CN1852708A - 人β防御素分泌促进剂 - Google Patents
人β防御素分泌促进剂 Download PDFInfo
- Publication number
- CN1852708A CN1852708A CNA2004800270414A CN200480027041A CN1852708A CN 1852708 A CN1852708 A CN 1852708A CN A2004800270414 A CNA2004800270414 A CN A2004800270414A CN 200480027041 A CN200480027041 A CN 200480027041A CN 1852708 A CN1852708 A CN 1852708A
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- China
- Prior art keywords
- acid
- defensin
- human beta
- secretion
- beta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明的目的在于,提供一种能够促进人β防御素分泌的β防御素分泌促进剂,其可以以外用剂、内服剂、食品等各种形态使用。有机酸具有促进人β防御素、特别是人β防御素-2的分泌的作用,以该有机酸为人β防御素分泌促进剂的有效成分使用。通过将该人β防御素分泌促进剂配合于外用剂、内服剂、食品中,可以使这些物质具有人β防御素分泌促进作用。
Description
技术领域
本发明涉及一种可以促进β防御素分泌的β防御素分泌促进剂。而且,本发明还涉及一种促进β防御素分泌的方法。
背景技术
众所周知,在植物、昆虫、两栖类、哺乳类等中,其机体内存在抗菌物质(抗菌肽)作为与生俱来的机体内防御机构。这称为天然免疫,承担着局部的感染防御。目前已知作为人体中的抗菌肽之一的防御素,具有对细菌、真菌、原虫、病毒等的抗菌活性,在机体内参与各种机体防御机构。
作为皮肤、肺、气管、肾、生殖器等的粘膜上皮上显现的防御素,已知有β防御素。现在,已离析并确定了6种人β防御素(人β防御素-1、人β防御素-2、人β防御素-3、人β防御素-4、人β防御素-5及人β防御素-6)的结构。特别是β防御素-2,已判明其具有在皮肤、肺、气管及口腔粘膜中进行特别强地表达,通过细菌感染和炎性细胞因子刺激表达诱导等特征(参照富田哲治等、「作为机体防御机构的防御素」、日本老年医学会杂志、2001年、第38卷、第4号、第440-443页),表明其与肺炎等的气管感染和炎症有密切关系。
另外,近年来有报告报道,β防御素不仅能防御局部感染,而且通过使杆细胞、T淋巴细胞、单核细胞的游动,也参与后天免疫。(参照Yang,D.,Chertov,O.,Bykovskaia,S.N.et.al.,“β-Defensins:linking innateand Adaptive immunity through dendritic and T cellCCR6”,Science,1999,vol.286、p.525;Territo,M.C.,Ganz,T.,Selsted,M.E.etal.,”Monocyto-chemotactic activity of defensins from humanneutrophils”,J.Clin.invest.,1989,vol.84,p.201 7;Lillard,J.W.,Jr.,Boyaka,P.N.,Chertov O.et al.,”Mechanisms for induction of acquired host immunity byneutrophil peptide defensins”,Proc.Natl.Acad.Sci.U.S.A.,1999,vol.96,p.651;长冈功等“Defensin的感热防御和在免疫应答中的作用”、临床免疫、2000年、第33卷、第577页)。
至此,已知炎性细胞因子和脂多糖类有促进人β防御素分泌的作用。然而,人β防御素的产生、分泌的机理,还没有充分判明。对上述物质以外的促进人β防御素分泌的方法,尚不明确。
发明内容
本发明的目的在于,提供一种能够促进人β防御素分泌的β防御素分泌促进剂。另外,本发明的目的还在于,提供一种可以以外用剂、内服剂、食品等各种形态使用的人β防御素分泌促进剂。
而且,本发明的目的还在于,提供一种有效促进人β防御素分泌的方法。
本发明人为解决上述课题进行了专心致志地研究,结果发现,有机酸具有促进人β防御素分泌的作用。本发明是基于这种见解进一步进行反复研究而开发的。
