CN1981028A - 选择和利用乳酸杆菌减少龋齿和引发龋齿的细菌 - Google Patents
选择和利用乳酸杆菌减少龋齿和引发龋齿的细菌 Download PDFInfo
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- CN1981028A CN1981028A CNA2005800192636A CN200580019263A CN1981028A CN 1981028 A CN1981028 A CN 1981028A CN A2005800192636 A CNA2005800192636 A CN A2005800192636A CN 200580019263 A CN200580019263 A CN 200580019263A CN 1981028 A CN1981028 A CN 1981028A
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Abstract
本发明涉及一种选择出来的新的乳酸杆菌菌株,该菌株具有提高了的性能,即通过抑制变异链球菌的活性并与口腔粘液和牙斑的更好结合而有效减少变异链球菌在哺乳动物口腔中的数量,从而防止、减少或治疗龋齿,以及来源于所述菌株的产品,包括施用于人类的治疗或预防龋齿的物质。
Description
背景技术
相关申请交叉引用
这是2003年01月29日提交的美国临时申请号10/353,407的部分内容的继续申请,其公开的内容在此引入作为参考。
发明领域
本发明涉及利用非病原菌性抗成龋因子乳酸杆菌菌株、产品以及利用这样的菌株、突变体、代谢物和其成分来治疗和预防由口腔细菌例如变异链球菌、和其他龋齿引发病原菌而导致龋齿的方法。
相关技术说明
人类和其它哺乳动物的口腔中带有很多不同种类的细菌,包括很多不同种类的乳酸杆菌。龋齿是一种由细菌引起的疾病。早在1890年,Miller在“化学寄生学说”中就提出龋齿是由口腔的细菌从消化的碳水化合物产生的酸而引发的,其将溶解牙齿的羟磷灰石。这一观点随后在无菌鼠中得到确认,例如,一般的口腔菌落,首先是链球菌属,其次是乳杆菌属涉及到龋齿的发生。这些“产酸的”种类残留于口腔中与龋齿的存在和发作相关(Locsche WJ,Microbiolog Rev.,1986:50:353-380)。链球菌属的组中有7种细菌,其中变异链球菌(血清型c、e、f)可以在90%的所有人类分离物中发现(Linder L.,Oral Mikrobiologi 1996,ISBN 91-7205-037-3)。有大量证据表明龋齿的发生需要在牙斑内有相对高比例的变异链球菌。这些细菌很好地粘附在牙齿表面,产生比其他细菌类型从糖类更高数量的酸,并且比其他细菌更好生活在酸性环境中,而且从蔗糖产生细胞外的多糖。当变异链球菌在牙斑中的比例高时(2-10%范围),患者患上龋齿的风险度就高。当变异链球菌在牙斑中的比例低时(小于0.1%),患者患上龋齿的风险度就低。由于其具有比其他细菌更高的酸耐受力,牙斑中的酸性条件有利于变异链球菌的生存和繁殖。
其它两种类型的细菌也通过牙质而与龋齿的进程相关。这些是几种类型的乳酸杆菌,以及粘性放线菌。这些细菌也是高度产酸的并且在酸性条件下生存良好。乳酸杆菌在龋齿中的作用已被确定(Smith et al.,Microbios 105:77-85,2001)。实际上,采用不同的可选择媒介或其他技术评估乳酸杆菌在唾液中的数量,加上评估变异链球菌的数量,很多年来一直被用作“龋齿检测”并作为一种力图鉴别各组之间龋齿风险度的方法。因此,某些从人类牙齿牙斑中分离的乳酸杆菌极可能是成龋因子(Fitzgerald et al.,J.Dent.Res.60:919-926,1981)。
一种细菌要成为龋齿形成中的首要病原菌,要求其要综合具有几种所要求的特征(Linder,1996):在牙齿表面粘附和克隆化的能力;在牙齿表面的有限表面聚集大量数量的能力;从食物中可发现的碳水化合物中快速产酸的能力;即使在牙斑的低pH中还能持续产酸的能力。
日常饮食中的蔗糖改变牙斑的厚度和化学性质。变异链球菌和其他一些牙斑细菌利用单糖成分(葡萄糖和果糖)和蔗糖二糖键的能量组装细胞外的多糖。这些实质上提高了牙斑的厚度,并且还将其细胞外的空间的化学性质从液态改变成凝胶态。而凝胶限制了某些离子的移动。厚的凝胶牙斑允许牙齿表面酸性环境的发展不受唾液缓冲液的影响。没有和蔗糖接触的牙斑比较薄并且更好被缓冲。因此含有高比例蔗糖的饮食增加了患龋齿的风险。较厚的牙斑发生于不讲口腔卫生的患者靠近牙龈边缘附近的齿沟和裂缝中。
