CN116831970A - 一种含有益生菌以及抗菌肽的口腔组合物 - Google Patents
一种含有益生菌以及抗菌肽的口腔组合物 Download PDFInfo
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- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/99—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from microorganisms other than algae or fungi, e.g. protozoa or bacteria
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及一种含有益生菌以及抗菌肽的口腔组合物,本发明开发的发酵乳杆菌CCTCCNo:M2016424和鼠李糖乳杆菌(GG)ATCC53103组成的益生菌本身也具有较好的抑制病原菌的效果,将益生菌与抗菌肽一起使用后特别是制备成为口腔护理产品后,能够有效的治理口腔病原菌,具有较好的应用前景。
Description
技术领域
本申请涉及生物领域,更具体的涉及口腔护理领域,具体的涉及一种含有益生菌以及抗菌肽的组合物。
背景技术
口腔是消化道的人口,具有特殊的微生态环境。口腔内定植的细菌达700多种,可致多种感染性疾病的发生。近年来,学者们陆续发现多种益生菌能制约口腔致病菌的生长,通过抑制致病菌粘附定植、释放抗菌物质、调节黏膜免疫等机制在龋病、口腔念珠菌病、牙周病、口臭等口腔疾病的防治中发挥作用,并有可能用于口腔肿瘤的治疗。
自21世纪以来益生菌在人类健康中扮演的角色吸引着研究者对其探索。研究者可以利用益生菌促进免疫功能,预防胃肠道疾病,并应用于心血管疾病、泌尿生殖道感染的治疗及癌症的控制。而在口腔微生态领域的研究仍处于早期探索阶段。近年来,益生菌通过对口腔微生物群落生态平衡的调控,引导了预防或治疗龋病的新方向。益生菌是指能改善宿主微生态平衡从而发挥有益作用,达到提高宿主健康水平的活菌制剂及其代谢产物。较多文献指出在口腔疾病如龋齿、牙龈炎和口臭的控制方面,益生菌的使用都具有较好的预防效果。口腔内天然存在着多种有益生作用的常驻菌,其中唾液链球菌K12、唾液链球菌M18已被开发为口腔益生菌产品。唾液乳杆菌W24等也被发现有益生作用。唾液链球菌KI2是从健康儿童口咽部分离出的一株有益生作用的链球菌,多项体外及临床试验表明其在防治咽炎、口臭、口腔念珠菌病等口腔疾病中发挥着重要作用,目前已有市售的唾液链球菌K12益生菌产品在多个国家上市。研究发现唾液链球菌K12与白色念珠菌共培养后能有效抑制白色念珠菌。口臭患者在使用洗必泰漱口液后再服用益生菌唾液链球K12,1周后85的患者口腔内挥发性硫化氢的产量显著降低。病口腔念珠菌病是最常见的口腔黏膜感染性疾病。临床研究表明益生菌能减少口腔念珠菌的数量。研究发现一组老年人在食用了含有鼠李糖乳杆菌LC705株以及丙酸菌的奶酪16周后,口腔中的念珠菌计数明显下降。由此可见,益生菌对于口腔的益处还是显而易见的。