亦即,本发明是如下记载的人β防御素分泌促进剂。
[1]一种人β防御素分泌促进剂,其特征在于,其以有机酸为有效成分。
[2]如[1]记载的人β防御素分泌促进剂,其有机酸是选自富马酸、苹果酸、柠檬酸、抗坏血酸、乳酸、乙酸、己二酸、酒石酸、肉桂酸、谷氨酸及丁二酸的至少一种。
[3]如[1]记载的人β防御素分泌促进剂,其有机酸是选自富马酸、苹果酸、柠檬酸和酒石酸的至少一种。
[4]如[1]记载的人β防御素分泌促进剂,其成为分泌促进对象的人β防御素是人β防御素-2。
[5]如[1]记载的人β防御素分泌促进剂,其是在***部或口腔内使用的。
[6]一种促进人β防御素分泌用的外用组合物,其含有如[1]~[4]中任一项记载的人β防御素的分泌促进剂。
[7]一种促进人β防御素分泌用的内服组合物,其含有如[1]~[4]中任一项记载的人β防御素的分泌促进剂。
[8]一种促进人β防御素分泌用的食品,其含有如[1]~[4]中任一项记载的人β防御素的分泌促进剂。
另外,本发明是如下记载的促进人β防御素分泌的方法:
[9]一种促进人β防御素分泌的方法,其特征在于,其给药或使其摄取有效量的有机酸。
[10]如[9]记载的促进人β防御素分泌的方法,其有机酸是选自富马酸、苹果酸、柠檬酸、抗坏血酸、乳酸、乙酸、己二酸、酒石酸、肉桂酸、谷氨酸和丁二酸的至少一种。
[11]如[9]记载的促进人β防御素分泌的方法,其有机酸是选自富马酸、苹果酸、柠檬酸和酒石酸的至少一种。
[12]如[9]记载的促进人β防御素分泌的方法,其成为分泌促进对象的人β防御素是人β防御素-2。
[13]如[9]记载的促进人β防御素分泌的方法,其在***部或口腔内促进人β防御素的分泌。
[14]如[9]记载的促进人β防御素分泌的方法,其使用如[1]~[5]中任一项记载的人β防御素促进剂作为有机酸。
[15]如[9]记载的促进人β防御素分泌的方法,其使用如[6]记载的内服组合物作为有机酸。
[16]如[9]项记载的促进人β防御素分泌的方法,其使用如[7]记载的食品作为有机酸。
[17]如[9]项记载的促进人β防御素分泌的方法,其使用如[8]记载的外用组合物作为有机酸。
而且,本发明是如下形态的用途:
[18]一种有机酸的用于制造人β防御素的分泌促进剂的用途。
[19]一种有机酸的用于制造促进人β防御素分泌的内服组合物的用途。
[20]一种有机酸的用于制造促进人β防御素分泌的食品的用途。
[21]一种有机酸的用于制造促进人β防御素分泌的外用组合物的用途。
[22]一种有机酸的用于促进人β防御素的分泌的用途。
附图说明
图1是表示在试验例1中,在将各有机酸应用于口腔内时,唾液中促进分泌的人β防御素-2的量(ng/min)的图。
图2是表示在试验例2中,在将各有机酸应用于口腔内时,唾液中促进分泌的人β防御素-2的量(ng/min)的图。
图3是表示在试验例3中,在将各种量的苹果酸应用于口腔内时,唾液中促进分泌的人β防御素-2的量(ng/min)的图。
具体实施方式
(1)人β防御素分泌促进剂
在本发明的人β防御素分泌促进剂中,成为分泌促进对象的人β防御素含有:人β防御素-1、人β防御素-2、人β防御素-3、人β防御素-4、人β防御素-5、人β防御素-6。在这些物质中,因为人β防御素-2能更有效地进行分泌促进,所以是最合适的分泌促进对象。
本发明的β防御素分泌促进剂的有效成分是有机酸。在本发明中使用的有机酸,只要是药学上、化妆学上或食品卫生上允许的物质,就没有特别限制。本发明中使用的有机酸,例如有:甲酸、乙酸、丙酸、丁酸、戊酸、己酸、正辛酸、正癸酸、月桂酸、肉豆蔻酸、软脂酸、硬脂酸、丙烯酸、丙酰酸、肉桂酸、咖啡酸等一元羧酸;草酸、丙二酸、丁二酸、正戊二酸、己二酸、庚二酸、富马酸、马来酸、苯二酸、异苯二酸、对苯二甲酸等二元羧酸;谷氨酸、天冬氨酸等氨基酸;乙醇酸、苹果酸、酒石酸、异酒石酸、柠檬酸、异柠檬酸、乳酸、羟基丙烯酸、α-羟基丁酸、甘油酸、羟基丙二酸、水杨酸、没食子酸、托品酸、抗坏血酸、葡糖酸等羟基酸;叶酸;泛酸;烟酸;以及其它糖衍生物等有机酸。这些有机酸中优选富马酸、苹果酸、柠檬酸、抗坏血酸、乳酸、乙酸、己二酸、酒石酸、肉桂酸、谷氨酸及丁二酸。更优选富马酸、苹果酸、柠檬酸及酒石酸。这些有机酸可以单独使用,也可以将2种以上任意组合使用。另外,在本发明中,也可以使用代替上述有机酸或与上述有机酸组合的药学上、化妆学上或食品卫生上允许的上述有机酸的盐作为有效成分。
另外,上述有机酸,也可以不一定是精制过的物质,只要是含有上述有机酸作为其中之一成分的物质,就可以作为本发明的人β防御素分泌促进剂的有效成分使用。