了解了该疾病特性的概念,也就清楚了预防和治疗龋齿需要阻断变异链球菌的作用,例如,通过改变饮食而减少细菌作用的基质,从而增强牙齿的表面结构或减少变异链球菌细菌的数量。因此,治疗应当尽量包括:利用药剂努力改变微生物菌落,例如局部采用双氯苯双胍己烷和氟化物;通过改变日常饮食和用例如山梨醇、阿巴斯甜、木糖醇取代甜食而减少日常饮食中的蔗糖数量,使得变异链球菌的新陈代谢变得更加困难;通过日常选择,减少饮食次数;添加氟化物,尤其是在刷牙期间通过日常使用;提高唾液的流动,在充分咀嚼期间利用机械刺激增加流动,或通过改变减少唾液流动的药物,或通过采用药物增加流动。
已经评估了防止龋齿的不同方法,例如,一种利用由噬菌体所产生的特异针对变异链球菌的溶胞酶的组合物(U.S.Patent No.6,399,098 of Fischetti et al.)。还有,一个玉米乳杆菌菌株通过遗传工程而被修饰从而在它的表面产生一种抗体以中和有害的链球菌(Hammarstrom L.,July 2002 issue of Nature Biotechnology);然而,这种采用遗传修饰的方法面临未知的安全方面的问题。
此外,一种鼠李糖乳酸杆菌菌株(ATCC 53013,strain GG)已经被引用作为一种减少远缘链球菌(Streptococcus sabrinus)和变异链球菌的益生菌的常用方法(Nase et al.,龋齿Res.35:412-420,2001)。进一步的工作表明在发酵牛奶中采用这种菌株作为发酵起始者不会影响存在于牛奶中的针对人成龋因子细菌的抗体的浓度(Wei et al.,口腔Microbio.&Immunol.17:9-15,2002)。鼠李糖乳酸杆菌GG在很多方面不同于路氏乳杆菌,包括发酵特性和分离来源。已发现的其他具有抑制牙斑形成活性的微有机体包括肠球菌、嗜酸性乳酸杆菌V20、以及乳酸乳球菌1370(Oh,U.S.Patent No.6,036,952)。为了抑制变异链球菌,也进行了被称为“竞争排斥”的其他工作。例如,路氏乳杆菌菌株ATCC 55730已经显示能抑制变异链球菌(Nikawa H.et al,News release by Hiroshima University July 11,2002)。一种在日本市场上称为LS1的片剂产品,包含一个唾液乳杆菌菌株(LS1)(byFrente Ltd.Japan),被宣布能抑制变异链球菌。
乳酸杆菌种类的菌株变化广泛,包括路氏乳杆菌,已被用于益生菌制剂中。路氏乳杆菌是天然发生的动物胃肠道中的抑制剂之一,常见于健康动物包括人类的肠中,偶见于生殖道、母乳和口腔中。已知其具有抗菌活性。例如,参见美国专利号5,439,678、5,458,875、5,534,253、5,837,238、和5,849,289。当路氏乳杆菌细胞生长在在甘油的存在的厌氧环境下,他们产生被称为无蛋白菌质(B-羟基-丙醛)的抗微生物物质。
在传统的有机酸之外被报道的其它抗微生物物质还有例如“Reutericyclin(新品种的乳酸杆菌)”(Holtzel,A.et al.AngewandteChemie Intemational Edition 39,2766-2768,2000)和“PCA(焦谷氨酸)”(Yang,Z.Dissertation,Univ.of Helsinki,March 2000),以及″Reutericin 6″(Toba T,et al.,Lett Appl Microbiol 13:281-6.)。众所周知,也包括路氏乳杆菌在内的乳酸杆菌通过局部营养竞争及其它代谢作用从而具有抑制其它微生物例如变异链球菌的能力。
路氏乳杆菌的粘蛋白结合蛋白已经被分离和描述。例如,参见美国专利号6,100,388。业已报道乳杆菌菌株粘附于不同的细胞系和宿主粘液。这被推测对于益生菌活性十分重要并且衍生自病原型细菌的病毒因子的概念,在近十年间发现了很多这样的相互作用(Klemm,P.and Schembri,M.A.(2000)Bcaterial adhesins:function andstructure.Int.J.Med.Microbiol.290,27-35.)。但并不很清楚乳酸杆菌菌株粘附口腔粘蛋白和其它来源的粘蛋白能力之间的重要差异。某些菌株善于粘附在口腔粘蛋白和其它粘蛋白上,例如胃粘蛋白,而有些菌株则仅善于粘附在胃粘蛋白上而较少粘附在口腔粘蛋白上,有些菌株却根本就不粘附任何类型的粘蛋白。因此,本发明选择方法的一部分是使用口腔粘蛋白来发现最好的菌株。
虽然路氏乳杆菌的有效抗细菌活性的可能性和某些结合特性是已知的,并且路氏乳杆菌菌株ATCC 55730和乳酸杆菌GG ATCC53103对变异链球菌的抑制作用也是已知的,而且一些其他的乳酸杆菌已声称为抗成龋因子,但是此前并不知道在乳酸杆菌菌株之间能减少口腔中变异链球菌的数量以及抗龋齿的能力所存在的实质差异,也不知道如何选择这样的菌株。