抗菌肽是一类具有微生物活性的免疫调节活性的小分子多肽,又称抗微生物免疫多肽。具有抗菌作用的短肽(100个以下的氨基酸组成)。是先天性免疫系统的重要组成部分,具有作用迅速,不易产生耐药性的优点,并对多数传统抗菌剂耐药的微生物有抗菌活性。而常规的抗菌肽有广谱杀菌的缺点,因此,这是一种能够保证正常菌群生态平衡同时可以选择性地杀灭正常菌群中的致病菌的抗菌肽出现,即特异性靶向抗菌肽。龋病预防的最根本原则为维持口腔微生物生态平衡,而变异链球菌在龋病的发生中扮演者重要角色。特异性靶向抗菌肽的出现不仅保证了生态平衡,同时能够靶向的杀灭病原菌。新型耐盐靶向抗菌肽对致龋变异链球菌的作用发现暴露在融合抗菌肽IMB-2中,95%的变形链球菌在15min时几乎失去活性,只有20%的血链球菌和戈登链球菌随着暴露而被杀死。而IMB-2在生理或高渗盐浓度时,仍会保持其活性,并发现该融合肽与预防剂量的NaF协同作用时可有效杀灭致病变异链球菌。另有研究发现抗菌肽C16G2可减少唾液链球菌产酸,预防及牙釉质脱矿。特异性靶向抗菌肽在龋病的预防领域具有的潜在应用前景,或许可以成为同微生态制剂一样有效的防龋制剂。
目前牙膏中应用的抗菌物质可分为化学合成抗菌物质和天然抗菌物质。其中添加天然抗菌物质的牙膏以其安全、环保等优势博得了广大消费者的青睐。某些天然抗菌物质含量达到一定量时对口腔中常见致病菌的抑菌效果是可以与化学合成抗菌物质相媲美的。如:添加0.3%和0.5%超临界CO2萃取蜂胶的牙膏与含有相同浓度玉洁纯的牙膏相比,二者对变形链球菌、中间普氏菌、牙龈卟啉单胞菌、具核梭杆菌这4种常见口腔致病菌的抑菌效果相当。由于抗菌肽具有较好的抗菌特异性,特别是抑制病原菌方面具有天然抗菌物质不可比拟的技术优势,在牙膏中的应用也是越来越普及。因此,开发较好的抗菌肽特性的牙膏特别是再辅以益生菌特性能够在杀灭有害菌的同时,促进口腔的恢复。
发明内容
发明人通过自建的肽库通过筛选,获得了特异性抑制口腔细菌的抗菌肽K-25和K-38。所述抗菌肽具有较强的抗菌特性,适宜于口腔护理产品的制备及应用。
进一步的,本发明的抗菌肽K-25其序列如SEQ ID NO:1所示。
进一步的,本发明提供了抗菌肽K-25在制备抑制口腔病原菌的口腔护理产品中的用途。
本发明的K-25和K-38多肽分别通过小鼠口服大剂量实验证明在连续给药10周后,小鼠并没有表现毒性,内脏器官通过检测也与正常小鼠相比无显著差异,表明本发明的多肽具有较好的安全性。
进一步的,本发明还提供了一组具有抑制口腔病菌的益生菌,所述益生菌是由发酵乳杆菌CCTCCNo:M2016424和鼠李糖乳杆菌(GG)ATCC53103组成。
进一步的,本发明还提供了益生菌联合抗菌肽在制备抑制口腔病原菌的护理产品中的用途。
具体的,用作口腔清洁用品和口腔治疗药品的添加剂。
具体的,本发明可以用于制备漱口水、牙膏、抑制病菌的药物。
具体的,本发明提供的一种具有抗菌作用的牙膏,具体的组成为黄原胶0.5%,CMC0.5%,山梨醇30%,甘油5%,香精1%,聚乙二醇1%,二氧化硅2%,磷酸氢钙40%,苯甲酸钠0.1%,焦磷酸钠0.2%,微生素K121%,发酵乳杆菌CCTCCNo:M2016424和鼠李糖乳杆菌ATCC53103等比例冻干粉
1%,多肽0.5%,水余量。
优选地,所述益生菌还可以被制备成为微胶囊的形式。
进一步的,所述微胶囊是以紫胶树脂钠盐-羧甲基壳聚糖复合物为璧材,益生菌为芯材制备得到的;所述微胶囊的璧-芯比为2~5g:1g。采用本领域常规的微胶囊制备方法即可制备获得。
进一步的额,本发明还提供了本发明的抗菌肽在制备抑制病原菌的药物中的用途。
有益效果
本发明的有益效果是:针对口腔病原菌筛选、鉴定获得了特异性的抗菌肽,所述抗菌肽具有较好的抑制口腔病原菌特别是菌膜形成的效果。同时,本发明开发的发酵乳杆菌CCTCCNo:M2016424和鼠李糖乳杆菌(GG)ATCC53103组成的益生菌本身也具有较好的抑制病原菌的效果,将益生菌与抗菌肽一起使用后特别是制备成为口腔护理产品后,能够有效的治理口腔病原菌,具有较好的应用前景。
附图说明
图1多肽对生物膜中细菌总面积的变化的影响
具体实施方式
以下结合具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
实施例1多肽抗菌肽活性鉴定