本发明的人β防御素分泌促进剂,可以是由上述有效成分构成的物质,也可以是在含有上述有效成分的基础上,含有其他的食品卫生上、药学上或化妆学上允许的基剂、载体或添加物等其他成分的物质。
本发明的人β防御素分泌促进剂的应用对象,没有特别限制,可以是生物体的任何部位或组织。从更优良的促进人β防御素分泌的观点考虑,鼻腔内、***部、呼吸道内、***部、口腔内、咽、眼、生殖器、皮肤、消化道内等是优选应用的对象,特别是这些的粘膜过渡部位及粘膜上皮是合适的应用对象。其中,在***部和口腔内中的人β防御素分泌促进作用特别优良,***部和口腔内是本发明的人β防御素分泌促进剂的最合适的应用对象。
本发明的人β防御素分泌促进剂,可以配合食品、内服药品、内服药外部品等,作为人β防御素分泌促进用的食品或内服组合物使用。另外,本发明的人β防御素分泌促进剂也可以配合外用药品、外用医药外部品、化妆品、外用品(橡皮膏)等,作为人β防御素的分泌促进用的外用组合物使用。
在配制含有本发明的人β防御素分泌促进剂的人β防御素分泌促进用的外用组合物时,可以在上述有效成分的基础上配合药学上或化妆学上允许的基材或载体,配制成所希望的形态。而且,在该外用组合物中,在不影响本发明效果的范围内,也可以配合各种表面活性剂、色素(染料、颜料)、香料、防腐剂、杀菌剂(抗菌剂)、增粘剂、抗氧化剂、金属密封剂、清凉化剂、防臭剂、pH调整剂等各种添加剂。另外,根据需要也可以含有配合于保湿剂、紫外线吸收剂、紫外线弥散剂、维生素类、植物提取物、皮肤收敛剂、抗炎剂(消炎剂)、美白剂、细胞激活剂、血管舒张剂、血液循环促进剂、皮肤机能亢进剂、抗过敏剂、抗组胺剂、抗生素等外用剂的公知的药效成分。
上述外用组合物,只能限于用于皮肤和粘膜,其形状没有特别限制。例如有:液状、乳液状、粉末状、悬浊液状、乳脂状、软膏状、奶油冻状、凝胶状、胶状、糊状、薄壳状、棒状、气溶胶状、喷雾状、搽剂、填充剂、粘贴剂等形状。另外,上述外用组合物的形状,可以根据给药对象部位适当设定。
另外,上述外用组合物是以发挥人β防御素的分泌促进作用为限度,具有人β防御素的分泌促进作用以外的作用的外用组合物,具体来讲,可以是创伤治愈剂、揩拭剂、净化剂(例如,洗颜料、清洁剂、身体洗净料等)、基础化妆料(例如,乳液、乳脂、洗液、油类及面膜等)、牙膏、漱口剂、口中清凉剂、口中用粘贴剂等形态的外用组合物。特别是从应用于口腔内发挥人β防御素的分泌促进作用的观点考虑,优选其是口中用粘贴剂、牙膏、漱口剂或口中清凉剂的形态。
另外,上述外用组合物也可以是灌肠剂、滴眼剂、滴鼻剂等形态。
另外,只要是使用蒸发性有机酸作为人β防御素分泌促进剂的有效成分的场合,也可以通过使有效成分挥发(蒸发),将其吸入,应用于鼻孔内、口腔内或支气管内。以这种形态使用的方法,例如有:加热含有有效成分的水溶液等,吸入得到的蒸气的方法。作为这样使有效成分挥发使用的形态,也可以配制上述外用组合物。配制成这种形态时,上述外用组合物可以通过根据需要含有芳香成分,由此作为芳香液使用。作为人β防御素分泌促进剂的有效成分使用的蒸发性有机酸,例如有:乙酸、丙酸、甲酸、丁酸、戊酸等。
关于上述β防御素分泌促进用的外用组合物中的上述人β防御素分泌促进剂的配合比例,可以根据该组合物的形态、有效成分的种类、使用对象的年龄和性别、期望的效果等适当设定。例如,相对上述外用组合物的总重量,上述人β防御素分泌促进剂的有效成分的比例,以总量计为0.001重量%以上,优选为0.005~99重量%,更优选为0.01~99重量%。
本发明的人β防御素分泌促进剂,通过应用于皮肤或粘膜,可以发挥β防御素分泌促进作用。对于应用该人β防御素分泌促进剂的量以及次数,根据有效成分的种类和浓度、使用者的年龄和性别、应用形态、所期望的程度适当设定。例如,可以将人β防御素分泌促进剂的有效成分0.1mg以上、优选0.5~10000mg以一日1~10次左右应用于皮肤或粘膜。
另外,在配制含有本发明的人β防御素分泌促进剂的人β防御素分泌促进用的食品时,可以在一般的食品制造中以上述有效成分为其中一个成分配合到食品(含饮料)中。另外,人β防御素分泌促进用的食品可以适当含有食品卫生上允许的各种食品添加剂。
上述食品,例如有:特定保健用食品、营养辅助食品、患者用食品等。更具体的例如有:饮料(碳酸饮料、清凉饮料、含乳饮料、醇类饮料、果汁饮料、茶类、营养饮料等)、粉末饮料(粉末果汁、粉末汤料等)、糕点类(口香糖、糖果、小甜饼、胡颓子、脆饼干、饼干、果冻、焦糖、柠檬糕点、可食性薄片、可食性薄膜、片剂等)、口中清凉剂(口香糖、糖、胡颓子、可食性薄片、可食性薄膜、片剂等)、乳制品(干酪、酸乳等)、面包、面类、串、调料(沾料、调味汁等)等。从口腔内的人β防御素的分泌促进的观点考虑,其中,合适的例如有:口香糖、胡颓子、清凉饮料、糖果、可食性薄片及可食性薄膜。