因此,本发明的目的之一是提供更好的选择出来的乳酸杆菌,其能够通过抗微生物活性并结合与口腔粘蛋白极好的粘附能力而减少口腔中变异链球菌的数量,并且因此成功地预防、减少或治疗龋齿。本发明的又一目的是提供包含这样的菌株、突变体、代谢物以及其成分的产品,包括施用于人体的用于预防或治疗与变异链球菌相关的龋齿的制剂。
其它的目的和优点将通过以下说明和附加的权利要求而更加清楚。
发明概述
这里,本发明包括选择出来的乳酸杆菌,该乳酸杆菌包括突变体、代谢物及其成分通过抑制活性而减少哺乳动物口腔中变异链球菌的数量的能力,以及结合与口腔粘蛋白和牙斑极好的粘附能力而用于预防、减少或治疗龋齿,以及从这样的菌株获得的产品,包括施用于人体的用于预防或治疗龋齿的制剂。
其它的目的和优点将通过以下说明和附加的权利要求而更加清楚。
发明详述和优选实施例
本发明包括一种产品,用于抑制龋齿细菌的活性和生长,包括至少一种经过选择的具有好的抗变异链球菌的抗微生物活性和好的口腔粘蛋白结合特性的乳酸杆菌菌株的细胞或代谢物或成分,并因此预防、减少或治疗龋齿。这样的菌株包括路氏乳杆菌CF2-7F(ATCC PTA-4965),路氏乳杆菌MF2-3(ATCC PTA-4964)以及尤其是路氏乳杆菌FJ1″Prodentis″(ATCC PTA-5289)和路氏乳杆菌FJ3(ATCC PTA-5290)。对于这些菌株公众可以从美国典型培养物保藏中心ATCC(Rockville,MD)获得,后两个已于2003年07月29日保存。
在这里所用的选择方法中,对变异链球菌的抑制作用,采用细菌细胞通过传统的微生物方法检测,以及通过在生长的检测菌株悬浮液中的分泌代谢物和成分而独立分析其抑制作用,该方法通过一种检测变异链球菌的ATP(腺嘌呤核苷三磷酸)水平的以及存活的变异链球菌细胞总体积的方法而测定(参考Nikawa.H.et al.Journal ofDentistery,Vol 26,No 1,pp.3 1-37,1998)。粘附能力采用包被在微滴定板上的口腔粘蛋白进行检测(参考Jonsson et al.2001 FEMSMicrobiol.lett.204:19-22)。还通过分泌代谢物和成分检测抑制作用的原因是本发明还可能用于非存活细胞或死亡的细胞的选择标准。
这种方法的详细描述将通过例子而被更加清楚的理解。
本发明的产品可以是任何用于放置在口腔中作为预防或治疗龋齿的产品、或者为了营养或增加体力的目的例如作为食物产品、牙齿治疗产品例如漱口药或其他特定的健康产品、口香糖、喉糖锭及其类似物。具体用于本发明的食物产品包括含有牛奶的产品例如酸奶、以及果汁、饮料及其类似物。可以用于本发明的牙齿治疗产品包括牙膏、液体牙齿清洁剂、漱口药、防口臭产品、以及类似物。
对于本发明的产品所需的效力,所选择的乳酸杆菌细胞或代谢物或成分的浓度取决于被咽下的食物的类型和数量(或者一种非食物牙齿治疗产品在口腔中的时间),但是,通常优选的是一种产品的日常摄入量为大约105~108CFU(菌落形成单位)或者更多。数量达到大约1010~1011CFU是可行的,并且可以被用于提高效应而不会给产品带来感观上不利的影响(它的味道或气味)。当产品是酸奶或其他乳酸发酵产品时,被用来生产产品的乳酸发酵菌株优选用于这一特定目的的标准培养物,并且本发明的抗成龋因子细菌、或代谢物或其成分可以在产品发酵之前或之后添加,水平为大约每天每份酸奶106~108CFU或如上所述的更多。
优选地,本发明的产品不包括其它抗细菌成分,至少不含那些抑制或杀死所选的乳酸杆菌菌株、代谢物、或其成分的物质、或干扰其抗成龋因子活性的物质。
乳酸杆菌菌株、代谢物、或其成分,可以作为一种添加剂以此类产品配方公知的方法混合入原料或揉进或覆盖在产品上。当采用细胞并且如果本发明所选的食物或其他产品要求一个加热步骤时,乳酸杆菌菌株应在加热后被加入。一旦所选的乳酸杆菌细胞进入产品中,优选的是不要将产品较长时间加热至60~70℃或更高。
结合以下的例子将更清楚的理解本发明的特点,其不是对本发明的限制。
例1.选择菌株的方法
根据本发明所采用的乳酸杆菌菌株的选择方法采用如下三个步骤:
a)
评估乳酸杆菌菌株的细胞对变异链球菌的抑制作用
用于检测抑制作用的菌株的一个例子是变异链球菌,ATCC25175(从美国典型培养物保藏中心ATCC获得,Manassas,VA,USA)。分离物生长在补充了0.5%酵母提取物(Difco)(TSBY)的胰酶解酪蛋白大豆培养液(Difco,Detroit,USA)中。细胞在指数生长期间通过离心1000xg而收获,用PBS洗涤两次并重悬于相同的缓冲液中。使用低强度超声装置处理细胞悬液以分散细菌聚集体。
在MRS培养液(Difco)上培养测试乳酸杆菌菌株,通过在1000xg下离心收获指数生长期的细胞,用磷酸盐缓冲盐水(PBS;pH6.8)洗涤两次并重悬于相同的缓冲液中。
