.albicans TIMM1768株以达到5.0×103cells/mL的方式用RPMI培养基稀释后,向96well微孔板中各添加100μL。各添加50μL/well的鱼精蛋白水解物溶液后,各添加50μL/well的桧木醇。在5%CO2下、37℃培养16小时后,进行结晶紫染色并测定出620nm的吸光度。抑制活性是根据将阴性对照(未添加鱼精蛋白水解物及桧木醇)的吸光度设为1时的各试验区的相对值算出。另外,也一并算出表1中所示的各浓度的桧木醇((有)Kiseitec制)及鱼精蛋白水解物“Pro”的FIC指数。
·结果
图9及图10中表示出由鱼精蛋白水解物与桧木醇的并用造成的体外评价的结果。表1中表示出FIC指数的算出结果。
[表1]
表1 IC90
桧木醇 | Pro | FIC |
0 | 5.95 | 1.00 |
0.001 | 5 | 0.84 |
0.004 | 3.9 | 0.66 |
0.008 | 3.8 | 0.65 |
0.016 | 2.95 | 0.52 |
0.031 | 3.2 | 0.58 |
0.055 | 2.5 | 0.49 |
0.063 | 2.45 | 0.49 |
0.125 | 2.35 | 0.56 |
0.25 | 2.3 | 0.71 |
0.5 | 1.65 | 0.93 |
0.63 | 1.25 | 1.03 |
0.73 | 0.625 | 1.05 |
0.8 | 0.313 | 1.09 |
0.54 | 0.156 | 0.73 |
0.77 | 0 | 1.00 |
其结果是,在低浓度的桧木醇与鱼精蛋白水解物的组合中显示出FIC≤0.5的协同作用。
根据以上的结果可以确认,鱼精蛋白水解物显示出与桧木醇的协同作用。
(实施例6)
(来自于其他鱼种鱼白的鱼精蛋白水解物的体外评价)
·菌株
Candida albicans TIMM1768
·试验物质
将依照实施例1制备的来自于各鱼种(细鳞大马哈鱼、鲱鱼)的鱼精蛋白水解物、以及来自于大马哈鱼鱼白的鱼精蛋白的菠萝蛋白酶分解物溶解于RPMI培养基中,使得试验物质中的鱼精蛋白水解物的浓度为0.625、1.25、2.5、5、10、20、40、80、160μg/mL,用于试验。
·评价方法
将C.albicans TIMM1768株以达到5.0×103cells/mL的方式用RPMI培养基稀释后,向96well微孔板中各添加100μL。各添加50μL/well的鱼精蛋白水解物溶液后,各添加50μL/well的RPMI培养基。在5%CO2下、37℃培养16小时后,进行结晶紫染色并测定出620nm的吸光度。抑制活性是根据将阴性对照(未添加鱼精蛋白水解物)的吸光度设为1时的各试验区的相对值算出。
·结果
图11中表示出各种鱼精蛋白水解物的体外评价的结果。
任意一种试验物质均显示出与来自于大马哈鱼鱼白的鱼精蛋白水解物同等的活性。根据该结果,显示出鱼精蛋白分解物的鱼种通用性。
(实施例7)
(利用体内评价体系的并用效果确认)
·菌株、实验动物、试验物质、组构成、评价方法
使用了与实施例4相同的菌株、实验动物、试验物质、组构成及评价方法。
由感染48小时后安乐死的小鼠依照常法制作出舌组织切片,在染色后,利用光学显微镜拍摄而得到染色图像。
·结果
图12中表示出由鱼精蛋白水解物与桧木醇的并用造成的舌组织观察的结果。在舌组织图像中,虽然鱼精蛋白分解物单独使用时在舌表面的粘膜内残存有菌丝,然而可以在组合试验区中清楚地确认菌丝的抑制。
SEQUENCE LISTING
<110> 玛鲁哈日鲁株式会社
<110> 学校法人帝京大学
<120> 含有抗真菌肽和萜烯醇的抗真菌组合物
<130> 15-0073-MN
<150> JP 2014-186288
<151> 2014-9-12
<160> 6
<210> 1
<211> 8
<212> PRT
<213> 大马哈鱼
<400> 1
Ile Arg Arg Arg Arg Pro Arg Arg
1 5
<210> 2
<211> 13
<212> PRT
<213> 大马哈鱼
<400> 2
Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg
1 5 10
<210> 3
<211> 14
<212> PRT
<213> 大马哈鱼
<400> 3
Val Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg
1 5 10
<210> 4
<211> 12
<212> PRT
<213> 大马哈鱼
<400> 4
Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg
1 5 10
<210> 5
<211> 11
<212> PRT
<213> 大马哈鱼
<400> 5
Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg
1 5 10
<210> 6
<211> 10
<212> PRT
<213> 大马哈鱼
<400> 6
Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg
1 5 10
2
Claims (11)
1.一种具有抗真菌活性的组合物,其包含鱼精蛋白水解物和萜烯醇作为有效成分。
2.根据权利要求1所述的具有抗真菌活性的组合物,其中,
所述鱼精蛋白水解物包含由以下的序列编号:1~3的任意一种氨基酸序列构成的肽及由其盐构成的肽化合物的至少1种,
序列编号:1
Ile Arg Arg Arg Arg Pro Arg Arg
序列编号:2
Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg
序列编号:3
Val Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg。
3.根据权利要求1或2所述的具有抗真菌活性的组合物,其中,
所述萜烯醇为选自单萜烯醇或倍半萜烯醇中的至少1种。
4.根据权利要求3所述的具有抗真菌活性的组合物,其中,
所述单萜烯醇为桧木醇或香叶醇、4-萜烯醇、薄荷醇、薄荷醇衍生物、里那醇。
5.根据权利要求4所述的具有抗真菌活性的组合物,其中,
所述倍半萜烯醇为广藿香醇或橙花叔醇。
6.一种抗真菌剂,其包含权利要求1至5中任一项所述的具有抗真菌活性的组合物。
7.一种食品,其包含权利要求1至5中任一项所述的具有抗真菌活性的组合物。
8.一种药品或准医药品,其包含权利要求1至5中任一项所述的具有抗真菌活性的组合物。
9.一种化妆品,其包含权利要求1至5中任一项所述的具有抗真菌活性的组合物。
10.在食品或化妆品的制造中使用权利要求1至5中任一项所述的具有抗真菌活性的组合物作为用于获得抗真菌活性的有效成分的方法。
11.在药品或准医药品的制造中使用权利要求1至5中任一项所述的具有抗真菌活性的组合物作为用于获得抗真菌活性的有效成分的方法。
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CN109077947A (zh) * | 2018-08-30 | 2018-12-25 | 湖北舒邦药业有限公司 | 一种医用眼科冷敷敷料及其制备方法 |
CN113301890A (zh) * | 2019-01-15 | 2021-08-24 | 和兴滤清器科技株式会社 | 抗炎症组合物 |
CN114080219A (zh) * | 2019-07-05 | 2022-02-22 | 宝洁公司 | 个人护理清洁组合物 |
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US11191705B2 (en) | 2018-09-10 | 2021-12-07 | The Procter And Gamble Company | Personal cleansing compositions |
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CN113301890A (zh) * | 2019-01-15 | 2021-08-24 | 和兴滤清器科技株式会社 | 抗炎症组合物 |
CN114080219A (zh) * | 2019-07-05 | 2022-02-22 | 宝洁公司 | 个人护理清洁组合物 |
Also Published As
Publication number | Publication date |
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US20170354177A1 (en) | 2017-12-14 |
DE112015004182T5 (de) | 2018-01-11 |
WO2016039229A1 (ja) | 2016-03-17 |
CN110075271A (zh) | 2019-08-02 |
JP6162341B2 (ja) | 2017-07-12 |
JPWO2016039229A1 (ja) | 2017-04-27 |
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