在上述促进人β防御素分泌用的食品中,配合人β防御素分泌促进剂的比例,可以根据有效成分的种类、使用对象的年龄、性别、期望的效果等适当设定。例如,相对上述食品的总重,上述人β防御素分泌促进剂的有效成分的比例,以总量计为0.01重量%以上,优选为0.02~100重量%,更优选为0.05~100重量%。
上述促进人β防御素分泌用的食品的每日摄取量,可以根据有效成分的种类和浓度、使用者的年龄和性别、食品的形状、期望的效果程度,适当设定促进人β防御素的分泌所必需的有效量。例如,该食品每日的摄取量,促进人β防御素分泌用的有效成分为0.1mg以上、优选0.5~10000mg的量。
另外,在配制含有本发明的人β防御素分泌促进剂的促进人β防御素分泌用的内服药品组合物或内服药外部品组合物时,在上述有效成分的基础上,配合药学上允许的基材或载体,可以配制成所希望的形态。另外,根据需要,可以任意配合结合剂、崩解剂、润滑剂、润湿剂、缓冲剂、保存剂、香料等药学上所允许的添加剂。
上述内服药品组合物或内服药品外部品组合物的形态,没有特别的限制,优选在粘膜上、特别是在口腔内能溶解的。例如,薄膜制剂、片剂、咀嚼片、粉剂、锭剂、颗粒剂、胶囊剂、糖浆制剂等。其中,从能在口腔内溶解的观点考虑,优选例如薄膜制剂、片剂以及咀嚼片。
上述内服药品组合物或内服药品外部品组合物的上述人β防御素分泌促进剂的配合比例,可以根据有效成分的种类、组成物的形态、使用对象的年龄和性别、期望的效果等适当设定。例如,相对上述内服药品组合物或内服药品外部品品组合物的总重,上述人β防御素分泌促进剂的有效成分的比例,以总量计为0.01重量%以上,优选为0.02~99重量%,更优选为0.05~99重量%。
上述内服药品组合物或内服药品外部品组合物的每日给药量,由于根据有效成分的种类和浓度、使用者的年龄和性别、组合物形状、给药方法、期望的程度等而异,因此不能做统一的规定,是促进人β防御素分泌的有效量即可。例如,每次的给药量,将促进人β防御素分泌用的有效成分为0.1mg以上、优选0.5~10000mg的量,每日1~10次左右给药。
如上所述,有机酸具有促进人β防御素分泌的作用。因而,本发明进一步提供一种有机酸用于制造人β防御素分泌促进剂的使用。以及本发明还提供一种有机酸用于制造促进人β防御素分泌用的外用组合物或内服组合物的有机酸的使用。
(2)促进人β防御素分泌的方法
如上所述,有机酸可以有效地促进人β防御素的分泌。因而,本发明提供一种使用有机酸促进人β防御素的分泌的方法。
本发明的促进人β防御素的分泌的方法,可以相对以促进人β防御素的分泌为目的身体部位,通过将有机酸以外用形态给药而进行。另外,本发明的促进人β防御素分泌的方法,可以通过将有机酸以内服形态给药或使其摄取而进行。本发明的方法,优选通过使用上述(1)的人β防御素的分泌促进剂、特别是人β防御素分泌促进用的外用组合物、内服组合物或食品来进行。
在本发明的方法中,被促进分泌的人β防御素、使用的有机酸、该有机酸的给药量和给药次数、成为分泌促进对象的身体部位(或组织)等,如上述(1)记载。
通过使用有机酸,可以有效地促进人β防御素的分泌。因而,本发明进一步提供一种用于促进人β防御素分泌的有机酸的使用。
(3)促进人β防御素分泌的方法-2
另外,本发明人发现,通过使口腔内的环境暂时成为酸性环境可以促进口腔内人β防御素的分泌。基于这样的见解,本发明进一步提供一种在口腔内的促进人β防御素分泌的方法。利用这样的方法促进人β防御素的分泌时,可以保持口腔内环境的暂时酸性,具体来讲,保持口腔内的pH为7以下,优选为6.2以下。另外,在这样的方法中,保持口腔内酸性环境的时间,可以是促进人β防御素分泌的有效保持时间。另外,在这样的方法中,为了使口腔内环境成为酸性,例如可以在口腔内给药上述有机酸。这样的方法的优选实施方式,例如,在口腔内给药上述人β防御素分泌促进剂的方法。根据这样的方法,由于可以保持口腔内健康,因此该方法对预防和缓和牙周病、口腔炎、龋齿、口臭等有一定作用。
需要说明的是,在上述(1)的人β防御素分泌促进剂的使用或上述(2)的人β防御素的分泌促进方法中,在皮肤和粘膜上的pH条件没有特别限制。
实施例
下面,例举实施例及试验例说明本发明,但本发明并不限定于这些实施例。需要说明的是,下面有时也将人β防御素略记为hBD-2。
实施例1口香糖
依照常用方法制造下述处方的口香糖。
配合量(重量%)
酸橙粉 5.0
(在酸橙粉中含有柠檬酸75重量%)
胶基(主要成分:乙酸乙烯酯) 22.0
木糖醇 35.0
麦芽糖醇 27.0
香料 适量
合计 100重量%