在具有1cm光程的1.0ml比色皿中测定细菌悬液的光密度,并将悬浮液最终浓度调至1.0×108CFU(菌落形成单位)/ml。
抑制测定进行如下:在无菌离心管中将变异链球菌和乳酸杆菌的悬浮液以100-0、75-25、50-50和25-75的比例混合(总体积100μL),添加BHI培养液直到10ml,涡旋混合10秒钟,并在37℃下孵育90分钟,伴以柔和摇动。作为对照,在对照试管中将变异链球菌悬浮液与等体积PBS混合(无乳酸杆菌)。随后每种悬液在1000xg下离心洗涤,用PBS洗涤两次,并在MS琼脂上进行平板培养以测定变异链球菌的CFU计数。通过如下公式获得变异链球菌的存活率%:
该测定应最少重复三次。所有获得的数据应进行统计学分析。
b)
评估乳酸杆菌菌株的代谢物或成分对变异链球菌的抑制作用
这里所用的检测抑制作用的菌株的例子也是变异链球菌,ATCC25175(从美国典型培养物保藏中心ATCC获得,Manassas,VA,USA)。分离物生长在补充了0.5%酵母提取物(Difco)(TSBY)的胰酶解酪蛋白大豆培养液(Difco,Detroit,USA)中。细胞在指数生长期间通过离心1000xg而收获,用PBS清洗两次并再悬浮于同样的缓冲液中。细胞悬浮液放入低密度超声设备中从而分散细菌团并且调节的最终浓度为108CFU/ml。
在MRS培养液(Difco)上培养测试乳酸杆菌菌株,通过在1000xg下离心收获指数生长期的细胞,用磷酸盐缓冲盐水(PBS;pH6.8)洗涤两次并重悬于相同的缓冲液中。
在具有1cm光程的1.0ml比色皿中测定细菌悬液的光密度,并将悬浮液最终浓度调至1.0×108CFU(菌落形成单位)/ml。100uL的乳酸杆菌悬浮液被加至2.0mL的MRS培养液中,并在37℃交互振荡(120rpm)48小时。孵育后,乳酸杆菌细胞通过离心去除,最终的悬浮液被过滤(每孔0.25μm)。
抑制检测采用如下方法进行。100μL的变异链球菌悬浮液被加入1.0mL的TSBY中并且1.0mL的每种乳酸杆菌待测菌株的悬浮液被混合,并且在37℃交互振荡(120rpm)24小时。作为对照,变异链球菌悬浮液在对照管中(无乳酸杆菌的上清液)与等体积PBS混合。随后,通过在1000xg离心而洗涤每种悬浮液,用PBS洗涤两次,生长的变异链球菌的腺嘌呤核苷三磷酸的数量通过Nikawa.H.等人在Journal of Dentistery,Vol 26,Nol,pp.31-37,1998.中公开的方法进行检测。
c)
评估乳酸杆菌菌株对口腔粘蛋白的粘附能力
收集待测的乳酸杆菌菌株。细菌在MRS培养液(Difco)中37℃培养16小时。平板在厌氧罐中在CO2+N2大气下孵育(GasPakSystem,BBL,Becton Dickinson Microbiology Systems,Cockeysville,MD,USA)。
作为人类唾液的口腔粘液如上所述被收集、离心、无菌过滤并包被微滴定孔中。粘液被收集在200ml冰冷磷酸盐缓冲盐水(PBS)(每1000mldH2中含有8.0gNaCl,0.2gKCl,1.44gNa2HPO4·2H2O和0.2gKH2P04)并且补充了0.05%Tween20(PBST)。最终悬浮液首先在11000g离心10min随后在26000g离心15min以便去除细胞和特定的物质。作为替代的粘蛋白是采用胃的粘蛋白(Sigma,M1778)。未加工的粘液制品存放在20℃。粘液材料用50mMNa2CO3缓冲液,pH9.7稀释至大约100μg/ml并在微滴定孔中(Greiner)(150μl每孔)在4℃缓慢旋转孵育过夜。孔采用含有1%Tween20的PBS封闭1小时并随后用PBST洗涤。采用BSA包被的孔作为对照。
待测菌株如上所述生长,在包含0.05%Tween20的磷酸盐缓冲盐水(pH7.3)(PBST)中清洗一次并在相同的缓冲液中稀释至OD6000.5。100微升细菌悬浮液被加入每孔中并在4℃孵育过夜。孔用PBST洗涤4次,并采用倒置显微镜检查结合情况。缓冲液被倒掉,在孔干了之后,在一台BioRad Gel Doc 2000仪器(BioRadLaboratories,Herkules,CA,USA)上检测整个表面的结合情况。所有检测都采用三份样本进行。
在采用乳酸杆菌细胞和代谢物及其成分抑制变异链球菌以及粘附至根据检测所选择的口腔粘蛋白方面都取得了最好的结果的乳酸杆菌菌株被选择出来。
例2菌株的选择
1、路氏乳杆菌SD2112(ATCC 55730)
2、路氏乳杆菌DSM 20016(DSM 20016)
3、路氏乳杆菌MM2-3(ATCC PTA-4659)
4、路氏乳杆菌CF2-7F(ATCC PTA-4965)
5、路氏乳杆菌MF2-3(ATCC PTA-4964)
6、路氏乳杆菌MF 14-C(Biogaia AB收集的培养物,Raleigh NC,USA)