将肽库中通过初筛具有一定抑制活性的多肽委托合肥森尔生物进行合成,具体合成的10条多肽分别是K-5、K-7、K-13、K-17、K-25、K-26、K-30、K-35、K-38、K-52。阳性对照肽为RLLRKFFRKLKKSV。
筛选用菌株:金黄色葡萄球菌ATCC25923、大肠杆菌ATCC25922、变异链球菌UA140。
取保存的金黄色葡萄球菌和大肠杆菌传代于营养琼脂斜面上,37℃培养18h后,转接至营养肉汤培养基置于37℃培养箱培养8h,用MH肉汤培养基倍比稀释成1×105CFU/ml的菌悬液备用。取保存的变异链球菌,传代于脑心浸液琼脂培养基上,37℃,厌氧培养16h后,转接至脑心浸液肉汤培养基置于37℃培养箱培养8h,用脑心浸液肉汤培养基倍比稀释成1×105CFU/ml的菌悬液备用的菌悬液备用。采用微量培养基稀释法测定多肽,准确配制浓度为1024μg/ml的多肽,无菌条件下,0.22μm滤器过滤,用无菌MH肉汤培养基或脑心浸液肉汤培养基将各药品倍比稀释为512,128,64,32,16,8,4,2,1μg/ml的溶液,取不同浓度的药液75μl至96孔板,同时设置75μl培养基加75μl的1×105CFU/ml菌液作阳性对照组,150μl的培养基作为不含药液和菌液的空白对照,将含金黄色葡萄球菌及大肠杆菌的96孔板置37℃培养箱培养18h,含变异链球菌的37℃培养箱厌氧培养18h,酶标仪测定OD600,药物能够抑制细菌生长的最低浓度,即为最小抑菌浓度(MIC)。结果如下表1所示。
表1各组多肽的最小抑菌浓度结果
从表1的结果可以看出,初筛获得的10个抗菌肽针对金黄色葡萄球菌ATCC25923、大肠杆菌ATCC25922、变异链球菌UA140均具有一定的抑菌活性,其中K-25和K-38是活性最好的二个抗菌肽,其作用比对照肽的抑制效果还要好。
实施例2 K-25抗菌肽活性再验证
菌株表兄链球菌6715、嗜酸乳杆菌ATCC 4356、血链球菌ATCC 10556、格氏链球菌ATCC 10558、黏性放线菌ATCC 19246、内氏放线菌ATCC 12140、牙龈卟啉单胞菌381、中间普雷沃菌ATCC 25611、具核梭杆菌10953、伴放线放线杆菌29523、白色假丝酵母菌ATCC 10691均由四川大学口腔疾病研究国家重点实验室提供。
变异链球菌、表兄链球菌、格氏链球菌、血链球菌、黏性放线菌、内氏放线菌采用TPY培养基培养;嗜酸乳杆菌采用Rogosa培养基培养;牙龈卟啉单胞菌、中间普雷沃菌、具核梭杆菌、伴放线放线杆菌采用BHI培养基培养;白色假丝酵母菌采用BA培养基培养。实验菌种冻干株接种于相应固体培养基上复苏,于80%N2、10%H2、10%CO2,37℃下厌氧培养36h,白色假丝酵母菌于恒温培养箱37℃需氧培养24h。检查菌落的生长形态,镜检无污染,涂片检查证实为纯培养后,挑取单个菌落于液体培养基中在相同的培养条件下培养增菌,CrystalSpecTM比浊仪测定菌悬液浓度,磷酸缓冲液(PBS)配制浓度为1×108CFU/mL和2×106CFU/mL的细菌菌悬液备用。
采用微量培养基稀释法测定K-25多肽,准确配制浓度为1024μg/ml的多肽,无菌条件下,0.22μm滤器过滤,用无菌MH肉汤培养基或脑心浸液肉汤培养基将各药品倍比稀释为512,128,64,32,16,8,4,2,1μg/ml的溶液,取不同浓度的药液75μl至96孔板,同时设置75μl培养基加75μl的1×105CFU/ml菌液作阳性对照组,150μl的培养基作为不含药液和菌液的空白对照,将含各种菌的96孔板置37℃培养箱培养,酶标仪测定OD600,药物能够抑制细菌生长的最低浓度,即为最小抑菌浓度(MIC)。结果如下表2所示。
表2 K-25多肽对各菌的最小抑菌浓度结果