实施例2柠檬糕点
依照常用方法制造下述处方的柠檬糕点。
配合量(重量%)
苹果酸 7.5
碳酸氢钠 7.5
木糖醇 40.0
麦芽糖醇 30.0
玉米淀粉 15.0
合计 100重量%
实施例3口中清凉剂(液状)
依照常用方法制造下述处方的口中清凉剂(液状)。
配合量(重量%)
乳糖 0.2
1-薄荷醇 1.0
乙醇 40.0
甘油 20.0
单月桂酸癸甘油酯 0.5
香料 0.1
纯水 剩余量
合计 100重量%
实施例4口中清凉剂(片剂)
依照常用方法制造下述处方的口中清凉剂(片剂)。
配合量(重量%)
酒石酸 45
1-薄荷醇 1
碳酸氢钠 24
乳糖 25
蔗糖脂肪酸酯 3
香味增强剂 1
甜味剂 1
合计 100重量%
实施例5食品(片剂)
依照常用方法制造下述处方的食品(片剂)。
配合量(重量%)
抗坏血酸 5.0
乳糖 85.5
木糖醇 5.0
蔗糖脂肪酸酯 4.0
香味增强剂 0.5
合计 100重量%
实施例6液体牙膏
依照常用方法制造下述处方的液体牙膏。
配合量(重量%)
富马酸 45
1-薄荷醇 1
碳酸氢钠 24
乳糖 25
蔗糖酯肪酸酯 3
香味增强剂 1
甜味剂 1
合计 100重量%
实施例7芳香液
依照常用方法制造下述处方的芳香液。
配合量(重量%)
纯水 54
无水乙醇 40
柠檬提取物 4
葡萄柚提取物 1
乙酸 1
香料 适量
合计 100重量%
实施例8滴鼻剂
依照常用方法制造下述处方的滴鼻剂。
成分名 配合量(重量%)
氯化钠 0.9
柠檬酸 1.0
pH调整剂 适量
纯水 剩余量
合计 100重量%
实施例9滴眼剂
依照常用方法制造下述处方的滴眼剂。
成分名 配合量(重量%)
氯化钠 0.9
氯化钾 0.1
黄素腺嘌呤二核苷酸 0.05
透明质酸钠 0.1
柠檬酸 1.0
pH调整剂 适量
纯水 剩余量
合计 100重量%
试验例1确认促进β防御素分泌的试验-1
为了评价各种有机酸的促进β防御素分泌的效果,以健康人1名为被验者,进行下列试验。
通过吐出法回收被验者在安静状态下3分钟分泌的唾液(下面,将此唾液记作对照)。其后,将富马酸50mg放入口腔内,保持1分钟后,与分泌的唾液一起回收。通过ELISA法测定回收的唾液中的人β防御素-2的浓度,依照下述计算式算出在1分钟内,利用该有机酸分泌的人β防御素-2的量。其中,下面计算式中的唾液量(ml),以1g唾液的重量=1ml唾液量,从回收的唾液重量(g)算出。用抗坏血酸、柠檬酸、苹果酸、乳酸、己二酸、乙酸和酒石酸代替富马酸,进行和上述同样的试验。需要说明的是,在使用乳酸和乙酸的情况下,通过将在50mg该有机酸中加水至总量为1g而配制成的水溶液吸入口腔内,进行上述试验。
计算式
[1分钟分泌的hBD-2的量(ng/min)]=
{[唾液中hBD-2的浓度(ng/ml)]×[唾液量(ml)]}/[唾液回收时间(min)]
#唾液回收时间,在对照的情况下是3分钟,在有机酸给药后的情况下是1分钟。
得到的结果如图1所示。由此可知,通过在口腔内应用有机酸,增大了唾液中分泌的人β防御素-2的量。由该结果可以确认,有机酸具有在机体内促进人β防御素-2的分泌的作用,特别是在口腔内的促进人β防御素-2分泌的作用优良。
试验例2确认促进β防御素分泌的试验-2
为了评价各种有机酸促进β防御素分泌的效果,以健康人6名为被验者,进行下列试验。使用柠檬酸、苹果酸、富马酸、L-谷氨酸、反式肉桂酸、L(+)-抗坏血酸、丁二酸、DL-酒石酸、己二酸、L-乳酸及乙酸作为有机酸。
通过吐出法回收被试验者在安静状态下3分钟分泌的唾液(下面,将此唾液记作对照)。其后,将有机酸50mg放入口腔内,保持1分钟后,与分泌的唾液一起回收。通过ELISA法测定回收的唾液中的人β防御素-2的浓度,依照下述计算式算出在1分钟内,利用该有机酸分泌的人β防御素-2的量。其中,下面计算式中的唾液量(ml),以1g唾液的重量=1ml唾液量,从回收的唾液重量(g)算出。需要说明的是,在使用乳酸和乙酸的情况下,通过将在50mg该有机酸中加水至总量为1g而配制成的水溶液吸入口腔内,进行上述试验。
计算式
[1分钟分泌的hBD-2的量(ng/min)]=
{[唾液中hBD-2的浓度(ng/ml)]×[唾液量(ml)]}/[唾液回收时间(min)]
#唾液回收时间,在对照的情况下是3分钟,在有机酸给药后的情况下是1分钟。
得到的结果如图2所示。由此结果可以看出,和试验1的结果同样,通过在口腔内应用有机酸,增大了唾液中分泌的人β防御素-2的量。
试验例3确认促进β防御素分泌的试验-3(浓度依赖性)
为了评价有机酸促进β防御素分泌的效果浓度的依赖性关系,以健康人3名作为被试验者,进行下列试验。