7、路氏乳杆菌MF52-1F(Biogaia AB收集的培养物,Raleigh NC,USA)
8、路氏乳杆菌MM7(Biogaia AB收集的培养物,Raleigh NC,USA)
9、路氏乳杆菌FJl,″Prodentis″(ATCC PTA-5289)
10.路氏乳杆菌FJ3(ATCC PTA-5290)
11.唾液乳杆菌LS1(由Frente Ltd,Japan分离自LS1片剂)
12.鼠李糖乳杆菌GG(ATCC 53103)
在本研究中,以上所列的乳酸杆菌菌株被选择用来测评利用其来抑制变异链球菌以及粘附口腔粘蛋白,例1中所产生的方法被采用。在采用乳酸杆菌细胞、代谢物及其成分抑制变异链球菌,以及粘附至根据检测所选择的口腔粘蛋白方面都取得了最好的结果的乳酸杆菌菌株被选择出来。抑制结果见表1,粘附结果见表2。
表1:根据所述的检测乳酸杆菌菌株的细胞以及悬浮物对变异链球菌的抑制作用。(S=选择了的)
菌株 | CFU/g存活变异链球菌的比例10∶1 | CFU/g存活变异链球菌的比例3∶1 | CFU/g存活变异链球菌的比例1∶1 | Pmol/L在悬浮物检测中变异链球菌的ATP数量 | 选择到下一步 |
路氏乳杆菌SD2112 | 2.0E+08 | 8.0E+07 | 6.0E+07 | 94644.9 | - |
路氏乳杆菌DSM20016 | 1.0E+08 | 2.0E+07 | 7.0E+06 | 479.1 | S |
路氏乳杆菌MM2-3 | 1.0E+08 | 7.0E+07 | 5.0E+07 | 35125.3 | - |
路氏乳杆菌CF2-7F | 1.0E+08 | 1.0E+07 | 7.0E+05 | 438.6 | S |
路氏乳杆菌MF2-3 | 2.0E+08 | 2.0E+07 | 4.0E+06 | 33158.8 | S |
路氏乳杆菌MF14-C | 9.0E+08 | 8.0E+07 | 7.0E+07 | 29644.3 | - |
路氏乳杆菌MF52-1F | 1.0E+08 | 8.0E+07 | 7.0E+07 | 3120.7 | - |
路氏乳杆菌MM7 | 2.0E+08 | 8.0E+07 | 7.0E+07 | 100110.0 | - |
路氏乳杆菌FJ1 | 1.0E+08 | 4.0E+06 | 7.0E+04 | 3374.3 | S |
路氏乳杆菌FJ3 | 1.0E+08 | 1.0E+07 | 4.0E+05 | 11364.1 | S |
唾液乳杆菌LS1 | 1.0E+08 | 8.0E+08 | 7.0E+09 | 502.8 | - |
鼠李糖乳杆菌GG | 2.0E+08 | 8.0E+07 | 7.0E+07 | 16113.2 | - |
表2:根据所述检测乳酸杆菌菌株的粘附作用(S=选择了的)(FS=最终选择的)
菌株 | ODxmm2胃粘液 | ODxmm2口腔粘液 | 这一步选择 | 较早一步选择 | 最终选择 |
路氏乳杆菌SD2112 | 0.39 | 0.78 | - | - | - |
路氏乳杆菌DSM20016 | 9.42 | 7.85 | S | S | S |
路氏乳杆菌MM2-3 | 11.6 | 3.55 | S | - | - |
路氏乳杆菌CF2-7F | 11.73 | 5.77 | S | S | FS |
路氏乳杆菌MF2-3 | 6.04 | 2.82 | S | S | FS |
路氏乳杆菌MF14-C | 0.2 | 0.17 | - | - | - |
路氏乳杆菌MF52-1F | 0.94 | 1.45 | - | - | - |
路氏乳杆菌MM7 | 0.39 | 2.14 | - | - | - |
路氏乳杆菌FJ1 | 7.51 | 2.77 | S | S | FS |
路氏乳杆菌FJ3 | 7.11 | 5.9 | S | S | FS |
唾液乳杆菌LS1 | 0.19 | 1.15 | - | - | - |
鼠李糖乳杆菌GG | 0.5 | 0.33 | - | - | - |
例3包含所洗菌株的产品的制造方法
在本例子中,路氏乳杆菌FJ1″Prodentis″(ATCC PTA-5289),基于一般良好的生长特性和采用上述方法针对变异链球菌抑制作用和粘蛋白结合情况在例2较早的选择中所表现出来的极佳结果而被选择出来,以便将该菌株加入一种口香糖中。路氏乳杆菌菌株生长并被冻干,采用工业上生产乳酸杆菌的标准方法。
包含所选菌株的口香糖生产过程的一个例子的包括如下步骤,要理解的是赋形剂、填充剂、口味、成胶剂、润滑剂、防结块剂、甜味剂以及其他口香糖的成分是本领域公知的,可以采用而不影响本产品的效果:
1、熔化。在容器中熔化Softisan 154(SASOL GMBH,BadHomburg,Germany)并加热至70℃以确保结晶结构完全分解。随后将其冷却至52~55℃(正好高于其凝固点)。
2、造粒。将路氏乳杆菌冻干粉末转移到Diosna高剪切混合器/造粒机或等价物中。在约1分钟的时间内缓慢添加熔化的Softisan154到路氏乳杆菌粉末中。无需额外的块化时间。添加过程中使用切碎机。
3、湿法筛分。造粒后立刻使用Tornado磨粉机将颗粒穿过1-mm筛网。将筛选的颗粒与干燥剂袋一起包装在由覆盖有铝箔的PVC制成的铝袋(alupouches)中,用热封机密封以形成小袋,冷冻贮存直至混合。颗粒批量分为两片一批。
4、混合。在搅拌器中混合所有成分至均匀混合。
5、压片。转移最终的混合物到旋转式压片机的料斗中,在Kilian压板中压制为总重765mg的小片。
6、成批包装。将口香糖与分子筛干燥袋一起包装在铝袋中。铝袋置于塑料桶中并在最后包装前贮存在阴凉处至少一周。
作为工业标准的过程中控制如下表3所示。
表3
IPC | 测试方法 | 界限 |
1 | 外观目视 | 澄清、均一的溶液 |
2 | 温度计温度 | 52~55℃ |
3 | 路氏乳杆菌测定 | CM003 |
4 | 外观目视 | 带有蓝色斑点的膏状,片体两面凸出。 |
5 | 重量均一性欧洲药典(Ph.Eur.) | 765mg±5% |
在该实施例中,接着如上将所选择的路氏乳杆菌培养物以107CFU/g产品的水平添加,该口香糖供人使用以作为预防龋齿的方法。SOFTISANTM的使用,其为一种氢化棕榈油,使得乳酸杆菌细胞包裹在脂肪中而得到环境的保护,这是本发明的优选实施例另一个独特的方面。
如上所述,本发明的产品可以是口香糖之外的产品形式,制备这些产品的方法是本领域公知的,并且可以用于制备包括本发明所选的路氏乳杆菌培养物的产品。
尽管某些代表性实施方案已列于此,本领域技术人员可容易地意识到能进行不背离本发明精神或范围的修改。
Claims (21)
1、一种路氏乳杆菌菌株FJ1“Prodentis”(ATCC PTA-5289)的生物纯培养物。
2、一种路氏乳杆菌菌株FJ3(ATCC PTA-5290)的生物纯培养物。
3、一种选择出来的乳酸杆菌的生物纯培养物,其适合于通过采用抑制活性的选择检测以及与口腔粘液的良好结合,从而减少口腔中变异链球菌数量的能力以预防或治疗哺乳动物中的龋齿。
4、一种抑制龋齿细菌生长的产品,其包括至少一种选择出来的路氏乳杆菌菌株的细胞,该菌株具有抗成龋因子细菌的抑制活性以及与口腔粘液的良好结合。
5、根据权利要求4的产品,其中至少一个菌株选自由路氏乳杆菌菌株FJ1“Prodentis”(ATCC PTA-5289)和路氏乳杆菌菌株FJ3(ATCC PTA-5290)组成的组。
6、根据权利要求4的产品,其中所述产品是一种食物产品。
7、根据权利要求6的产品,其中所述食物产品选自由酸奶、果冻、布丁、口香糖、喉糖锭、糖果、巧克力、饼干、甜点、干酪、果汁和茶组成的组。
8、根据权利要求6的产品,其中所述食物产品是一种含有牛奶的产品。
9、根据权利要求8的产品,其中所述食物产品是酸奶。
10、根据权利要求4的产品,其中所述产品是一种牙齿处理产品。
11、根据权利要求10的产品,其中所述产品是一种漱口药。
12、一种用于生产抗成龋因子产品的方法,包括在所述产品中加入至少一种选择出来的具有抗成龋因子细菌的抑制活性以及与口腔粘液的良好结合的路氏乳杆菌菌株的细胞。
13、根据权利要求12的方法,其中至少一种菌株选自由路氏乳杆菌菌株FJ1″Prodentis″(ATCC PTA-5289)和路氏乳杆菌菌株FJ3(ATCC PTA-5290)组成的组。
14、根据权利要求12的方法,其中所述产品是一种食物产品。
15、根据权利要求14的方法,其中所述食物产品选自由酸奶、果冻、布丁、口香糖、喉糖锭、糖果、巧克力、饼干、甜点、干酪、果汁和茶组成的组。
16、根据权利要求14的方法,其中所述食物产品是一种含有牛奶的产品。
17、根据权利要求16的方法,其中所述食物产品是酸奶。
18、根据权利要求12的方法,其中所述产品是一种牙齿处理产品。
19、根据权利要求18的方法,其中所述产品是一种漱口药。
20、根据权利要求12的方法,其中所述乳酸杆菌细胞被包裹在所述产品中。
21、根据权利要求20的方法,其中所述乳酸杆菌细胞被包裹在所述产品中的氢化棕榈油中。
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US10/869,185 | 2004-06-14 | ||
US10/869,185 US7517681B2 (en) | 2003-01-29 | 2004-06-14 | Selection and use of lactic acid bacteria for reducing dental caries and bacteria causing dental caries |