菌株名称 | MIC(μg/ml) |
嗜酸乳杆菌 | 32 |
血链球菌 | 8 |
格氏链球菌 | 8 |
内氏放线菌 | 128 |
黏性放线菌 | 64 |
牙龈卟啉单胞菌 | 4 |
中间普雷沃菌 | 64 |
具核梭杆菌 | 32 |
伴放线放线杆菌 | 128 |
白色假丝酵母菌 | 64 |
从表2的结果可以看出,K-25肽对大部分兼性厌氧菌均具有较好的抑制活性,对专性厌氧菌以及白色假丝酵母菌的MIC值也较好。其中,多肽对牙龈卟啉单胞菌和格氏链球菌以及血链球菌的抑菌效果最为显著。
实施例3 K-25抗菌肽对生物膜形成的影响
生物膜标本的制备:在直径6cm的玻璃培养皿中放入18mm×18mm规格的无菌盖玻片,在0h,同时加入变异链球菌UA140菌悬液1mL、K-25抗菌肽(浓度分别是0、10、100、200μg/ml)和含有0.25%蔗糖的TSB培养基3mL。N295%,CO25%,37℃厌氧培养24h,取出玻璃片,PBS冲洗2次,去除表面浮游细菌,立即于室温下暗箱中染色。荧光染料的配制及染色:用荧光染料CFSE、PI分别标记活菌和死菌。染色结束后用PBS洗涤,除去残留染料。将上述已完成荧光染色的生物膜标本放置在激光共聚焦显微镜(CLSM)下观察。物镜×20,目镜×10,观察生物膜结构的激发光为510/480。以样本最强信号点为焦平面,以该平面为参照点,2μm为步距进行断层扫描(沿Z轴进行),最后进行三维重建,得到生物膜立体结构。通过专业软件处理记录生物膜中细菌总面积和生物膜活性。其中生物膜中细菌总面积的变化用减少率来表示,即(实验组-对照组)/对照组。结果如图1所示。
由表1可知,与对照组不做任何处理的生长时间为24h的变异链球菌生物膜相比,随着多肽浓度的增加,使得生物膜中细菌总面积减少率逐渐降低,在浓度为200μg/ml时,减少率高达88.93±1.42%,比阳性对照肽的效果也好(*表示与不加抗菌肽相比,差异显著,P<0.01),即本发明的K-25多肽可以强烈抑制变异链球菌生物膜的形成。
实施例4益生菌的制备及功效验证
将来自于中国典型培养物保藏中心的发酵乳杆菌CCTCCNo:M2016424先活化,随后接种到添加10%蔗糖的MRS液体培养基中,30℃培养48h。将发酵液4℃,4000rpm离心20min收集菌体。
ATCC53103鼠李糖乳杆菌(GG)先活化,随后接种到添加碳酸钙的MRS液体培养基中培养,具体组成为葡萄糖20.0g;蛋白胨10.0g;牛肉浸粉10.0g;酵母浸粉5.0g;柠檬酸氢二铵2.0g;乙酸钠5.0g;磷酸氢二钾2.0g;硫酸镁0.58g;硫酸锰0.25g;吐温80 1.0mL;蒸馏水1000mL;调节pH6.2-6.4;再添加碳酸钙5.0g,115℃灭菌20min。将该菌株接种到培养基中37℃培养48h,将发酵液4℃,4000rpm离心20min收集菌体。
将二个菌体调整到相同浓度后,按照1:1的比例进行混合均匀后冻干保存,备用。
口含片1的制备:由20%鼠李糖乳杆菌和发酵乳杆菌冻干菌粉、5%山梨糖醇、2%硬脂酸镁、余量是全脂奶粉制成口含片。
口含片2的制备:由20%鼠李糖乳杆菌冻干菌粉、5%山梨糖醇、2%硬脂酸镁、余量是全脂奶粉制成口含片。
口含片3的制备:由20%发酵乳杆菌冻干菌粉、5%山梨糖醇、2%硬脂酸镁、余量是全脂奶粉制成口含片。
对照组口含片不添加冻干菌粉用等量全脂奶粉代替。
按照本领域常规的检测方法,将每组受试者20人在餐后1h后,口含本发明的口含片10min。