通过吐出法收集被试验者在安静状态下3分钟分泌的唾液(下面,将此唾液记作对照液)。其后,将0.01重量%的苹果酸水溶液1ml(苹果酸摄取量0.1mg)放入口腔内,保持1分钟后,与分泌的唾液一起回收。通过ELISA法测定回收唾液中的人β防御素-2的浓度,依照下述计算式算出1分钟内通过摄取0.1mg苹果酸而分泌的人β防御素-2的量。其中,下面计算式中的唾液量(ml),以1g唾液的重量=1ml唾液量,从回收的唾液重量(g)算出。而且,用0.05、0.1、0.2、0.5和1重量%的苹果酸水溶液(摄取量0.5、1、2、5、10mg),进行和上述同样的试验。
计算式
[1分钟分泌的hBD-2的量(ng/min)]=
{[唾液中hBD-2的浓度(ng/ml)]×[唾液量(ml)]}/[唾液回收时间(min)]
#唾液回收时间,在对照的情况下是3分钟,在有机酸给药后的情况下是1分钟。
得到的结果如图3所示。从图3可知,唾液中分泌的人β防御素-2的量随苹果酸水溶液浓度的增大而增大。从此结果可以确认,有机酸的促进人β防御素-2分泌的效果有浓度依赖性,即使是0.01%的浓度(摄取量0.1mg),也具有人β防御素-2分泌诱导效果。
工业实用性
已知人β防御素具有以下优良的特性:(a)由于其自身具有抗菌性,因此在短时间内可以发挥抗菌作用;(b)由于其在机体内分泌,因此即使对于难以采用外用或内服的形态给药现有的抗菌剂的部位,也可以发挥其优良的抗菌作用。(c)使杆状细胞和记忆T淋巴细胞游动(chemolaxis)(亦即,调动免疫活性细胞参与后天免疫)。
本发明的人β防御素的分泌促进剂,在应用过的部位中,可以促进β防御素的分泌,特别是人β防御素-2的分泌。其原因在于,根据本发明的β防御素分泌促进剂,可以促进β防御素的分泌增强机体内的抗菌作用和免疫作用,因此,可以提高机体防御机构的防御作用。由此,本发明的β防御素分泌促进剂,可以有效预防和缓和由细菌、真菌、病毒、原虫感染引起的症状。特别是有效预防特应性皮炎的二次感染、预防粉刺、防止口臭、防止脚臭、预防剃须或脱毛后的二次感染、预防尿布疹的二次感染、预防痱子的二次感染、预防烫伤的二次感染、预防因使用类固醇引起的感染等的皮肤护理。另外,对细菌、真菌、病毒、原虫感染引起的皮肤皲裂、皮肤干燥、手的皲裂等皮肤护理有效。
另外,本发明的人β防御素分泌促进剂,有望具有基于人β防御素的分泌促进作用的药理效果。因此,本发明的人β防御素分泌促进剂,例如,在眼内给药的情况下,可以用于预防和治疗病毒性结膜炎、细菌性结膜炎、麦粒肿等;在鼻腔和咽内给药的情况下,可以用于预防和治疗感冒、流感等;在鼻腔内给药的情况下,可以用于预防和治疗鼻炎、脓性鼻涕、副鼻窦炎等;在口腔内给药的情况下,可以用于预防和治疗牙周病、口炎、龋齿等;在***部使用的情况下,可以用于预防和治疗单纯疱疹等;在皮肤使用的情况下,可以用于预防和治疗癣菌病、脓疱病、疣、***、水痘、传染性生殖器疱疹、念珠菌病、带状疱疹、单纯疱疹、粉刺、特应性皮炎、创伤治愈剂等;在其他部位使用的情况下,可以用于预防或治疗肺炎、胃炎、肿瘤、后天性免疫不全症候群、锥虫病等。在这些疾病中,特别是对于预防和治疗由细菌、真菌、病毒、原虫等参与的疾病有效果。
另外,本发明的人β防御素分泌促进剂,因为在口腔内和***部可以发挥其更优良的人β防御素分泌促进作用,所以作为预防和治疗牙周病、口炎、龋齿、口臭、单纯疱疹等的药,特别有效。因此,本发明的人β防御素分泌促进剂,适用于保持健康的口腔内环境的口部护理制品。
Claims (22)
1.一种人β防御素分泌促进剂,其特征在于,以有机酸为有效成分。
2.如权利要求1记载的人β防御素分泌促进剂,其有机酸是选自富马酸、苹果酸、柠檬酸、抗坏血酸、乳酸、乙酸、己二酸、酒石酸、肉桂酸、谷氨酸及丁二酸的至少一种。
3.如权利要求1记载的人β防御素分泌促进剂,其有机酸是选自富马酸、苹果酸、柠檬酸及酒石酸的至少一种。
4.如权利要求1记载的人β防御素分泌促进剂,其成为分泌促进对象的人β防御素是人β防御素-2。
5.如权利要求1记载的人β防御素分泌促进剂,其是在***部或口腔内使用的。
6.一种促进人β防御素分泌用的外用组合物,其含有如权利要求1~4中任一项记载的人β防御素分泌促进剂。
7.一种促进人β防御素分泌用的内服组合物,其含有如权利要求1~4中任一项记载的人β防御素分泌促进剂。
8.一种促进人β防御素分泌用的食品,其含有如权利要求1~4中任一项记载的人β防御素分泌促进剂。
9.一种促进人β防御素分泌的方法,其特征在于,给药或使其摄取有效量的有机酸。
10.如权利要求9记载的促进人β防御素分泌的方法,其有机酸是选自富马酸、苹果酸、柠檬酸、抗坏血酸、乳酸、乙酸、己二酸、酒石酸、肉桂酸、谷氨酸及丁二酸的至少一种。