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CN1981028A true CN1981028A (zh) | 2007-06-13 |
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US (1) | US7517681B2 (zh) |
EP (1) | EP1765975A1 (zh) |
JP (2) | JP5566007B2 (zh) |
KR (2) | KR101143734B1 (zh) |
CN (1) | CN1981028A (zh) |
AU (1) | AU2005252605B2 (zh) |
BR (1) | BRPI0511372B1 (zh) |
CA (1) | CA2569141C (zh) |
IN (2) | IN244537B (zh) |
MX (1) | MX287430B (zh) |
NZ (1) | NZ552585A (zh) |
SG (1) | SG128035A1 (zh) |
WO (1) | WO2005121312A1 (zh) |
ZA (1) | ZA200700210B (zh) |
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WO2010044736A1 (en) * | 2008-10-14 | 2010-04-22 | Mcneil Ab | Multi portion intra-oral dosage form and use thereof |
US20120128645A1 (en) | 2009-07-16 | 2012-05-24 | Hiroshima University | Prophylactic, ameliorating or therapeutic agent for oral diseases |
US20110293710A1 (en) * | 2010-02-02 | 2011-12-01 | Delphine Saulnier | Immunomodulatory properties of lactobacillus strains |
IT1398648B1 (it) * | 2010-03-09 | 2013-03-08 | Probiotical Spa | Prodotto alimentare comprendente batteri probiotici rivestiti con un rivestimento di origine vegetale. |
JP2012092094A (ja) * | 2010-09-30 | 2012-05-17 | Wakamoto Pharmaceutical Co Ltd | 油脂中に乳酸菌を含有する口腔用組成物 |
GB201206599D0 (en) | 2012-04-13 | 2012-05-30 | Univ Manchester | Probiotic bacteria |
WO2014171478A1 (ja) | 2013-04-17 | 2014-10-23 | サントリーホールディングス株式会社 | ラクトバチルス属菌含有組成物 |
CA2908031A1 (en) * | 2013-04-17 | 2014-10-23 | Suntory Holdings Limited | Bacterium belonging to genus lactobacillus |
KR102095339B1 (ko) * | 2017-06-01 | 2020-05-27 | 한국생명공학연구원 | 신규한 락토바실러스 류테리 균주 및 이를 유효성분으로 포함하는 치주질환 예방 또는 치료용 조성물 |
KR101966772B1 (ko) * | 2017-07-11 | 2019-04-09 | 주식회사 다케어 | 락토바실러스 루테리 cs 132(kctc 11452bp) 또는 이의 배양물을 포함하는 구강병원균 억제조성물 |
KR102001074B1 (ko) * | 2018-12-07 | 2019-07-18 | 주식회사 메디오젠 | 충치 억제 활성을 갖는 유산균 조성물 |
KR102230517B1 (ko) * | 2019-07-09 | 2021-03-22 | 주식회사 메디오젠 | 충치 억제 활성을 갖는 락토바실러스 살리바리우스를 포함하는 조성물 |