受试者的口腔样品采集方法为,在试吃开始前用牙线采集受试者牙菌斑样本,作为上述实验的前值,试吃2周后,同样用牙线收集相同位置的牙菌斑样本,并通过荧光定量PCR进行口腔内变异链球菌和牙龈卟啉单胞菌定量分析评价上述实验效果。受试者服用口含片后口腔中变异链球菌和牙龈卟啉单胞菌数量较试吃前显著性下降50%即判定为有效,受试者在服用口含片后口腔中变异链球菌和牙龈卟啉单胞菌数量维持不变或致病菌数量增加则判定为无效。每组有效率%=该组有效受试者人数/该组总人数×100%。
表3益生菌功效验证结果
实验分组 | 有效率(%) |
口含片1 | 85.0% |
口含片2 | 60.0% |
口含片3 | 50.0% |
对照组 | 0 |
由表3结果可见,本发明的鼠李糖乳杆菌和发酵乳杆菌二者组合使用,其能够有效的抑制口腔内变异链球菌和牙龈卟啉单胞菌的数量,具有很好的推广应用价值。
实施例5益生菌和K-25多肽的功效验证
口腔细菌的防治,采用牙膏的形式较为常见。本发明采用如下的方法制备得到了益生菌联合抗菌肽的牙膏,其配比如下表4所示。
表4牙膏的配方比例
此外,设置不含K25多肽、其他成分与表4相同的对照1,设置不含冻干粉、其他成分与表4相同的对照2。
牙膏的制作:将甜味剂,稳定剂等添加剂预先溶解在适量水中。将粘合剂在高速搅拌下分散在保湿剂中,时间为6分钟。将去离子水加入到制膏机中,加入预先混合的添加剂,粘合剂溶液,高速搅拌10分钟。加入磨擦剂、发泡剂、和/或益生菌和/或多肽,在真空状态下高速搅拌2分钟。加入香精,在真空状态下高速搅拌20分钟,出料时真空度要求达0.095MPA以上。膏体用复合软管包装。
每组受试者20人,分别使用等量的牙膏进行刷牙,每次刷牙时间4min,每天早晚各1次,实验共10d。
以京东购买的“佳洁士草本牙膏家庭装防蛀护龈清洁口腔啫喱清爽薄荷型男女士通用”牙膏为阳性对照。
受试者的口腔样品采集方法为,在第一次刷牙前前用牙线采集受试者牙菌斑样本,作为上述实验的前值,刷牙10d后,同样用牙线收集相同位置的牙菌斑样本,并通过荧光定量PCR进行口腔内变异链球菌和牙龈卟啉单胞菌定量分析评价上述实验效果。受试者10d后口腔中变异链球菌和牙龈卟啉单胞菌数量较实验前前显著性下降50%即判定为有效,受试者在刷牙10d后口腔中变异链球菌和牙龈卟啉单胞菌数量维持不变或致病菌数量增加则判定为无效。每组有效率%=该组有效受试者人数/该组总人数×100%。
表5益生菌联合抗菌肽的牙膏效验证结果
实验分组 | 有效率(%) |
益生菌联合抗菌肽的牙膏 | 100% |
对照1 | 70.0% |
对照2 | 80.0% |
阳性对照组 | 60.0% |
由表5结果可见,本发明的鼠李糖乳杆菌和发酵乳杆菌冻干粉与抗菌肽一起使用后制备的牙膏能够在10d的时间内即可有效的抑制口腔内变异链球菌和牙龈卟啉单胞菌的数量,与阳性对照组相比,效果显著。
本领域技术人员不脱离本发明的实质和精神,可以有多种变形方案实现本发明,以上所述仅为本发明较佳可行的实施例而已,并非因此局限本发明的权利范围,凡运用本发明说明书所作的等效结构变化,均包含于本发明的权利范围之内。
Claims (6)
1.一种抗菌肽K-25,其特征在于氨基酸序列如SEQ ID NO:1所示。
2.权利要求1所述的抗菌肽K-25在制备抑制口腔病原菌的口腔护理产品中的用途。
3.权利要求1所述的抗菌肽K-25在制备抑制口腔病原菌的药物中的用途。
4.权利要求1所述的抗菌肽K-25联合益生菌在制备抑制口腔病原菌的口腔护理产品中的用途;所述益生菌是由发酵乳杆菌CCTCCNo:M2016424和鼠李糖乳杆菌(GG)ATCC53103按照1:1的比例混合组成。
5.如权利要求2或4所述的用途,其特征在于所述的口腔护理产品是牙膏。
6.如权利要求3所述的用途,其特征在于所述药物中还含有药学上可接受的载体。
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