11.如权利要求9记载的促进人β防御素分泌的方法,其有机酸是选自富马酸、苹果酸、柠檬酸和酒石酸的至少一种。
12.如权利要求9记载的促进人β防御素分泌的方法,其成为分泌促进对象的人β防御素是人β防御素-2。
13.如权利要求9记载的促进人β防御素分泌的方法,其在***部或口腔内促进人β防御素的分泌。
14.如权利要求9记载的促进人β防御素分泌的方法,其使用如权利要求1~5中任一项记载的人β防御素促进剂作为有机酸。
15.如权利要求9记载的促进人β防御素分泌的方法,其使用如权利要求6记载的内服组合物作为有机酸。
16.如权利要求9记载的促进人β防御素分泌的方法,其使用如权利要求7记载的食品作为有机酸。
17.如权利要求9记载的促进人β防御素分泌的方法,其使用如权利要求8记载的外用组合物作为有机酸。
18.一种有机酸在制造人β防御素分泌促进剂中的使用。
19.一种有机酸在制造人β防御素分泌促进用内服组合物中的使用。
20.一种有机酸在制造人β防御素分泌促进用食品中的使用。
21.一种有机酸在制造人β防御素分泌促进用外用组合物中的使用。
22.一种有机酸在促进人β防御素的分泌中的使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP328704/2003 | 2003-09-19 | ||
JP2003328704 | 2003-09-19 | ||
PCT/JP2004/014024 WO2005027893A1 (ja) | 2003-09-19 | 2004-09-17 | ヒトβディフェンシン分泌促進剤 |
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CN1852708A true CN1852708A (zh) | 2006-10-25 |
CN1852708B CN1852708B (zh) | 2010-09-22 |
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US (1) | US20070093416A1 (zh) |
EP (1) | EP1671629A4 (zh) |
JP (1) | JP4847756B2 (zh) |
KR (1) | KR20060076775A (zh) |
CN (1) | CN1852708B (zh) |
AU (1) | AU2004273738B2 (zh) |
BR (1) | BRPI0414543A (zh) |
CA (1) | CA2538760A1 (zh) |
HK (1) | HK1092057A1 (zh) |
TW (1) | TW200524585A (zh) |
WO (1) | WO2005027893A1 (zh) |
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CN103037889A (zh) * | 2010-06-16 | 2013-04-10 | 纳米智能生物医学工程株式会社 | 具有抗菌或消炎活性的肽及包含所述肽作为活性成分的药物组合物 |
CN107918010A (zh) * | 2017-11-27 | 2018-04-17 | 陕西科技大学 | 一种高灵敏液晶型非标记免疫传感器检测人类β防御素‑2的方法 |
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KR20090030281A (ko) | 2006-06-28 | 2009-03-24 | 오츠카 세이야쿠 가부시키가이샤 | 치아 에나멜질의 용해 저해제 |
JPWO2008096730A1 (ja) * | 2007-02-09 | 2010-05-20 | 国立大学法人名古屋大学 | 抗炎症剤及びその用途 |
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-
2004
- 2004-09-17 CN CN2004800270414A patent/CN1852708B/zh not_active Expired - Fee Related
- 2004-09-17 CA CA002538760A patent/CA2538760A1/en not_active Abandoned
- 2004-09-17 KR KR1020067005330A patent/KR20060076775A/ko not_active Application Discontinuation