KR102210092B1 (ko) * | 2019-07-09 | 2021-02-01 | 주식회사 메디오젠 | 충치 억제 활성을 갖는 락토바실러스 루테리 mg505 를 포함하는 조성물 |
IT202100000176A1 (it) * | 2021-01-07 | 2022-07-07 | Metis Healthcare S R L | Preparazioni orali a base di carnosina ad attività antivirale |
CN113652340A (zh) * | 2021-08-24 | 2021-11-16 | 江苏江大源生态生物科技股份有限公司 | 一种益生菌制剂、菌种筛选装置及筛选方法 |
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KR102637772B1 (ko) | 2023-09-21 | 2024-02-20 | 주식회사 큐옴바이오 | 위건강과 구강질환 관련 미생물 및 병원성 미생물에 대한 항균활성을 갖는 산삼 유래 락토바실러스 플란타럼 wg.q7 균주 및 이의 용도 |
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- 2005-05-30 EP EP05747457A patent/EP1765975A1/en not_active Ceased
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- 2005-05-30 KR KR1020117017996A patent/KR101261172B1/ko active IP Right Grant
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- 2005-05-30 AU AU2005252605A patent/AU2005252605B2/en not_active Ceased
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103478390A (zh) * | 2013-08-13 | 2014-01-01 | 华侨大学 | 一种预防和辅助治疗牙周炎的口香糖的制备方法 |
CN103478390B (zh) * | 2013-08-13 | 2015-04-15 | 华侨大学 | 一种预防和辅助治疗牙周炎的口香糖的制备方法 |
Also Published As
Publication number | Publication date |
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KR20070030819A (ko) | 2007-03-16 |
JP2012130358A (ja) | 2012-07-12 |
MX287430B (es) | 2011-06-13 |
CA2569141A1 (en) | 2005-12-22 |
IN244537B (zh) | 2010-12-17 |
AU2005252605A1 (en) | 2005-12-22 |
BRPI0511372B1 (pt) | 2020-09-15 |
EP1765975A1 (en) | 2007-03-28 |
JP2008502360A (ja) | 2008-01-31 |
KR101261172B1 (ko) | 2013-05-09 |
AU2005252605B2 (en) | 2010-08-12 |
CA2569141C (en) | 2012-05-29 |
US20050002874A1 (en) | 2005-01-06 |
KR101143734B1 (ko) | 2012-05-10 |
SG128035A1 (en) | 2007-01-30 |
US7517681B2 (en) | 2009-04-14 |
BRPI0511372A (pt) | 2007-12-04 |
KR20110093951A (ko) | 2011-08-18 |
NZ552585A (en) | 2009-08-28 |
MXPA06014516A (es) | 2007-03-12 |
WO2005121312A1 (en) | 2005-12-22 |
JP5566007B2 (ja) | 2014-08-06 |
ZA200700210B (en) | 2008-05-28 |
IN2006DE07653A (en) | 2007-08-17 |
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