- 2004-09-17 EP EP04773408A patent/EP1671629A4/en not_active Withdrawn
- 2004-09-17 JP JP2005514130A patent/JP4847756B2/ja active Active
- 2004-09-17 BR BRPI0414543-7A patent/BRPI0414543A/pt not_active IP Right Cessation
- 2004-09-17 WO PCT/JP2004/014024 patent/WO2005027893A1/ja active Application Filing
- 2004-09-17 US US10/572,204 patent/US20070093416A1/en not_active Abandoned
- 2004-09-17 AU AU2004273738A patent/AU2004273738B2/en not_active Ceased
- 2004-09-20 TW TW093128401A patent/TW200524585A/zh not_active IP Right Cessation
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2006
- 2006-11-20 HK HK06112727.9A patent/HK1092057A1/xx unknown
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101591672B (zh) * | 2009-05-22 | 2011-09-07 | 西北农林科技大学 | 一种包含hBD3乳腺特异性表达载体的重组牛胎儿成纤维细胞 |
CN103037889A (zh) * | 2010-06-16 | 2013-04-10 | 纳米智能生物医学工程株式会社 | 具有抗菌或消炎活性的肽及包含所述肽作为活性成分的药物组合物 |
US8980844B2 (en) | 2010-06-16 | 2015-03-17 | Nano Intelligent Biomedical Engineering Corporation Co. Ltd. | Peptide having antibacterial or anti-inflammatory activity and pharmaceutical composition containing the same as an active ingredient |
CN103037889B (zh) * | 2010-06-16 | 2016-01-20 | 纳米智能生物医学工程株式会社 | 具有抗菌或消炎活性的肽及包含所述肽作为活性成分的药物组合物 |
CN107918010A (zh) * | 2017-11-27 | 2018-04-17 | 陕西科技大学 | 一种高灵敏液晶型非标记免疫传感器检测人类β防御素‑2的方法 |
Also Published As
Publication number | Publication date |
---|---|
EP1671629A4 (en) | 2008-11-26 |
HK1092057A1 (en) | 2007-02-02 |
US20070093416A1 (en) | 2007-04-26 |
TW200524585A (en) | 2005-08-01 |
KR20060076775A (ko) | 2006-07-04 |
EP1671629A1 (en) | 2006-06-21 |
AU2004273738A1 (en) | 2005-03-31 |
CN1852708B (zh) | 2010-09-22 |
JP4847756B2 (ja) | 2011-12-28 |
CA2538760A1 (en) | 2005-03-31 |
TWI342773B (zh) | 2011-06-01 |
WO2005027893A1 (ja) | 2005-03-31 |
AU2004273738B2 (en) | 2011-02-03 |
BRPI0414543A (pt) | 2006-11-07 |
JPWO2005027893A1 (ja) | 2006-11-24 |
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